| 
Past Issues
Volume 14, number 11/12
November/December 2000
Contents
No Gay Blood, Please!
Discrimination and 'the greater good' collide over blood-giving
Is A Vaccine Possible?
New discoveries rekindle hopes of researchers and patients
A PI Bonus
Protease inhibitors may have unexpected benefits
Should Gay Men Be Allowed
to Donate Blood?
By Derek Link
When the Red Cross arrived at the Library of Congress in 1998 for
its annual blood donation drive, gay library employee Charles McMoore
registered, then rolled up his sleeve to perform what he felt was
a civic duty. As he sat before the nurse who was to take his blood,
he was asked several dozen routine questions about his medical and
personal history.
Among the intimate questions asked of Mr. McMoore by the Red Cross,
and posed to all prospective donors by all blood banks in the land,
were these: Had he been diagnosed or treated for a sexually transmitted
disease in the last year? Had he had an organ transplant in the
last five years? Had he visited a prostitute in the last year? And
then the one question that struck him like a brick: Had he ever
had sex with another man, even once, since 1977?
As an openly gay man in a committed relationship, Mr. McMoore answered
yes. As a result, he was denied permission to donate blood. Since
Mr. McMoore is not infected with HIV, and had no other reason for
being denied permission to donate, he filed a sexual orientation
discrimination complaint against the Red Cross with the District
of Columbia Human Rights Commission. The complaint against the Red
Cross by Mr. McMoore was eventually settled privately. Although
his pursuit of legal redress is unusual, his experience is familiar
to any gay man who has tried to participate in a volunteer blood
drive.
Gay men, in all practical senses, are prohibited from donating
blood in the United States because of a U.S. Food and Drug Administration
(FDA) policy first formulated in the mid-1980s, when the HIV epidemic
was new, the nation gripped in panic, and HIV testing still in development.
In recent years, this policy has come into sharper focus because
individual gay men, but not, notably, major gay or HIV organizations,
have raised objections to local blood drives as discriminatory.
The debate has become so heated at many universities that several
now prohibit the Red Cross or other blood banks from organizing
blood drives on their campuses.
Is the policy a discriminatory relic of an earlier era? Is the
policy based on the nasty ideas that gay blood is "dirty" or that
all gay men have HIV? Since the nation faces a severe shortage of
blood, why are otherwise healthy gay men prohibited from blood donation?
What is the basis of this policy, and what, if anything, is the
FDA willing to do about it?
The answers to these questions require taking a look back at the
early years of the epidemic, understanding current patterns of HIV
transmission, estimating the numbers of gay men in the United States,
and examining how the nation's blood supply is collected and regulated.
The Blood Safety System
Shortly after an epidemic was first recognized in gay men in 1981,
persons with hemophilia and others who received blood transfusions
also began developing the strange new illness that would become
known as AIDS. At that time, no one knew what caused the new disease,
and agreement about how it spread was still several years away.
It soon became apparent, however, that the mystery illness was transmissible
through blood products and transfusions, and blood safety officials
had no way to identify who might be capable of spreading it.
In this information vacuum, blood safety officials at the FDA
decided to exclude from blood donation those emerging as the first
"risk groups" for the new illness: gay men and Haitians foremost
among them. Because of a high rate of Hepatitis B virus (HBV) infection
among gay men, blood safety officials started screening donated
blood for antibodies to HBV, using it as a surrogate to identify
individuals who might have the new illness. After HIV was identified
as the cause of AIDS in 1983 and an HIV test developed over the
next year, blood safety officials at the FDA finally mandated HIV
screening for the blood supply in 1985.
During this early period, the nation's blood supply's safety systems
were revealed to be inadequate and overly influenced by the commercial
interests of major blood products companies. Tens of thousands of
blood transfusion recipients and persons with hemophilia became
infected with HIV during this period, many unnecessarily so —
because of corporate and institutional inertia, indecision, and
perhaps darker reasons. Several years, many lawsuits, research studies
and millions of dollars later, the FDA eventually developed a redundant
safety process to protect the integrity of the blood supply.
Today, blood safety is assured by a three-stage safety system.
The system has redundancy built in because the FDA assumes that
mistakes may be, and indeed are, made at any step of the process.
The first step is "donor deferral" — that is, a policy of restricting
those who are most likely to introduce HIV or other infectious agents
into the blood supply. Donor deferral is meant to minimize the chance
that an HIV-infected unit of blood is ever drawn in the first place.
The policy is most evident in the intimate questions asked of all
who donate blood. It is the most visible step in the blood safety
process, and the point when gay men confront the fact that their
blood is unwanted.
Donor deferral is a complex process. Each question asked can lead
to different restrictions. A person who recently received a tattoo
cannot donate blood for twelve months after being inked, nor can
a person who's visited a prostitute. Pregnant women cannot donate
until six weeks after delivery. A person who has had tuberculosis
must wait two years after successful curative therapy to give blood.
The list of restrictions is long and complex and not all seem obviously
justified. (See box: The Top 52 Reasons for Not Being Able to Donate
Blood.)
What rankles gay men the most is that any homosexual activity since
1977 results in, what is essentially, a lifetime ban on blood donation.
Homosexuality is placed in the same class as prostitution and intravenous
drug use, practices that also result in a permanent ban on giving.
For a well-adjusted, HIV-negative, upper middle-class, homosexual
college student, this seems like a smear and smells discriminatory.
The only other permanent restrictions are for people with medical
conditions like cancer and heart disease. The contradiction for
gay men becomes apparent when one considers that a heterosexual
man can have unprotected anal sex with female prostitutes for years,
stop, and then donate blood twelve months later, while a gay man
in a monogamous relationship who practices safe sex is forever barred
from donation.
Obviously many men lie when questioned on these touchy topics.
The questionnaire is carefully worded, of course. It does not inquire
if a man identifies himself as gay, but rather asks the more general
question if he "has had sex with another man." Who is more likely
to answer this honestly — an openly gay man, a closeted but
married man, or a bonafide heterosexual who had sex a few times
in 1983 with his college roommate? Blood safety officials assume
some fraction of prospective donors will fib on this question, which
leads to the next stage of the process.
The second stage of the blood safety system involves testing all
donated blood for infectious agents, including hepatitis viruses,
HIV, HTLV (a cancer-causing virus), and syphilis. Many people erroneously
believe this is the full extent of the blood safety process. The
tests for HIV and other infectious agents are very good, and every
day, units of infected blood are identified and discarded at this
stage. However, testing all blood for HIV is not, by itself, an
adequate safety measure.
Most may be familiar with the concept of a "window period" with
new HIV infections — that is, a time of weeks to months when
a recent HIV infection may not be detected by standard HIV tests.
Because the tests spot antibodies to the virus, and antibodies take
time to develop in a newly infected person, there is a period when
one can test "HIV negative" yet still transmit the virus to others.
This "infectious window" remains open due to the current limitations
of testing technology. When HIV testing first became available,
the tests were not very refined — they often left open as much
as a six-month window for HIV to slip through. Improvements in testing
technology have narrowed the window period to no more than a few
weeks. But the testing technologies in place cannot close the window
entirely because of the way HIV establishes an infection in a new
host.
We have to assume that some people who have recently been infected
with HIV donate blood and that a few of these infected units get
into the blood supply despite HIV testing. The present risk of acquiring
HIV from an infected blood transfusion is about one in every million
units of blood, with almost every infected unit having slipped through
during the window period.
To help close the window, the U.S. government has invested in a
variety of technologies to detect fragments of HIV itself, rather
than the delayed antibody response. p24 testing is used by blood
banks to detect HIV antigens that appear in blood before antibodies
develop. The FDA estimates that HIV p24 antigen testing can detect
HIV-infected blood donations, on average, five days before antibodies
are detectable by standard screening tests.
