What is the viral reservoir?

Highly active antiretroviral therapy (HAART), has dramatically improved the lives of many HIV+ people and has led to a substantial decline in AIDS and AIDS-related deaths in the United States and other developed countries. However, it’s now believed that HIV stay hidden in "reservoirs" comprised of long-lived blood cells. The virus is dormant within these cells, so the cells appear to be "normal" and escape the reach of anti-HIV drugs and the immune system. These "reservoirs" of HIV hide throughout the body, including the brain, lymphoid tissue, bone marrow, and genital tract.

When are the reservoirs formed?

The reservoirs are formed during the acute or initial phase of infection and are well established within several weeks of infection.

What happens to the reservoirs of people on HAART?

For patients on HAART, there is a very gradual decrease in the size of the reservoirs. But the decrease is very slow. In most patients, the reservoirs would be expected to be "empty" until after decades (60 years) of therapy. For some well suppressed patients who maintained viral load measurements constantly under 50 copies at each test, the reservoir may empty considerably more quickly, but still years of therapy would be needed.

Why should we attack the reservoirs?

When someone stops taking HAART, the sleeping virus springs into action and floods their bodies with millions of new copies. Previous studies demonstrated that in order to deplete the reservoir completely, patients should be treated for several years with HAART. Long term treatment of patients with HAART is undesirable given the side effects and the eventual emergence of drug resistance. Therefore, it is necessary to develop strategies to increase the turnover rate of the reservoir of latently infected cells.

What determines the rate at which the reservoirs are depleted?

The reservoir of HIV infected cells can be compared to a water reservoir filled by stream or aqueduct. The stream or aqueduct which "fill" the reservoir represents continuing viral replication that occurs even on HAART in most people. The rate at which the reservoir decreases is related to two factors; the continual filling by the incoming stream, and the rate of "evaporation" or natural slow depletion of the reservoir.

Does current HAART stop "adding water to the sink"?

Currently HAART for most patients does not "slow" off the incoming stream so the evaporation process is partially compensated by new virus. Therefore, HAART decreases virus replication greatly but does not suppress it completely.

How can we stop residual "filling of the reservoir"?

ARA expects that with newer HIV targets, HAART will unable to stop the residual fillings of the reservoir. Then the reservoir will decrease more rapidly. However, this process will still be slow and require years of HAART with its attendant side effects, and potential for development of resistance. ARA among others has been searching for ways to substantially speed up the natural depletion or evaporation of the reservoirs in an effort to eliminate the remaining virus.

How we can "empty the reservoir faster"?

One strategy might be the activation of latently infected cells in the continued presence of HAART. The rationale for a latent virus activation strategy is that, by stimulating latently infected cells to replicate and express infectious virus, such cells will die more rapidly and/or will present viral components (e.g., such as viral envelope) on their surfaces. This in turn will make such cells more detectable by the immune system and/or render them more susceptible to targeted destruction by potential therapeutics. Key to the strategy is to administer the activating agent concurrently with HAART to prevent the infection of uninfected cells.

Other researchers have tried to attack HIV reservoirs. The methods that seemed most promising were an attempt using interleukin-2 (IL-2)*, and another that used IL-2 along with anti-CD3* antibodies. Despite promising early results, the virus rebounded in patients once treatment was stopped.

*CD3 is a protein expressed at the surface of T lymphocytes (blood cells, mediator of immunity) and are involved in activation of these cells following antigen stimulation.

Anti CD3 antibody: antibody against CD3 proteins that activate T lymphocytes and immune response identical to antigen-induced immunity.

The uniformly exciting findings from these studies are moving ARA closer to determine if prostratin’s unique properties in cell cultures can be used to treat HIV in humans.

What is prostratin?

On a research trip to Western Samoa, Dr. Paul Cox, ethnobotanist from Brigham Young University, came across healers who were using a small native tree known as the mamala to treat a disease they called fiva samasama—yellowing fever, or hepatitis—made from its stem. The bark was being used to treat viral infections; the leaves were used to treat back pain and the root to alleviate diarrhea. Samples of these native remedies were sent to scientists at the U.S. National Cancer Institute (NCI), where plant-derived substances are routinely screened against different diseases. Dr. Michael Boyd and his colleagues at NCI isolated the active chemical from the remedy, prostratin and discovered its powerful effects against HIV, which suggested that prostratin could be used to activate viral reservoirs. Depending on the dose, prostratin both inhibits and stimulates HIV production in infected cultures.

Can prostratin increase the decay rate of reservoirs?

ARA has initiated a number of research collaborations to determine the potential effects of prostratin in human beings. These collaborations includes Drs. Jerome A. Zack (UCLA Center for AIDS Research), Eric de Clercq (Rega Institute in Belgium), Ivan Hirsch (The French National Institute of Health and Medical Research), Jose Alcami (Spanish Institute of Health), Michelangelo Foti (University of Geneva, Switzerland), and Copeland, Karen (University of Ottawa). Already, we have convincingly shown in test-tube studies that prostratin, when present at the time of introduction of HIV, prevents the virus from infecting cells and thus acts like an entry inhibitor. This is exciting because it attacks the virus at a different stage than the other three classes of FDA-approved anti-HIV drugs. It also appears to work on a cellular target rather than a viral target. If confirmed in ongoing experiments, this may mean that it’s more difficult for HIV to mutate around a cellular target and gain resistance.

More importantly, we've learned that prostratin can activate dormant virus from a number of different types of cells where HIV reservoirs lurk in the human body. Continuing studies with

Dr. Zack will look at the specific ways that prostratin activates HIV within these reservoirs.

What has ARA done with prostratin?

Based on encouraging preliminary data, ARA applied for the exclusive license from the U.S. Federal Government to develop prostratin. The license was granted this spring based on our drug research expertise, our leadership position in the community and our proven reputation for facilitating between many different groups of researchers and scientists.

Can we try prostratin now?

There is a lot of work still needed before prostratin can be tested in humans. ARA has developed an aggressive scientific plan to move prostratin forward to clinical trials. Our next round of studies should provide important data to help us determine if prostratin should and could safely proceed to human clinical trials as a way of eliminating the reservoir of latent HIV in infected individuals. ARA and UCLA will further study the effects of prostratin on various T-cell populations in animals to create a better picture of prostratin’s antiviral properties. Several additional potential reservoirs of latent virus have been discovered, and ARA will look at them to study their importance.

What does ARA plan next?

This fall, ARA will meet with FDA officials to determine the required studies necessary for a Phase I study (including additional toxicology studies). A test must be developed to measure plasma levels of prostratin, and finally, if all goes well, limited Phase I trials will begin. This trial will possibly involve testing of HIV tissue levels in gut-associated lymphoid tissue in collaboration with Dr. Peter Anton of UCLA (also a member of ARA’s Medical Executive Committee).

Why do we need your help?

The search for a cure for HIV infection must go beyond treatments that merely slow the virus down. Targeting HIV where it hides is crucial to improving the lives of HIV+ people everywhere and possibly ending this pandemic. We hope that prostratin may be a key tool in the arsenal against HIV and its hiding places, and we’re funneling critical resources into moving the compound as swiftly and safely forward as possible. But we can’t do this without your support.

Moving promising drugs forward from "test-tube" studies to human clinical trials requires hundreds of thousands of dollars. Your continued generosity helps fund important and very exciting research like prostratin, and helps pave the way for the total elimination of HIV from the human body. With your help, we are making a difference. For further information about Prostratin, you can download the Spring 2001 issue of SEARCHLIGHT, AIDS ReSearch Alliance’s periodic research journal.