Prostratin / HIV Viral Reservoirs FAQs

1. What are the HIV viral reservoirs?

2. When are the HIV reservoirs formed?

3. What happens to the reservoirs of people on HAART?

4. Why should we attack the reservoirs?

5. What determines the rate at which the reservoirs are depleted?

6. Does current HAART stop “adding water to the sink”?

7. How can we stop residual “filling of the reservoir”?

8. What strategies will “empty the reservoir faster”?

9. What is prostratin?

10. Can prostratin increase the decay rate of reservoirs?

11. What has ARA done with prostratin?

12. Can we try prostratin now?

13. What does ARA plan next?

14. How can you help?

It is now believed that HIV stays hidden throughout the bodies of people infected with the virus in “reservoirs” comprised of long-lived blood cells.  The cells are infected with HIV, yet the virus is dormant – or latent – within these cells, so the cells appear to be “normal” and thus escape the reach of anti-HIV drugs and the immune system. These “reservoirs” of HIV are located throughout the body, including in the brain, lymphoid tissue, bone marrow and genital tract. These reservoirs persist, even in the presence of Highly Active Antiretroviral Therapy (HAART).

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.  So gradual in fact, that for most patients, the reservoirs would not be expected to be “empty” until after decades (60-80 years) of therapy.  For some patients who maintain well-suppressed viral load measurements (consistently under 50 copies/ml at each test), the reservoir may empty considerably more quickly, but years of therapy would still be required. 

Why should we attack the reservoirs?

When someone who is taking HAART stops treatment, the dormant virus springs into action and floods their bodies with millions of new viral copies.  Previous studies demonstrated that in order to deplete the reservoir completely, patients would need to be treated for decades with HAART. But long-term treatment of patients with HAART is undesirable given the side effects, the expense and the eventual emergence of drug resistance due to HIV’s ability to mutate. 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 reservoir of water filled by a stream. The stream that fills the reservoir represents continuing viral replication that occurs in HIV positive individuals, including most of those on HAART. The rate at which the reservoir decreases is related to two factors: Continual filling by the incoming stream and the rate of “evaporation,” or naturally occurring depletion of the reservoirs.

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

For most patients, HAART does not “slow” the incoming stream so the evaporation process is partially compensated by new virus.Therefore, HAART decreases viral replication greatly but does not suppress it completely.

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

As newer classes of drugs are added to HAART, ARA expects that HAART will eventually be able to stop residual filling of the HIV reservoirs, forcing the reservoirs to decrease more rapidly. However, this process will still be slow and require years of HAART, with its attendant side effects and the potential for development of drug resistance. ARA, among other researchers, has been searching for ways to speed the natural depletion, or evaporation, of the reservoirs in an effort to eliminate remaining virus.

What strategies will empty the "reservoir" faster?

One possible strategy involves activating the latently infected cells in the continued presence of HAART. The rationale for using a latent virus activation strategy is two-fold.  By stimulating latently infected cells to replicate and express infectious virus, such cells will die more rapidly in the process.  Once the cells begin replicating, the cells will present viral components (such as the viral envelope) on their surfaces, making them more detectable by the immune system and rendering them more susceptible to targeted destruction by potential therapeutics.  The key to this strategy is the simultaneous administration of the activating agent concurrently with HAART to prevent the infection of uninfected cells.

ARA’s research using prostratin has taken a huge step forward in reservoir depletion strategy. [LINK TO PROSTRATIN] Other researchers have tried ways to attack HIV reservoirs.  Early methods included an attempt using interleukin-2 (IL-2) and IL-2 along with anti-CD3 [LINK TO GLOSSARY]  antibodies. Despite initial promising indications, the virus rebounded in patients once treatment was stopped.  Researchers in Texas tried to eliminate the HIV reservoir using valproic acid on four HIV-positive individuals with undetectable plasma viral loads. Valproic acid, an anti-convulsant, is a drug in wide use for epilepsy and bipolar disorder that has shown the ability to block the system that cells use to keep DNA “quiet.”  The researchers observed a statistically significant decrease in frequency of infection in resting CD4+ cells in three of the four patients.  The Free University of Brussels looked at the use of prostratin with valproic acid and found that the combination of prostratin and valproic acid was more effective than either compound alone.

What is prostratin?

Dr. Paul Alan Cox, an ethnobotanist who routinely explores the world’s ecosystems to study native pharmacology, came across healers in Western Samoa who were using a tea made from the bark of a small native tree known as the mamala to treat a disease they called fava sama sama - hepatitis. Samples of this remedy 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. Their initial work suggested that prostratin could be used to activate viral reservoirs.

Can prostratin increase the decay rate of reservoirs?

ARA has initiated a number of research collaborations to examine the potential use of prostratin as part of a Reservoir Ablation Strategy (RAS). These collaborations include 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) and Michealangelo Foti (University of Geneva, Switzerland). 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 development is exciting because it attacks the virus at a different stage than the other four classes of FDA-approved anti-HIV drugs. It also appears to work on a cellular target rather than a viral target. 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. The findings from these studies are moving ARA closer to determining if prostratin’s unique properties in cell cultures can be used to treat HIV in humans.

What has ARA done with prostratin?

Based on encouraging preliminary data, ARA was awarded an exclusive license by the U.S. National Institutes of Health (NIH) to develop prostratin. The license was granted in 2001 based on ARA’s drug research expertise, our leadership position in the community and our proven reputation for facilitating collaboration among researchers and scientists. In 2001, ARA was awarded an NIH grant under the DART program (NIH-DART) to perform pre-clinical studies for prostratin.

Can we try prostratin now?

Prostratin is not yet ready for human tests.  There are still questions of safety and efficacy that must be answered. ARA is following an aggressive scientific plan to answer those questions and move prostratin forward to clinical trials.

What does ARA plan next?

At the beginning of 2006, AIDS Research Alliance engaged one of the world's largest pharmaceutical research and development services companies to complete pre-clinical research on prostratin (including additional toxicology studies). The experiments included in the study are required for submission of an Investigational New Drug (IND) application to the Food and Drug Administration (FDA) and initiation of a Phase I human clinical trial.  These studies, at a projected cost of $1.2 million, are scheduled to be concluded by Fall 2006. If all goes well, limited Phase I trials will begin, possibly testing of HIV levels in gut-associated lymphoid tissue, in collaboration with Dr. Peter Anton of UCLA (also a member of ARA’s Scientific Advisory Committee).

How can you 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 positive people everywhere and possibly ending this pandemic. We hope that prostratin may be a major tool in the arsenal against HIV, and we’re funneling critical resources into moving the compound forward swiftly and safely, but we need your support.

Moving promising drugs forward from test-tube studies to human clinical trials requires millions of dollars. Your generosity helps fund important and 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.



 

http://www.usatoday.com/news/health/aids/2001-12-14-aids-samoa.htm
http://www.time.com/time/reports/heroes/plant5.html
http://www.amfar.org/cgi-bin/iowa/programs/researchb/record.html?record=176 http://www.forbes.com/global/2002/1125/076.html
[ PROSTRATIN NEWSLETTER PDF]
[ A&U ARTICLE]
[Glossary Medical Terms]

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