To improve this performance further, the FDA and others have invested
in a new HIV testing technology called Nucleic Acid Testing (NAT).
NAT testing is in advanced stages of evaluation for use in blood
screening. It has the potential to shave a few extra days off the
window period, and could, in practical effect, close the window
almost completely. However, the FDA has not yet licensed this test
for blood screening purposes, and more research remains ahead.
"HIV RNA viral load" testing — familiar to anyone who is HIV
infected and receiving health care in the United States — is
a technology that not only quantifies the amount of HIV in a person's
blood but also has the potential to detect HIV infection sooner
than any other technology available. "It wins hands down," said
FDA blood expert Michael Busch at a recent public hearing. But cost
and technological complexity have raised objections from the blood
industry and others. In any event, the window remains slightly open,
and although a technological fix is possible, it is expensive and
not quite ready for general use.
The third stage of blood safety in the United States is the regulation
and quality control of the blood banks themselves. The collection,
processing, and distribution of blood is a big business in the United
States. The FDA ensures that blood banks operate according to good
manufacturing practices. These include having automated systems
and making sure HIV-infected units of blood are properly labeled
and separated from the usable blood when they are identified. This
is perhaps the messiest part of the blood safety system.
Recently the FDA filed a lawsuit against the American Red Cross,
which collects about half the blood in the United States. The FDA
filings maintained the Red Cross has "a long-standing and ongoing
failure to comply with good manufacturing practice standards in
collecting, processing and distributing blood used in medical procedures."
The Red Cross "has not been in compliance since at least 1985,"
the FDA maintains, and increasingly tough action by the government
has failed to correct these problems. Over the past decade, the
FDA has taken similar steps against other blood banks, including
the New York Blood Center, the major source of blood for the New
York region.
In summary, the blood safety system in the United States has three
parts:
- Keeping potentially HIV-infected people out of the donor pool
so the fewest number of possibly infected units of blood move
on to the next stage of the process. Restricting gay men from
donating blood is a direct consequence of this part of the blood
safety system.
- Testing all blood donations for a range of infectious diseases,
including HIV, so that if an infected person does donate, the
blood is identified. This involves using standard HIV antibody
screening tests, p24 tests, and researching new technologies to
close the small "window period" that remains.
- Regulating and inspecting the blood banks themselves to ensure
they implement procedures correctly and have safety measures in
place to identify HIV-infected units of blood and ensure that
none enter the blood supply. Yet, despite this three-step process,
every year about ten people in the United States acquire HIV due
to a contaminated unit of blood that slipped through the window
period undetected.
What to Do about Gay Men
Knowing how the blood supply is protected, the problem with allowing
gay men to donate blood can be considered in a simple arithmetical
way: Gay men continue to be at very high risk for HIV and there
are relatively few gay men. Depending on which study you believe,
gay men comprise certainly no more than 10 percent of the population
and probably less than 5 percent.
Of course safe sex works, and many gay men are in monogamous relationships.
But HIV prevention is not perfect. Gay men continue to become infected
with HIV in substantial numbers, despite the best prevention efforts.
Researchers put the annual infection rate for urban gay men in their
teens or twenties as 1 to 3 percent annually. This number sounds
small, but it is cumulative. In some major cities, like New York,
around 15 to 20 percent of gay men are now infected with HIV —
and the prevalence is higher in some regions and ethnic groups.
Furthermore, gay men in monogamous relationships still become infected.
People cheat on their lovers, whether gay or straight, but the risks
of such cheating, especially if unsafe sex is involved, are increased
for gay men because of the high prevalence of HIV in the pool of
potential sex partners.
The official thinking for why gay men should not be allowed to
donate, therefore, goes something like this: If the blood donor
pool is opened to healthy gay men, not many more potential donors
are included given the small numbers of gay men overall. Assume
5 percent of the 130 million American males are gay, which gives
a rough estimate of 6.5 million gay men in the United States. Assume
at least 85 percent of these men are healthy, HIV-uninfected, with
no other exclusions and that they would donate blood at roughly
the same rate as the rest of the population (less than 5 percent).
This results in an expansion of the donor pool by only about 250,000
people. At the same time the donor pool is opened up to a much larger
number of potentially HIV-infected people. The risk of allowing
gay men to donate is therefore disproportionate to the benefit of
a relatively small increase in the donor pool.
This cold calculation gives a sense of the underlying argument
for a level of caution when considering the issue but does not answer
why all gay men, or at least any man who has had sex with a man
since 1977, should be permanently barred from blood donation. Why
not expand the donor pool by 250,000 when the nation faces a blood
shortage? Is there some other way to formulate a policy based on
science that recognizes epidemiological reality but also feels less
discriminatory and stigmatizing to healthy gay men?
A recent meeting of the Blood Products Advisory Committee of the
FDA addressed this question. At the start of the meeting, the committee
agreed that the permanent ban on gay men seemed discriminatory,
lacked a firm foundation in science, and should be changed. A majority
of committee members indicated they would vote to change the policy.
Public statements from the Gay and Lesbian Medical Association,
the Human Rights Campaign, various hemophilia groups, and the American
Association of Blood Banks all urged a change in the policy. Only
the American Red Cross urged no change be made. But, what should
the policy be changed to?
The FDA proposed changing the lifetime ban to five years, bringing
the gay ban in line with the length of time organ or tissue transplant
recipients are barred from blood donation. In other words, any man
who has had sex with another man during the last five years would
be barred from donating. The blood bank association urged a one-year
ban, putting the gay ban in line with that for visiting a prostitute,
and the gay doctors made a similar proposal. Any of these approaches
are unlikely to feel less discriminatory, and are unlikely to have
much practical effect for the majority of gay-identified men. The
only men who may be included in the donor pool as a result of such
a change would be those who had their last homosexual experience
five or more years ago.
The committee seemed poised to recommend a change in the gay donation
policy, but then the slides on herpes virus 8 were presented. Human
herpes virus 8 (HHV-8) is a newly discovered virus thought to be
the cause of Kaposi's sarcoma (KS). HHV-8 is also widespread among
gay men, which helps explain the early, baffling concentration of
KS among gay AIDS patients but not heterosexual ones. Although KS
in gay men is almost always the result of infection with both HIV
and HHV-8, there have been a few isolated cases of KS in gay men
with HHV-8 alone. Data emerging on HHV-8 show that it shares a similar
epidemiological profile with HIV. Gay men begin acquiring HHV-8
during late adolescence when sexual activity begins, and its incidence
accelerates through early adulthood. By age 40, about one-third
of gay men seem to be infected with HHV-8. The virus appears rarely
in the U.S. heterosexual population.
HHV-8 is most likely transmitted orally, but no blood test is routinely
available to detect those who have it. In Africa, where HHV-8 is
endemic, the virus seems to be acquired in childhood. HHV-8 has
also been transmitted through kidney transplants and dialysis procedures.
Can HHV-8 be transmitted through a blood transfusion? No one knows.
Faced with this uncertainty, the committee changed its mood, and
declined to recommend a specific revision of the gay blood donation
policy.
After deciding not to alter the policy, the committee outlined
a series of research questions for the FDA that may help the agency
revisit the issue at a later date:
- How many gay men abstain from sex for one, two and five years?
- How many gay men are there in the United States?
- How does HIV incidence vary among sub-groups of gay men?
- How is HHV-8 transmitted?
- Can gay men with a higher risk of having HIV be identified
more precisely in the screening questionnaires?
All of these are fascinating and important questions, and answers
to each could have a broader use in fighting the epidemic. However,
given the paucity of epidemiological data generated about gay men
after 15 years of research, these questions are unlikely to be answered
soon, if ever. So what can gay men do now?
Surviving the Blood Drive
One easily addressed sore point for excluded donors arises from
the manner in which blood is collected in this country. The stigma
and discrimination gay men and others feel when asked to donate
is more directly related to how blood drives are conducted rather
than to the exclusion policy. In our high-tech world, awash in fabulous
commodities, life-giving blood has only one low-tech source: People.
