[Press kit]

Past Research and Current Initiatives:
Making the Connection
rom the moment the first AIDS cases were studied, scientists knew that it would be crucial to learn to restore the
supply and function of T cells, the immune cells that fight infectious diseases and cancers, the very cells that HIV
destroys. Treatment research focused at first on the development of drugs against HIV, i.e. on antiretroviral drugs.
The recent availability of powerful triple antiretroviral drug combinations has indeed substantially reduced (sometimes to
undetectable levels) the amount of HIV in the blood of infected people and many of them experience dramatic improvements in the length and quality of their lives.
However, antiretroviral therapy cannot, by itself, be the functional equivalent of a cure. While T cell counts do rise
with successful antiretroviral treatment, not all of the new cells are healthy and functional. Antiretroviral treatment cannot
repair the damage inflicted by HIV to the immune system. For example, the thymus, a gland that is critical to the manufacture of healthy T cells, is gradually destroyed by HIV Thus, even if HIV could be eradicated entirely from a person's body,
that person would be expected to remain at least partially immune deficient and susceptible to certain opportunistic infections and cancers.
AmFAR has long suspected that this would be the case and has made important early investments in research on
immune restoration, in the hope that HIV's damage to the immune system need not be permanent. In November 1993, the
Foundation devoted an entire targeted grants cycle to this issue, awarding over $900,000 to ten research teams. Among
them, that of Dr. Andre Nahmias of Emory University used its AmFAR Basic Science Grant to perfect a surgical technique
for thymus transplantation. In an animal model, as well as a pilot trial in humans, Dr. Nahmias' thymus transplants
produced new, fully functioning T cells.
However, in 1994, when Dr. Nahmias received his grant, the protection offered by today's new antiretroviral drug
combinations was not available, and the restoration of his patients' immune systems was therefore only temporary. Any
gain in immune function was swiftly suppressed by HIV's relentless destruction of immune cells. Now, because HIV can be
controlled with potent antiretroviral treatments, immune restoration can be evaluated in combination with these treatments. With the help of our supporters, we hope to invest $1 million in grants awarded specifically to explore various
approaches to immune restoration for people on potent antiviral treatments.
AmFAR is making a similar investment in vaccine research for without a safe and protective vaccine, the spread of HIV
cannot be stopped-no matter how good our treatments are. Without a vaccine, treatment will not only have to continue
indefinitely in ever increasing numbers of patients, but its long-term costs will immeasurably increase the epidemic's overall
economic burden. In developing countries, even the simplest and least expensive treatments are already out of reach of
most people. In addition, the likelihood that multi-drug-resistant strains of HIV will develop also increases with time.
Ultimately, given the global environment in which we live, such new strains of HIV will spread to every community in every
nation. Our goal must be to control HIV spread worldwide as soon as possible. Without a vaccine, we can't.
AmFAR's investment in the quest for a protective anti-HIV vaccine dates back to 1986, when the Foundation funded
research carried out by Dr. Murray B. Gardner of the University of California, Davis, and Dr. Nancy T. Chang of the Baylor
College of Medicine in Houston (see sidebar).
*0O: AmFAR Plays a Lead Role in Vaccine Research
* 0
* In 1996, AmFAR helped fund a study designed to make a thorough assessment of the current state of HIV vaccine develop* ment. Written by the AIDS Vaccine Advocacy Coalition and entitled, Industry Investment in HIV Vaccine Research, it was
* the first comprehensive examination of existing private-sector HIV vaccine research and development. Published in Decem* ber 1996, the report put forward a series of policy recommendations f:or industry and government and was immediately:
0~
*circulated among high-ranking AlDS policy makers, including the Presidential Advisory Council on AIDS/HlV Harold Varmus,.
* Director of the National Institutes of Health; and David Baltimore, Director of the NIH initiative on HIV vaccine research.~
*Specifically, the report called upon the President to "make the development of a safe, effective and inexpensive vaccine by the
oyear 2007 a national priority." Last May, during a commencement address at Morgan State University in Baltimore, Presi* 0
* dent Clinton made just such an announcement.

