Eradicating HIV Reservoirs
Figure 1. The HIV latent reservoir. Infection of CD4+ T cells by HIV will result in cell death or apoptosis in most cells. However, some cells will return to a quiescent state, transitioning into a memory CD4+ T cell. These cells contain an integrated copy of the viral genome (red) within their DNA (black) and are transcriptionally silent with no viral gene expression.
Cure Strategy: Eradicating the HIV Reservoirs
HIV is able to remain a chronic, life-long infection due to its ability to stay hidden within infected blood cells. These cellular “reservoirs” contain the genetic code of HIV. They remain invisible to our body’s immune defenses, and are not sensitive to anti-HIV drugs.
Latent reservoirs of HIV are located throughout the body, including the brain, lymphoid tissue, bone marrow, and the genital tract. These reservoirs persist, even in the presence of Highly Active Antiretroviral Therapy (HAART), today’s standard of care. While HAART is able to deplete the reservoir, it does so very slowly. Mathematical models have shown that most patients would have to be on HAART for 60-80 years before their HIV reservoirs are depleted.
One proposed eradication strategy is to activate these latently infected cells in the continued presence of HAART. The rationale for the strategy is two-fold. By stimulating latently infected cells to replicate and express the virus, such cells will die more rapidly [HIV-induced cell death]. Once the cellular reservoirs begin producing HIV, the infected cells will be recognized by the immune system. The key to this strategy is the simultaneous administration of an activating agent concurrently with HAART, and perhaps other therapies to prevent new or spreading infection.
Figure 2. Targeting the viral reservoir. Treatment with prostratin will result in activation of latent viruses, inducing viral gene expression. A combination approach will include HAART and additional compounds that may result in enhanced immune responses, inhibiting new infections and increasing HIV-induced cell death.
AIDS Research Alliance is developing the drug candidate prostratin, which research suggests activates latently infected cells to produce virus. Our goal is to target these cells using a combination approach that will purge virus from the latent reservoirs.
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AIDS Research Alliance & HIV Reservoir Bibliography
Scientists at AIDS Research Alliance co-authored the following articles with collaborating researchers:
- Biancotto, A., J. C. Grivel, F. Gondois-Rey, L. Bettendroffer, R. Vigne, S. Brown, L. B. Margolis, and I. Hirsch. 2004. Dual role of prostratin in inhibition of infection and reactivation of human immunodeficiency virus from latency in primary blood lymphocytes and lymphoid tissue. J Virol 78:10507-10515.
- Hezareh, M. 2005. Prostratin as a new therapeutic agent targeting HIV viral reservoirs. Drug News Perspect 18:496-500.
- Hezareh, M., M. A. Moukil, I. Szanto, M. Pondarzewski, S. Mouche, N. Cherix, S. J. Brown, J. L. Carpentier, and M. Foti. 2004. Mechanisms of HIV receptor and co-receptor down-regulation by prostratin: role of conventional and
- Kitchen, S. G., N. R. Jones, S. LaForge, J. K. Whitmire, B. A. Vu, Z. Galic, D. G. Brooks, S. J. Brown, C. M. Kitchen, and J. A. Zack. 2004. CD4 on CD8(+) T cells directly enhances effector function and is a target for HIV infection. Proc Natl Acad Sci U S A 101:8727-8732.
- Korin, Y. D., D. G. Brooks, S. Brown, A. Korotzer, and J. A. Zack. 2002. Effects of prostratin on T-cell activation and human immunodeficiency virus latency. J Virol 76:8118-8123.novel PKC isoforms. Antivir Chem Chemother 15:207-222.
- Rullas, J., M. Bermejo, J. Garcia-Perez, M. Beltan, N. Gonzalez, M. Hezareh, S. J. Brown, and J. Alcami. 2004. Prostratin induces HIV activation and downregulates HIV receptors in peripheral blood lymphocytes. Antivir Ther 9:545-554.
- Witvrouw, M., C. Pannecouque, V. Fikkert, A. Hantson, B. Van Remoortel, M. Hezareh, E. De Clercq, and S. J. Brown. 2003. Potent and selective inhibition of HIV and SIV by prostratin interacting with viral entry. Antivir Chem Chemother 14:321-328.