Collecting blood is laborious, messy, and invasive, and most banked
blood is collected in public during school and office blood drives.
During a blood drive, coworkers and fellow students are rounded
up and exhorted to donate. But, as we've seen, some people shouldn't
give blood. When asked, "Why didn't you donate?" awkward, embarrassing
moments can ensue if people feel compelled to discuss sensitive
behaviors or personal medical conditions in an insecure social setting.
What male employee at an auto plant, for example, wants to say to
a fellow mechanic, "I can't give blood 'cause I fool around with
guys?"
Members of other risk groups blacklisted by donor deferral may
feel the insult and anxiety experienced by gay men when pressured
to donate even more acutely. While a gay man who knows his HIV-negative
status may fib and donate without causing harm, individuals with
HIV do not have that option. People with HIV or hepatitis C virus
(HCV), to name only two, face a difficult choice of either revealing
their status (and certain presumed behaviors) or appearing selfish
and unwilling to volunteer for a good cause. Either way they face
stigma. These problems are compounded when there is a risk that
a person can be fired or even meet physical violence if they are
discovered to be gay or HIV positive.
A search of the medical literature, and interviews with blood supply
experts, yielded virtually no insights into better blood collection
strategies. Given the shortage of blood nationwide, this seems like
a major oversight. Clearly new blood collection initiatives are
needed, and hopefully methods can be found that will not place people
in uncomfortable situations.
A review of "blood drive organizing kits" illustrates the problem.
The packets, available from any local blood bank, help a civic-minded
person organize a blood drive in his or her school or work place.
The packets advise organizers to "be persistent!" "Ask every employee
personally, and confirm their participation." "Involve management
and give managers updates on who is participating!" Of twenty-three
blood drive packets reviewed, only one from the New York Blood Center
advised organizers to respect the privacy of employees who decline
to donate. One easy and immediate improvement would be to train
blood drive organizers — obviously well intentioned people
— to understand that some people cannot donate blood, and that
their privacy must be protected. Another tactic to preserve one's
privacy might be to become familiar with the myriad reasons why
people can't donate, then toss out a plausible excuse when the blood
drive organizer pounces. Or, if you must, simply call in sick when
the blood mobile pulls up.
p24 or HIV RNA?
A report in the Annals of Internal Medicine (Jan 2, 2001) makes
clear some of the differences between early detection with HIV RNA
assays and with p24 tests. While HIV RNA testing detected all early
infections in their study, p24 detected only 88.7%. For the purposes
of blood screening, this obviously leaves the window slightly open.
For clinical use, the cost of an HIV RNA test is $100.00 compared
to $20.00 for p24. More significantly, for the clinic and for blood
screening, is that HIV RNA, while highly sensitive, is less specific
about what it detects than the p24 assay. This means that a greater
number of people tested for HIV RNA will have falsely positive results.
Individuals who test positive for HIV RNA will need to be counseled
and tested again before they can be correctly diagnosed. The authors
comment, "Éfalse-positive results on HIV RNA assays require follow-up
testing and extensive post-test counseling and are associated with
substantial psychological distress." As it stands, the extra counseling
burden, additional assay costs and an unacceptable risk of mistakenly
telling people they might be infected keep us from closing the blood-safety
window entirely.
Footnotes:
Daar ES, et al. Diagnosis of Primary HIV-1 Infection. Ann Intern
Med. 2001;134:25-9
| The Top 52
Reasons for Not Being Able to Donate Blood |
|
| Temporary Restirctions |
| Condition |
Length of time (before you can give blood) |
| Not feeling well for any reason |
Until symptoms are over |
| Difficulty breathing, shortness of breath, asthma |
No difficulty breathing on day of donation |
| Ears, nose, or skin pierced, acupuncture |
One year after procedure unless done under sterile conditions |
| Blood transfusion |
One year after receiving blood |
| Abortion or miscarriage |
Six weeks if after the first trimester (12 weeks) |
| Dental work |
Seventy-two hours after root canal or after tooth is pulled |
| Have had sex with a male or female prostitute within the past
12 months, even once |
Twelve months after last incident |
| Measles, mumps, chicken pox |
Three weeks from day of exposure (can give blood if vaccinated
or had disease in past) and no signs or symptoms |
| Tuberculosis (T.B.) |
Two years after completion of treatment |
| Have been an inmate of acorrectional institution for more
than 72 consecutive hours |
One year from date of release |
| Sniffed cocaine within last 12 months or had sex with someone
who sniffed cocaine in last 12 months |
Twelve months after last incident |
| Cold, sore throat, respiratory infection, flu |
Until symptoms are over |
| Antibiotics (except antibiotics for acne) |
Two days after treatment is over if taken for infection |
| Tattoos |
Twelve months after procedure |
| Full-term pregnancy |
Six weeks after delivery |
| Surgery, serious injury |
When healing is completed |
| Sexually transmitted disease: venereal disease, chlamydia,
genital herpes, syphilis, gonorrhea |
Twelve months following diagnosis and treatment |
| Open-heart surgery (except coronary artery bypass) |
Three years after surgery |
| Lyme disease |
Six months after date of last signs or symptoms/48 hours |
| Accutane |
One month after taking last dose |
| Aspirin |
If donating platelets by apheresis, three days after last
dose |
| Have had sex with anyone listed in the first five categories
in the Permanent Restrictions listed below |
Twelve months after last incident |
|
| Permanent Restirctions (Please
do not give blood if you:) |
- Have used intravenous drugs (illegal IV drugs), even
once
- Are a man who has had sex with another man since 1977,
even once
- Are a hemophiliac
- Have ever had a positive antibody test for HIV (AIDS
Virus)
- Are a man or woman who has had sex for money or drugs
any time since 1977
- Have had hepatitis any time after your eleventh birthday
- Have had cancer (except localized skin cancer)
- Have multiple sclerosis
- Have had myocardial infarction, coronary artery bypass
surgery
- Have had a stroke
- Have had babesiosis or Chagas disease
- Have taken Tegison for psoriasis
- Have Creutzfeldt-Jacob disease (CJD) and/or an immediate
member of your family has CJD.
Source: New York Blood Center |
Booster Shot: A Vaccine
Primer and Update
By Richard Jeffreys
The field of HIV prevention has its share of raging controversies,
but there's one thing almost everyone agrees on — an effective
HIV vaccine is desperately needed. After an embarrassing burst of
optimism for a failed first-generation product in the early 1990s,
vaccine research has been widely perceived as stagnant. But in the
past year or so, promising new research is starting to rekindle
hopes that an HIV vaccine is possible.
The way the next generation vaccines may work, however, is still
considered less than perfect by some researchers. An ideal vaccine
would be one that prevents HIV from ever establishing itself in
the body. Known as "sterilizing immunity," such a vaccine would
leave an individual free from HIV after an exposure. With our current
technology, that may be very difficult to achieve. This has led
researchers to concentrate on developing vaccines that, if unable
to prevent infection, may at least prevent the virus from subsequently
causing illness. Several vaccine candidates attempting this approach
are now entering human trials, and the scientists involved are cautiously
optimistic that their studies may prove successful. But questions
remain about what counts as "success." If a vaccine allows HIV to
enter the body but then controls it, is there a chance that the
virus could be reactivated later in life and cause disease? Might
regular booster vaccinations be required to maintain control? Only
long-term studies can provide answers, and with infection rates
in some countries poised to explode, there is the compelling argument
that, for those at risk, some protection against AIDS is better
than none at all.
To grasp the science behind these issues, it's necessary to delve
into the complex workings of the immune system. Over the past decade,
AIDS research has helped revolutionize our understanding of how
the immune system fights infection and has opened new windows onto
how vaccines really work.