(Continued from page 2)
Many other scientists have followed his lead and
are now using the gene gun. Dr. Johnston has
reported that for injection with a syringe, one
needs much more DNA to stimulate the same level
of immunity against bacterial infections in mice.
Robert F. Siliciano, M.D., Ph.D., John Hopkins
University School of Medicine: CD4+ T Cell
Responses to HIV-1 in Natural Infection (1991).
Dr. Siliciano showed that utilization ofgpl20, the
outer envelope of HIV, as was done in AIDS vaccine field trials, may actually lead to the death of
the very T cells that one is trying to protect. This
can occur as this viral protein binds to CD4+ T
cells, making them "bystander" targets for
destruction by killer T cells. Recognition of this
process has helped identify those AIDS virus
proteins that are more appropriate for vaccine
preparations, and eliminate others that may
actually be harmful.
Luis D. Giavedoni, Ph.D., University of California, Davis, School of Veterinary Medicine:
Immune Enhancing and Attenuating Effects of
Interferon-gamma (1993, an AmFAR Scholar
Award). An AmFAR Scholar working in the laboratory of Professor T. Yilma at the University of
California, Davis, Dr. Giavedoni engineered a new
type of vaccine against SIV, the simian (monkey)
equivalent of HIV-2, and demonstrated its efficacy in these animals. He built upon the work of
others in first deleting the viral gene nef, thereby
blocking the ability of the virus to cause disease,
at least in adult monkeys, without reducing its
ability to stimulate the immune system. He then
went on to add a gene for gamma-interferon to
the mutant virus. Expression of interferon further reduced the risk of infection from the
mutant virus vaccine, while increasing its ability
to induce a natural immune response.
Philip L Johnson, M.D., Children's Hospital
Research Foundation: Immunization for AIDS
by AAV-Mediated Gene Transfer (1992). Dr.
Johnson utilized the mechanics of gene therapy
to transfer genes coding for the production of
certain pieces of HIV protein directly into cells.
By this method, he turned these cells into factoies capable of constantly manufacturing small
amounts of vaccine material. Dr. Johnson accomplished his study using an adeno-associated virus
(AAV), which is harmless to humans, but capable
of entering their immune system cells. This strategy is being tested against SIW the virus that causes
AIDS in monkeys.
Samuel C. Kayman, Ph.D., Public Health
Research Institute of New York: Presenting
Conformation- and Glycosylation-Dependent
Epitopes (1994, an AmFAR/Ronald Harf Memorial Scholar Award). Dr. Kayman showed that
the serum of a laboratory worker infected with
HIV contained antibodies that are highly
effective in neutralizing several strains of HIV
Working with Abraham Pinter, Ph.D., one of
AmFAR's earliest grantees, Dr. Kayman demonstrated that these antibodies block a specific por
tion of the HIV coat protein called V1/V2. Their
studies suggest that vaccines which stimulate a
person to make antibodies against the V1/V2
region will induce broadly protective responses.
Paul A. Johnson, Ph.D., University of California, San Diego: HSV-HIV. A Safe, Live and
Effective Vaccine (1995, an AmFAR/Metropolitan Life Foundation Grant). Dr. Johnson is
constructing an HIV vaccine by combining parts
of two viruses, HIV and HSV, the cold sore virus
herpes simplex virus. The HSV-disease-causing genes removed-will carry small, harmless
pieces of HIV to the immune system, preparing
the immune system for defense against infectious
HIV. Because the vaccine is actually a virus, it will
more closely simulate infection with HIM. Dr.
Johnson's research should aid in the design of an
effective vaccine for HIV, as well as a better understanding of herpes viruses.
Baek Kim, Ph.D., University of Washington, Seattle: A New Anti-HIV Strategy: Arresting Viral
Evolution (1997, a Gift for Life Research Grant).
Dr. Kim plans to identify those natural and
lab-induced mutations in the reverse transcriptase
(RT) of HIV which lead to enhanced faithfulness
of viral growth. According to Dr. Kim, "A vaccine might be developed with an HIV variant
whose mutant RT has greatly increased replicated
fidelity and could not rapidly generate the requisite genomic diversity to evade the host immune
response and/or standard anti-viral therapies.
This type of disabled virus, which would not
escape from selective pressures by generating
resistant variants, would minimize safety concerns
regarding production of an attenuated virus
vaccine."
This listing was compiled in November 1997 with
the assistance of Dr. Jeffrey Laurence, AmFAR's
Senior Scientific Consultant for Programs. A listing of those proposals that are to be funded over
the next few months as a result of AmFAR's new
vaccine initiative will appear in the next issue of
the Newsletter.