Remembrance of Things Past
The key concept behind vaccination is immune system memory. The
famous experiments of Edward Jenner uncovered this aspect of immunity
in the late 1700s. Jenner noticed that women and girls who milked
cows regularly seemed resistant to the scourge of smallpox, and
he guessed the reason might be connected with their exposure to
cowpox, a very similar disease that struck cattle. In an experiment
that would be considered far from ethical today, Jenner made a preparation
from cowpox lesions and gave it to a young boy to inhale. Despite
subsequent exposures to smallpox, the boy avoided disease.
Remarkably, it has taken over two centuries to begin to understand
exactly why Jenner's guesswork paid off. The technical challenges
involved in studying the immune system have, until recently, obscured
many details of how the body "remembers" past infections in order
to protect against future exposures. Even more relevant to HIV/AIDS,
the way the body controls infectious agents that stay in the body
for life — like hepatitis B or TB, for example — has also
been a mystery.
Unraveling Immunity: T-cells, B-cells, and Antibodies
The immune system is like a complex army of cells that perform
many different functions in the battle to maintain health. The first
line of defense against infection is called innate immunity. This
refers to cells such as neutrophils and natural killer (NK) cells
that respond to infections in a general way without specifically
recognizing or "remembering" the infectious agent responsible. The
more important aspect of immune function when it comes to vaccines
and most serious illnesses is called adaptive immunity. Members
of the adaptive immune system — T-cells and B-cells —
actually target specific infectious agents and then afterwards provide
the body with a "memory" of these particular bugs.
T-cells and B-cells both belong to a class of cells called lymphocytes.
The job of B-cells is to make antibodies. Antibodies are like flags
that stick to infectious agents as they float freely in the bloodstream,
thus marking them for destruction and elimination from the body.
The production of antibodies is key for protection against certain
kinds of infections, such as those caused by bacteria. However,
for viruses like herpes and HIV, which actually insert themselves
into the body's cells (the technical term for these nasties is "intracellular
pathogens"), antibodies don't work as well. To control this type
of inside-the-cell infection, it appears that the body depends on
its T-cells.
Our understanding of the role of T-cells in immunity has progressed
by leaps and bounds over the past few years. For this we must thank
the involuntary altruism of thousands of mice, which have been specifically
bred for the study of the T-cell immune system. Technological approaches
to analyzing T-cell function have also improved. New insights into
how T-cells work have provided the basis for many of the latest
HIV vaccines and proposed immune-based treatments for HIV infection.
The next section of this article attempts to summarize our new understanding
of T-cells and their functions.
Down to a T: Helpers and Killers
There are two important families of T-cells in the body, and markers
on the cell's surface can identify them. T-cells with a marker called
CD4 belong to a family known as T-helper cells. T-helper cells fulfill
the commander's role in the immune response, delivering signals
to other immune system cells that allow them to carry out their
functions. CD8 markers are found on another important family of
T-cells called cytotoxic T-lymphocytes or CTLs for short. "Cytotoxic"
means that they can kill cells in the body that have been infected
with a virus or another pathogen — for this reason CTLs are
also known as killer T-cells.
T-cells start life in the cell-making factories buried within our
bones. From there the immature or "progenitor" T-cells travel to
a small organ located just behind the breastbone called the thymus.
The thymus acts a boot camp for T-cells, and only cells that graduate
are allowed to enter the body's circulation as new recruits to the
immune system army.
Several important events occur in the thymus. It's there that a
T-cell acquires the CD4 or CD8 marker that signals the cell's function.
Both CD4 and CD8 T-cells also develop a structure called a T-cell
receptor (TCR). The TCR is a docking bay for pieces of infectious
agents, like viruses and bacteria that have been picked up by one
of the body's scavenger cells. The TCR has to recognize not only
the infectious agent, but also a protein called MHC that identifies
the scavenger cell as trustworthy. The MHC is like a secret handshake
the T-cell needs to receive before it can act. If the T-cell's TCR
locks snugly onto a piece of an infectious agent combined with an
MHC protein, an immune response can be triggered. Any piece of infectious
agent that can fit into a TCR and trigger an immune response is
called an antigen. It is the TCR that allows an immune response
to be directed against a specific pathogen. New TCRs are produced
and individualized in the thymus by an essentially random shuffling
of the T-cell's genetic code, or DNA. Billions of T-cells with many
differently shaped TCR docking bays are made in this way. This seems
to be the body's method of making sure that for any potential pathogen,
there will be at least some T-cells able to recognize its antigens.
There's a downside to this process. T-cells are also made with
TCRs able to dock with pieces of one's own body tissues, or self-antigen.
If these anti-self cells leave the thymus and enter the circulation,
there can be an immune response against the very body that the T-cells
are supposed to protect. This problem is called autoimmunity. So
the final task for the thymus is to eliminate T-cells with TCRs
that might cause autoimmune responses. In fact, 95 percent of newly
made T-cells are destroyed in the thymus for this very reason. Members
of the remaining 5 percent graduate from T-cell boot camp, enter
the circulation and start patrolling for antigen to fit their TCR
and trigger a T-cell response.
These fresh T-cells are called naive, because they have not yet
responded to an infection. They can be thought of as the rookie
T-cells of the immune system. If a new infection (or fake infection
in the form of a vaccine) shows up, naive T-cells with TCRs that
can dock with pieces of the infectious agent will be the ones recruited
to respond. This first encounter of naive T-cells with a new infection
is called the primary immune response.
An average adult is estimated to have one to two trillion naive
T-cells on patrol at any given time. New naive T-cells are made
and graduate from the thymus every day, replacing an equivalent
number of naive cells that never found an infection to respond to.
Scientists estimate that the body makes about one to four billion
new naive T-cells a day during adulthood, though this number declines
dramatically as individuals age.
From Naive to Memory, or Jenner Explained
The events set into motion when a naive T-cell docks with antigen
fitting its TCR are key to understanding immunity. To walk through
what scientists think occurs, it's helpful to look at the immune
response to a viral infection most everyone has experienced: Chickenpox.
Chickenpox is caused by an easily transmitted virus called herpes
zoster virus (HZV). Most people become infected with HZV during
childhood. When the virus first arrives in the body, immune sentries
chop it up and its pieces are transported to the lymph nodes by
immune system foot soldiers called dendritic cells. The lymph nodes
are immune system command centers and T-cells visit them regularly,
eager to mix it up with infectious agents. When a dendritic cell
carrying HZV fragments arrives at the lymph node, it displays pieces
of the virus for passing T-cells to inspect. This is called antigen
presentation. Any naive T-cell with a TCR that docks snugly to HZV
antigen will be embraced by the dendritic cell. This removes the
T-cell from patrol and starts the immune response process against
HZV.
The T-cell/dendritic cell embrace lasts several days, during which
time signals are exchanged that cause the T-cell to prepare for
battle. Eventually, the T-cell becomes activated, which means that
it starts to make copies of itself. And each copy made starts to
make copies of itself, also. Since a single naive T-cell can make
twenty or more copies of itself, this multiplication process generates
a cascade of millions of T-cell clones that all have the same kind
of TCR, in this case TCRs that specifically dock with HZV antigen.
This army of activated, HZV-specific T-cells leaves the lymph nodes
on a search-and-destroy mission. Their task is to find and eliminate
HZV-infected cells and limit the ability of the virus to reproduce.
To perform this mission, activated T-cells also develop enhanced
infection-fighting skills. They release chemicals called cytokines
and chemokines that can communicate with other cells and, in some
cases, directly block viral replication. CD8 killer T-cells release
chemical weapons such as "perforin" that punch holes in virus-infected
cells.
Most people can remember what it felt like when the war between
the immune system and HZV was raging. Fever, swollen lymph nodes
and blistering skin are the unforgettable hallmarks of chickenpox.
As you might guess, many of these symptoms stem from the activity
of the HZV-fighting T-cells themselves. Swollen lymph nodes result
from the proliferation of naive T-cells when they become activated.
Fever is partly a result of the cytokines and chemokines that the
T-cells release (one of the best known cytokines is called IL-2,
and when used as a treatment, IL-2 is notorious for causing fever
and flu-like symptoms).
Fortunately, after a week or so of this misery, the T-cells have
usually gained the upper hand. HZV replication is controlled, and
most of the newly made, activated T-cells automatically die off.
The symptoms of chickenpox subside. What has been long suspected,
but only recently proven, is that some of the HZV-specific T-cells
survive. Out of the twenty or so duplicates made by each naive T-cell
activated by the virus, it seems that two to five cells become memory
T-cells. These memory T-cells can be thought of as a SWAT team the
body retains to deal with HZV should it ever try to cause trouble
again. HZV, like hepatitis B and tuberculosis, is an example of
an infectious agent that remains in the body for life.
Recent studies have helped show how memory T-cells prevent infections
from recurring. Remember the lingering embrace between the antigen-presenting
dendritic cell and the naive T-cell? A memory T-cell can become
activated and get into battle after a much shorter embrace —
the immune system equivalent of a hug, perhaps. Memory T-cells also
seem to be able to copy themselves more rapidly, and they start
releasing cytokines, chemokines, and other infection-fighting chemicals
almost instantly (See "Genes Are Go," sidebar, this page).
As you may have already realized, it's the difference between naive
and memory T-cell response rates that were responsible for the success
of Edward Jenner's experiment and all the vaccines that came after.
The dried cowpox used by Jenner to vaccinate the young boy was presented
to naive T-cells, and those cells with TCRs fitting the cowpox antigens
responded and left a legacy of cowpox-specific memory T-cells. The
similarities between cowpox and smallpox antigens meant that this
SWAT team of T-cells was able to respond rapidly when the boy was
later exposed to smallpox. And most importantly, thanks to this
rapid response, deadly disease was averted.
In addition to two trillion or so naive T-cells, an adult usually
has a pool of around three trillion memory T-cells. This pool contains
memory T-cells produced in response to past infections, and in some
ways can be thought of as a library containing a body's history
with infectious disease. AIDS is a horrific illustration of the
importance of these memory T-cells — the opportunistic infections
that are the hallmark of AIDS are all caused by pathogens that stay
in our bodies for life. When the memory T-cell squads that control
these infections are diminished in number by HIV infection, pathogens
such as pneumocystis, candida, cytomegalovirus, and toxoplasma can
become active and cause disease.
Vaccine Memories: The Importance of T-cell Subsets
It is here in the T-cell story that we must climb to another level
of complexity. For the sake of clarity — never easy to achieve
when discussing the immune system — the above discussion of
chickenpox talked about T-cells in a general way. But as already
mentioned, the CD4 and CD8 markers identify two important groups
of T-cells — helpers and killers — with very different
functions. Although the process (described above) that leads to
the creation of memory T-cells is similar for both CD4 and CD8 T-cells,
the ways antigens are presented to CD4 and CD8 cells are somewhat
different. This is important since researchers would like a vaccine
that creates a squad of both CD4 and CD8 memory T-cells.
CD4 helper T-cells seem to divide into two major groups. Type 1
(called Th1) CD4 T-cells provide important help to CD8 killer T-cells.
Type 2 (called Th2) CD4 T-cells help B-cells make antibodies. Again,
these distinctions become critical when designing vaccines. Researchers
are now trying to work out what type of memory T-cell squad is more
important for protecting against a particular infection. If antibodies
are important, then a vaccine had better trigger the development
of Th2 CD4 memory T-cells that will respond rapidly to provide help
for B-cells. If a pathogen manages to penetrate cells in the body
and CD8 killer T-cells are needed to eliminate or control it, then
a squad of Th1 CD4 memory T-cells has to be created to help get
those killer cells going. For some infections — including HIV
— it may be best to trigger both Th1 CD4 and CD8 killer memory
T-cells. That way, the whole team will be ready to roll.
It's important to stress that one type of T-cell response does
not mean the other type can't respond simultaneously. However, the
relative strength of the different types of T-cell response appears
to be important for determining whether an infection is successfully
battled. Looking back at the example of HZV, it's likely that all
of these different T-cell players get involved in the battle —
both Th1 and Th2 CD4 T-cells, CD8 killer T-cells, B-cells, and antibodies.
Based on experience with other viruses, many researchers suspect
that it's the teamwork between Th1 CD4 and CD8 killer T-cells that
plays the most important role in controlling HZV over the long haul.
These suspicions are supported by research in animals with similar
viruses that stay in the body for life but remain controlled by
memory T-cells. Conversely, with other infections the strength of
the Th2 CD4 T-cell response and the production of effective antibodies
by B-cells seems key.
You may be wondering what types of immune responses were created
by your childhood vaccinations. Philip Kourilsky, a researcher from
the Pasteur Institute in France, has recently highlighted the fact
that for almost all commercially available vaccines (such as hepatitis
B, measles, polio, etc.) what makes them effective — and which
T-cell responses they create — is not known. "We've had many
successful vaccines over the past decades but we've missed a chance
to see how these vaccines work," Kourilsky said at a recent HIV
vaccine meeting. Up until recently the assumption had been that
antibodies were responsible for the success of vaccines, but it
is now thought that this isn't the case, a point stressed at the
same meeting by Neal Nathanson, former director of the U.S. Office
of AIDS Research. "Hepatitis B vaccine is a good example. It's amazingly
effective but no one knows how it works. And what's really interesting
is that it does work, even though hepatitis B is a persistent infection
— like HIV." Supporting Nathanson's interest is a study that
compared people who controlled hepatitis B infection naturally with
those who had been vaccinated. In that study, natural immunity seemed
to rely on Th1 CD4 T-cell responses, not the Th2 responses that
are associated with antibody production.
Killer T-cells, Dude
While scientists may never get around to analyzing how older vaccines
do their job, HIV researchers are benefiting greatly from the latest
advances in T-cell research. Several vaccine candidates that are
specifically designed to create Th1 CD4 and CD8 killer memory T-cell
responses against HIV are now entering clinical trials for the first
time.
Attempts to create CD8 killer T-cell responses have been assisted
by the development of a vaccine technology called "naked DNA." This
strategy uses sections of DNA that contain genes for making fake
HIV proteins that can act as antigens to trigger an immune response.
Because these fake antigens have the same structure as real HIV
antigens, naive T-cells are embraced and memory T-cells specific
for HIV antigen are created. One downside is that the dendritic
cells needed to present these antigens to T-cells are not very impressed
by the fakery involved. As a result, the memory T-cell response
to naked DNA vaccination alone is rather weak.
Researchers have addressed this problem by following naked DNA
vaccination with a booster shot. The booster shot uses harmless
bird viruses that have also been tinkered with so that they too
produce fake HIV antigens. The booster bird virus does a better
job of fooling the antigen-presenting cells than plain DNA, thus
causing a massively enhanced T-cell response.
One of the first inklings of the potential success of this strategy
came in an article published in 1998 by a group of Australian researchers
led by Dr. Stephen Kent. Kent's team tried a naked DNA shot followed
by a bird virus (called fowlpox) booster in macaque monkeys. Strong
Th1 CD4 memory T-cell and CD8 memory T-cell responses were created
by the vaccine regimen. They later injected real HIV into the monkeys
and found that, after a short burst of viral replication, the memory
T-cells kicked in and reduced HIV activity to undetectable levels.
However, the type of monkey used in that experiment doesn't progress
to AIDS or develop high levels of HIV replication — even without
vaccination. While it was a good first step, more studies were needed.