"We applaud the president's vaccine initiative, but stress that
this project will require a large infusion of federal money,
which must not be siphoned from other programs that support people living with HIV and AIDS.... The government
cannot neglect the housing, drug assistance and other social
service needs this epidemic creates for thousands of Americans. Nor can we reduce our commitment to continued
research in basic science, development of AIDS treatments,
and HIV-prevention strategies." - Winnie Stachelberg,
Legislative Director of the Human Rights Campaign, as
reported in the Summer 1997 issue of HRC Quarterly.
"HIV vaccine development will benefit greatly from what
was learned during the first decade of HIV vaccine research
and particularly from an evolving knowledge of the pathogenesis of HIV and other viruses, and a better understanding of immune function. This is not to imply an abrupt
alteration in what must be a continuing evolution in concept
and practice, but rather to emphasize that many targets and
objectives that were only minor during the first decade will
become major in the second decade." -Maurice R. Hilleman,
Merck Institute for Therapeutic Research, Merck Research
Laboratories, "Whether and when an AIDS vaccine?" in the
November 1995 issue of Nature Medicine.
"The question here is not whether the treatments that are
currently available for AIDS do enough, or whether there is
enough to go around. The question is whether we have a
need for a qualitatively different approach to AIDS. For any
particular individual, the need for an AIDS vaccine might
only become real when the vaccine actually exists. Vaccines
may be the only realistic way of eradicating AIDS; they should
be developed for use throughout the world and they should
be made accessible to all." - Adrian Marinovich, AIDS Vaccine Advocacy Coalition (AVAC)
"An ideal vaccine to prevent infection with HIV-1 should be
safe, easy to administer, stable under adverse storage conditions, inexpensive, and capable of inducing long-lasting immunity against a broad spectrum of strains of HIV- 1. This is
a challenging list of qualities, given the complex biologic
features of HIV-1 infection. Conquering this problem will
require the cooperation of many nations and ethnic groups,

representing many different lifestyles and perspectives and
using diverse approaches." -Barney S. Graham, M.D., Ph.D.,
and Peter E Wright, M.D., Vanderbilt University School of
Medicine, Nashville, "Candidate AIDS Vaccines," in the Nov.
16, 1995 issue of The New England Journal of Medicine.
"In a time when a good part of our community has seen the
pall of discouragement lifted, we must fight to ensure that
the other part also enjoys a renewed sense of hope. We need
a vaccine. We need more effective treatments. We need to
stop the needless deaths that steal away the hopes and dream
of our nation. We need an end to AIDS as we know it. All of
this we can achieve, but only through the continued commitment of our elected officials, and under the watchful eyes
of all AIDS advocates worldwide." - Daniel Zingale,
Executive Director of AIDS Action, in the July 1997 issue of
the Journal of the International Association of Physicians in
AIDS Care, p. 3 7.
"Although there is incomplete understanding of how the
immune system responds to and fights HIV, we believe a
vaccine for AIDS will be possible.... NIAID supports a large
and expanding program of preclinical and clinical research
that is attempting to generate immunity to HIV in humans
using a wide variety of vaccine approaches." -Jack Killen,
M.D., Director, Division of AIDS, National Institute of
Allergy and Infectious Diseases, National Institutes of Health,
November 1997.
"Many countries have a Ministry of Science that tries to centralize scientific decision making and funding. In the United
States we have scientific programs in many different government agencies, as well as in industry and the not-for-profit
sector. That means that if somebody has an idea and they
send it to the NIH, and the NIH says it's a lousy idea, that
person can go to other funding sources. Many ideas are
funded that way. And that's terrific, because it means that
there is no orthodoxy. And it also keeps NIH more flexible,
because once NIH becomes too rigid or orthodox, there will
be others to fund more innovative research." - David
Baltimore, Ph.D., Director, National Institutes of Health AIDS
Vaccine Advisory Committee, quoted from an interview in
the IAVI Report, Vol. 2, No. 2, Summer 1997, p. 7.

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