A year later Dr. Harriet Robinson, a former colleague of Kent's,
published similarly promising results obtained with her own version
of what's being called the "prime-boost strategy." Robinson actually
feels she may have bested Kent's efforts by using a method for delivering
the naked DNA under the skin (intradermally). Robinson also challenged
her vaccinated monkeys with a potentially lethal form of monkey
HIV called SHIV. After publishing her results Robinson pointed out
that "protection did not prevent infectionÉwhat we saw were contained
infections." Although SHIV took root, virus could not be detected
using viral load tests, showing that the memory T-cell response
had squelched SHIV replication very effectively.
In both the Kent and Robinson studies, it was notable that antibody
responses to the vaccines were variable and often not detectable.
The researchers concluded that the Th1 CD4 and CD8 killer T-cell
response generated by these vaccines was able to control virus activity
in the absence of antibody. This observation truly heralds a new
era for vaccine research, which for so long has been hamstrung by
the notion that antibodies are central to all types of protective
immunity.
Meet the Candidates
Equipped with a better understanding of the immune responses required
to control HIV, several companies and research teams are moving
their vaccine candidates into human trials.
Stephen Kent's vaccine has now been named Co-X-Gene. The manufacturer
is a small Australian company called Virax with limited resources,
leading to some concerns about their ability to move the product
forward. As this article went to press, Virax announced they have
entered into partnership with Aventis Pasteur, a huge French vaccine
manufacturer that produces a billion doses of commercial vaccines
a year. Flush with this injection of support, Virax plans clinical
trials of Co-X-Gene during 2001, with larger trials possible within
three years.
Merck & Co., the pharmaceutical giant, has also been quietly working
away on a T-cell based HIV vaccine. Merck is also using a naked
DNA and fowlpox booster strategy, although researchers there claim
to have modified the DNA so that it generates HIV antigens more
efficiently. Merck surprised everyone by announcing the first human
safety study of this product last year. The government's assistant
director of AIDS vaccine research, Margaret Johnston, waxed enthusiastic
in the Wall Street Journal: "It's good to see Merck involved, and
testing an approach that is right now thought to be on the cutting
edge." The trial is already under way, with one of the participating
sites being the State University of New York at Stony Brook. Potential
volunteers can call Michael Thorn, RN, at 516/444-1659 for more
information.
Another DNA vaccine made by Apollon, Inc. is also in human trials.
Currently, the product does not feature a bird virus booster but
could potentially be modified if studies support such a move. Temporarily
laboring under the rather forgettable name of APL-400-03, the vaccine
is under study at the National Institutes of Health [contact: Grace
Kelly, 1-800-772-5464, extension 57744, and the University of Pennsylvania,
contact: Kim Lacy at 215/662-6434].
Further afield, a collaboration between English and Kenyan researchers
plans safety testing of a DNA vaccine with a booster made from a
type of virus called vaccinia (the full name is modified vaccinia
Ankara, or MVA). The initial studies will be in the UK with further
work scheduled in Nairobi, Kenya.
In Uganda, plans are under way to test the first-ever oral HIV
vaccine candidate. The brainchild of researchers at Robert Gallo's
Institute of Human Virology in Baltimore, this novel approach uses
genetically modified salmonella bacteria to produce HIV antigens
in the gut. Because most HIV transmission occurs through vaginal
or anal mucosal surfaces, stimulating a strong T-cell response in
these kinds of tissues could be particularly useful. The always
cautious Dr. Tony Fauci, head of the US National Institute of Allergies
and Infectious Diseases (NIAID), recently relayed a cheekily guarded
optimism about the product to the journal Nature: "We have been
burned before in trying to predict how a candidate will fare before
the trial even starts. Having said that, I like this approach."
While this is a sampling of the newer vaccines furthest along in
development, the scent of potential success may soon prompt more
products into the field. In anticipation, NIAID recently announced
a revamping of their HIV Vaccine Trials Network (HVTN), expanding
it to include sites in sub-Saharan Africa, Asia, Latin America,
and the Caribbean. Significantly, the effort is being led by veteran
T-cell immunologist Lawrence Corey, M.D., from the Fred Hutchinson
Cancer Research Center (FHCRC) in Seattle. Hopefully, the HVTN will
be able to conduct the type of follow-up necessary to answer questions
about the long-term efficacy of T-cell based vaccines and the ultimate
outcome of an HIV infection that is controlled rather than evicted
from the body.
Having crossed the cusp of a new millennium, there is a sense that
HIV vaccine research has also reached a turning point. Not only
is there optimism that the immune system can be prepared to do battle
with this wily virus, but several promising new strategies may eventually
prove able to block HIV's ability to create a home for itself in
the human body. One thing is certain: The clouds of despair that
dimmed the vaccine horizon are beginning to clear.
Revenge of the Antibodies
Although vaccine approaches focusing on T-cells have come to the
fore, researchers have not entirely given up on antibodies. The
difficulty has been triggering the body to produce antibodies that
actually block HIV replication. HIV's outer envelope is notorious
for mutating rapidly to avoid the antibody attack, and some scientists
speculate that this is part of the virus's defense against the immune
system. With some smart thinking, two teams of researchers believe
they may be starting to surmount this problem.
Jack Nunberg from the University of Montana has worked out a way
to generate antibodies that block HIV as it prepares to gain entry
into T-cells. This first step of the entry process is called fusion,
and Nunberg has dubbed his souped-up antibodies "fusion-competent."
The clever idea that led to creation of these antibodies was to
literally freeze HIV just as it was changing shape to fuse with
a T-cell. The immune systems of mice were then used to make antibodies
to these previously hidden parts of the virus. Isolated in the test
tube, these antibodies were able to block replication of a wide
variety of HIV strains collected from around the world. There is
much more work to be done before this strategy can be tried in humans,
but Nunberg remains cautiously optimistic that his research will
eventually bear fruit.
At the National Cancer Institute in Maryland, Dr. John Schiller
is trying another cleverly designed antibody-based approach. It
was discovered several years ago that HIV uses two T-cell surface
molecules when latching onto and invading a cell. One latch has
long been known to be the CD4 molecule itself, which is vital to
helper T-cell function. Early attempts to block the CD4 latch failed
spectacularly. The second latch HIV needs is a receptor called CCR5,
the function of which — if any — is not known. What is
known is that some people naturally lack CCR5 receptors on their
T-cells due to a genetic mutation. Not only are these people highly
resistant to HIV infection, but as far as anyone can tell they are
perfectly healthy. These observations have prompted several drug
companies to design drugs that block CCR5, betting that they might
become effective treatments for HIV.
Dr. Schiller had another idea — why not try to get the body
to make antibodies that block CCR5? This approach has a number of
advantages: a vaccine that created antibodies against CCR5 just
might offer the kind of long-term protection against HIV infection
seen in people naturally lacking the CCR5 receptor. And as a treatment,
a shot or two of a vaccine would be immensely preferable to the
daily ingestion of a drug. Schiller has reported success with the
approach in mice and is moving on to macaque monkeys. "If we can
do it in macaques, then the chances that it won't work in humans
are small," says Schiller. If either Nunberg or Schiller hit the
jackpot, antibodies will be back in the HIV business.
Out With the Old?
Lest we forget, there are HIV vaccines further along in human trials
than those discussed in the body of this article. Unfortunately,
they were developed prior to the recent significant insights into
T-cell immunity. AIDSVAX is a vaccine that uses a fake copy of HIV's
outer envelope to try to stimulate antibodies against the virus.
Many researchers now feel that this product may have a limited protective
effect, if any. This dour outlook emerged as several breakthrough
HIV infections occurred during early AIDSVAX trials. Pasteur Merieux
Connaught's ALVAC vaccine attempts to induce both antibodies and
T-cell responses by combining pieces of HIV's envelope with a bird
virus booster. The results so far have been disappointing, with
killer T-cells being detected in only one-third of study participants.
UK killer T-cell expert Dr. Andrew McMichael, when asked his opinion
by the journal Science, was underwhelmed: "Two-thirds of the people
(had) no killer T-cell response, and, if killer T-cells are important,
they wouldn't be protected."
Pick Your Antigens and Adjuvants
Two additional details are critical to the design of an effective
HIV vaccine. Naked DNA, bird viruses, and a variety of other strategies
can be used to deliver fake HIV antigens (pieces of HIV that can
trigger an immune response) into the body. But which pieces of HIV
should be used? Early vaccine research focused on HIV's outer envelope,
but it has become apparent that the rapid mutation of this viral
cloak may be part of its defense against the immune system. It also
seems that HIV's envelope proteins create antibody responses, not
the Th1 CD4 and CD8 killer T-cell activity now thought to be vital
for a successful vaccine. Researchers are now targeting certain
inner proteins of HIV called core proteins that are revealed only
after the virus has infected a T-cell. The genes that make these
core proteins have catchy names like gag, pol, nef, and tat. In
some cases single proteins may be able to induce T-cell immune responses.
Italian researcher Barbara Ensoli has tried a vaccine that uses
HIV's tat protein, and this approach was sufficient to protect two
thirds of her vaccinated cynomolgus monkeys from active HIV replication.
Ensoli acknowledges, however, that single protein approaches can
probably be improved upon if combined with other vaccines. The most
important lesson from recent vaccine studies is that HIV's core
proteins create much stronger Th1 CD4 and CD8 killer T-cell responses
than the ever-changing viral envelope. Whether particular core proteins
have unique advantages when it comes to vaccination is not yet known.
Because a T-cell with a TCR that fits an HIV gag protein won't respond
to tat, it may be better to include as many core proteins as possible,
thereby maximizing the number of T-cells that respond to the vaccine.
Adjuvants are special vaccine ingredients designed to boost what
researchers call "immunogenicity." Simply shooting a fake HIV protein
into the body does not necessarily ensure that dendritic cells will
be inclined to pick it up, take it to the lymph nodes, and present
it to T-cells the way they would with a real virus. An adjuvant
is designed to help fool the antigen-presenting dendritic cells
into treating the vaccine like the real thing. Many older vaccines
use adjuvants made up of bits of dead bacteria suspended in an emulsion
of oil and soap that helps mobilize a larger immune response. Naked
DNA vaccines can contain bits of bacteria-like DNA called CpG motifs,
and these also appear to have adjuvant effects (although, there
are some yet-to-be researched questions about the safety of these
CpG adjuvants). Bird virus boosters seem to trigger the body to
produce cytokines that help spark antigen presentation, which is
another reason they have become favorites in HIV vaccine studies.
Research into adjuvants continues, with a recent study actually
using a patient's own dendritic cells to carry vaccine antigens
into the lymph nodes. A single shot of dendritic cells generated
a huge T-cell response. Unfortunately, harvesting, then re-infusing
dendritic cells is costly and it's unclear whether this approach
can be made affordable enough for widespread use.
For more information:
An illustrated pamphlet, Understanding the Immune System, is available
from the National Institutes of Health (NIH) website: http://www.niaid.nih.gov/publications
For more on vaccines, Understanding Vaccines http://www.niaid.nih.gov/publications/vaccine/undvacc.htm
Immune System Terms
Immune memory: The ability of the immune system to store information
about prior infections or vaccinations so as to respond quickly
if the infection is re-encountered.
Antibodies: Antibodies coat, mark for immune destruction, or render
harmless foreign matter such as bacteria, viruses, or dangerous
toxins. Antibodies also tag virus-infected cells, making them vulnerable
to attack by other components of the immune system. Each antibody
attaches itself to a single specific chemical sequence in an antigen.
T-helper cells: Also known as CD4 cells, T helpers are a type of
T lymphocyte involved in protecting against viral, fungal, and protozoal
infections. The CD4 cell modulates the immune response to an infection
through a complex series of interactions with antigen presenting
cells, and lymphocytes that directly attack foreign antigens, such
as killer T-cells.
Killer T-cells: Immune system cells that kill cancerous and virus-infected
cells. Also known as cytotoxic T-lymphocytes (CTL).
Antigen: A foreign substance, usually a protein that stimulates
an immune response. An antigen contains several subunits called
epitopes that are targets of specific antibodies and killer T-cells.
Naive T-cell: A T-cell arising from the immune system's production
of fresh cells in the bone marrow. Naive T-cells respond to newly
encountered pathogens containing antigens the immune system has
not processed before. The naive T-cells' activation and proliferation
create an acquired immune response to the newly encountered pathogenic
agent. After the disease is eradicated, a portion of the T-cell
population engendered by the activated T-cells constitute a reservoir
of memory cells, which proliferate and respond very quickly to any
recurrence of the disease.
Primary immune response: The first encounter of a naive T-cell
with antigen that results in activation, proliferation, and, finally,
creation of memory T-cells.
Dendritic cells: Immune cells with long, tentacle-like branches
called dendrites. Among the dendritic cells are the Langerhans cells
of the skin and follicular dendritic cells in the lymph nodes. Most
dendritic cells (other than the follicular type) function as antigen
presentation cells.
Antigen presentation: The display of digested bits of foreign bodies
on the surface of macrophages or dendritic cells in the lymph nodes
for circulating T-cells to recognize. Upon recognition, the T-cells
become activated.
Cytokines: Proteins produced by the white blood cells that act
as chemical messengers between cells. Cytokines can stimulate or
inhibit the growth and activity of various immune cells in response
to the particular type of disease present.
Memory T-cells: A T-cell that bears receptors for a specific foreign
antigen encountered during a prior infection or vaccination. After
an infection or vaccination, some of the T-cells that participated
in the response remain as memory T- cells, which can rapidly mobilize
and clone themselves should the same antigen be re-encountered during
a subsequent infection.
Genes Are Go: Giving
Memory T-cells a Head Start
The reason memory T-cells outperform naive T-cells when responding
to infections is related to the activity of genes within the cell.
Genes are short stretches of DNA that contain code for making certain
proteins. The proteins then perform specific functions in the body.
Most of us are familiar with the idea that we inherit genes from
our parents for things like eye color. It's often less appreciated
that our genes are at work every second that we are alive. Every
cell in our body (apart from red blood cells) contains a complete
copy of our DNA blueprint (called the genome) and all our genes
are contained within it. However, cells only use the genes they
need to function. A T-cell uses certain genes to make the proteins
it needs to fight infection. A kidney cell will use different genes
to perform the waste-eliminating functions of the kidney. One way
to think about this is that each cell carries a complete library
containing the thousands of instruction manuals needed for making
an entire body. But each cell checks out only those volumes needed
to carry out its specific functions.
X-Factors
By Bob Huff
Compounds become useful drugs only if their beneficial qualities
far outweigh any harmful or unwanted activity. But drugs can have
subtle, unintended effects — both good and bad — that
may remain unnoticed until after they are in widespread use. The
class of drugs known as protease inhibitors (PIs) caused a revolution
in treating HIV after they were introduced in 1996, but they have
also been blamed for a range of disturbing metabolic side effects.
Now there are reports that some of the HIV PIs may protect against
disease in an unexpected way.
Recent in vitro research suggests that HIV-protease inhibitors
may also demonstrate inhibitory activity against Pneumocystis
carinii (responsible for PCP),1 against Candida albicans,
a fungus that causes thrush,2 and against Toxoplasma
gondii, which can infect the brain.3 Each of these
pathogens can cause serious disease in immune-compromised persons.
It should be stated at the outset that the clinical implications
of these test-tube observations are likely to be slight, mainly
because the low-cost antibiotic trimethoprim/sulfamethoxazole (Bactrim)
does a superior job of preventing PCP and toxoplasmosis and because
those at risk for opportunistic infection (OI) ought to be receiving
prophylactic treatment. But this research is interesting nonetheless
because it sheds light on the complex interactions between bodies
and drugs that lie just out of reach of medical certainty.
HIV protease is one of a family called aspartyl proteases, enzymes
that cleave strings of amino acids at precise points with the scissors-like
action of two matched aspartic acid molecules. Non-HIV aspartyl
protease enzymes, such as renin, are known to be active in human
as well as many other forms of life. The candidate compounds for
HIV protease inhibitors were selected because they specifically
blocked the target viral enzyme while virtually ignoring human ones.
There have been suggestions that some of the unusual side effects
associated with PI use, such as lipid abnormalities and insulin
resistance, could perhaps originate with low-level non-specific
inhibition of human enzymes, including human aspartyl proteases.
The issue is unclear since other mechanisms and other drugs are
also suspected. What the new research finds is that other organisms,
including certain HIV-associated pathogens, may rely on PI-susceptible
aspartyl proteases to perform essential functions.
As most people know, Pneumocystis carinii pneumonia (PCP)
is a deadly lung infection that can strike immune-impaired people
with fewer than 200 CD4 T-cells. A group of Italian researchers
has reported inoculating Pneumocystis trophozoites onto human embryonic
lung cells, then exposing them to several PIs and to Bactrim as
a control. Each of the PIs, nelfinavir, indinavir, ritonavir, and
saquinavir, demonstrated partial, dose-dependent pneumocystis inhibition
with activity falling short of Bactrim at the concentrations tested.
Although blood levels of PIs can far exceed the concentrations attained
in this experiment, the amounts of drug that actually reach the
alveoli of the lungs, where pneumocystis does its damage, are unknown.
Though the PIs were not dramatically effective against PCP, evidence
that pneumocystis is dependent upon an aspartyl protease suggests
a potential new target for anti-PCP drug research.
A different group of Italian researchers explored the inhibitory
effects of indinavir and ritonavir on the growth of Candida albicans.
They established that a particularly virulent form of C. albicans
associated with HIV infection produces a secretory aspartyl protease
and that this protease is inhibited by the HIV PIs. Then, in an
experimental mouse model of vaginal candidiasis, the researchers
demonstrated that the PIs had a therapeutic efficacy comparable
to that of fluconazole, a gold-standard antifungal. These findings,
they suggest, help explain clinical observations of promptly improved
oral candidiasis in patients who begin HAART — even before
their CD4 counts recover.
In the late '80s, after Bactrim prophylaxis was shown able to prevent
most episodes of Pneumocystis carinii pneumonia (PCP), researchers
turned their attention to preventing some of the second-line —
yet no less deadly — opportunistic infections. One of these
was toxoplasmic encephalitis, caused by Toxoplasma gondii, a protozoan
parasite that can be acquired by contact with cat feces or uncooked
meat. When an immune-compromised, parasite-infected person experiences
CD4+ T-cell counts falling below 100, their risk of developing a
brain infection with T. gondii increases. Fortunately, as was subsequently
learned, Bactrim, when routinely taken to prevent PCP helps prevent
toxoplasmosis, also.
A team of French researchers recently conducted a study to see
if some of the HIV antiretroviral drugs have activity against the
T. gondii parasite. They selected a particularly virulent strain
of toxoplasma and grew it in a laboratory human cell line. Varying
concentrations of the nucleoside reverse transcriptase inhibitors
(NRTI) AZT, ddI, d4T, ddC, 3TC as well as the HIV protease inhibitors
saquinavir, ritonavir, indinavir and nelfinavir were tested. All
of the HIV drugs were compared to the standard treatment for toxoplasmosis,
pyrimethamine plus sulfadiazine.
The NRTIs ddI, d4T, 3TC, and ddC had no effect on the growth of
T. gondii. AZT had a mild inhibitory effect on the parasite at a
relatively high concentration of 100 micrograms/mL. More significantly,
there was no observed antagonism between AZT and pyrimethamine —
results that contradicted a 1989 report.4 Also, contrary
to a 1997 report, ddI showed no anti-toxoplasma inhibitory activity.5
Overall, the NRTIs neither potentiated nor antagonized the standard
toxoplasmosis treatment regimen.
Of the PIs, indinavir had an unremarkable inhibitory effect in
line with that of AZT, and saquinavir killed toxoplasma at concentrations
that also killed the human host cells. But, nelfinavir and ritonavir
were standouts. Highly inhibitory to T. gondii at concentrations
of about 10 micrograms/mL, each PI entirely blocked parasite growth
at levels safely attainable in humans. Although no native T. gondii
aspartyl protease has been discovered, this research suggests that,
as with pneumocystis, there must be one at work and that it may
be an attractive target for anti-toxoplasma drug development.
With the advent of HAART, the incidence of all OIs has dropped
dramatically. Current OI treatment guidelines recommend that people
with fewer than 200 CD4 cells take Bactrim as prophylaxis against
PCP (also protective against toxoplasmosis) — whether they
are on HAART or not. Despite the success of combination therapy
with PIs, not everyone with advanced disease is able to respond
with T-cells rising to protective levels. Often it is because they
have developed resistance to every available drug and cannot suppress
the virus. For others, immune reconstitution remains stunted despite
HAART-mediated control of viral replication. Until we know more
about T-cell recovery, we must presume that people with very low
T-cell counts remain at risk for developing any and all of the classic
opportunistic infections that define AIDS.
These data might lead some to wonder if certain PIs should be prescribed
for individuals with dangerously low T-cell counts. All things being
equal, if there is added protective benefit from taking nelfinavir
or ritonavir above and beyond their ability to suppress viral replication,
should these drugs be preferred as standard of care for at-risk
individuals?
It's not that clear. Keith Henry, an HIV clinician who is concerned
about seeing rising rates of morbidity in his practice after several
years of decline, doesn't think so. "It's interesting, but these
test-tube studies are subject to a lot of spin. There's no substitute
for good medical management, prophylaxis and finding a treatment
regimen that suppresses virus."
Finding new and unexpected uses for existing drugs is not unusual.
Thalidomide was introduced as a tranquilizer, became notorious as
a teratogen, and is now being investigated in HIV care for treating
apthous ulcers and wasting syndrome. Low-dose ritonavir has insinuated
itself into an increasing number of HIV treatment regimens by virtue
of its unsurpassed ability to inhibit a liver enzyme system and
thus raise the blood concentrations of other PIs — a trait
unrelated to its antiretroviral properties.
Maybe it's not surprising that biologically active substances,
when let loose in a complex system of chemical interdependencies,
often have unexpected effects. Research is continuing into the mechanisms
of treatment toxicity, including those that may be PI-related. Perhaps
these reports of peripheral treatment benefits can help researchers
unravel some of the complex interactions between HIV, the body,
and the pharmacy.
Footnotes:
1. Atzori C, et al. In vitro Activity of Human Immunodeficiency
Virus Protease Inhibitors against Pneumocystis Carinii. Journal
of Infectious Disease. 2000 May; 181(5):1629-34.
2. Cassone A, et al. In vitro and in vivo Anticandidal Activity
of Human Immunodeficiency Virus Protease Inhibitors. Journal
of Infectious Disease. 1999 Aug; 180(2):448-53.
3. Derouin F, et al. Anti-Toxoplasma Activities of Antiretroviral
Drugs and Interactions with Pyrimethamine and Sulfadiazine in vitro.
Antimicrobial Agents and Chemotherapy. 2000 Sep; 44(9):2575-7.
4. Israelski D, et al. Zidovudine antagonizes the action of pyrimethamine
in experimental infection with Toxoplasma gondii. Antimicrobial
Agents and Chemotherapy. 1989 Jan; 33(1):30-4.
5. Sarciron M, et al. Effects of 2',3'-dideoxyinosine on Toxoplasma
gondii cysts in mice. Antimicrobial Agents and Chemotherapy.
1997 Jul; 41(7):1531-6.4
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