A cure for HIV appears more scientifically feasible than ever, and its urgency remains undiminished despite highly effective antiretroviral treatment, according to presentations at AIDS 2010 and at a preceding meeting sponsored by the International AIDS Society, titled "Toward a Cure: HIV Reservoirs and Strategies to Control Them."
While ART has dramatically reduced illness and increased survival, people with HIV still do not achieve a normal life expectancy, Sharon Lewin from Monash University in Melbourne said at the AIDS 2010 opening plenary.
A growing body of evidence indicates that chronic immune activation and inflammation due to persistent HIV infection can lead to a host of problems throughout the body despite suppressed viral load and well-preserved immune function. In addition, even modern antiretroviral medications still have long-term toxicities. Finally, funding universal life-long treatment for millions of people worldwide appears increasingly unsustainable.
In the November 27, 2010, issue of AIDS, for example, Tae-Wook Chun and Anthony Fauci from NIAID and colleagues reported that even people who started antiretroviral drugs during acute HIV infection and maintained viral load suppression for a decade still had detectable viral genetic material in resting CD4 cells using the most sensitive tests. One man with a very small reservoir of CD4 cells harboring latent HIV -- estimated at 1 per 1.7 billion -- still experienced viral rebound 50 days after interrupting ART.
A growing number of researchers from government, academia, and the pharmaceutical industry are looking at a variety of approaches to either completely eradicate HIV from the body or achieve a functional cure by disabling the virus or strengthening the immune system.
Investigators have looked at a variety of agents that can activate resting cells and force gene expression and release of latent virus, making it susceptible to antiretroviral drugs. Several studies have shown that histone deacetylase (HDAC) inhibitors such as valproic acid and vorinostat can flush latent HIV out of hiding, and work is underway to develop related drugs that can safely be used by HIV positive people who remain healthy on ART.
Another strategy involves altering CD4 cells to make them resistant to HIV. This approach was inspired in part by the "Berlin Patient," an HIV positive man who received a bone marrow stem cell transplant to treat leukemia. Gero Hütter, a German hematologist, located a donor with the naturally occurring CCR5-delta32 mutation, which protects cells from HIV entry. Three years after the first transplant, the man shows no evidence of remaining virus in his blood, resting cells, or reservoir sites such as the gut.
While widespread bone marrow transplantation is not realistic, researchers have tried to build on this proof-of-concept in other ways, such as altering cells using gene therapy to make them HIV-resistant. One method now being studied in clinical trials involves removing CD4 T-cells from a patient, using zinc finger technology to remove a gene for the CCR5 coreceptor, and returning the altered cells to the body.
Altering the hematopoietic stem cells that give rise to CD4 cells and other immune cells would likely be a longer-lasting -- possibly lifelong -- approach. In the August 2010 issue of Nature Biotechnology, Paula Cannon from the Keck School of Medicine at the University of Southern California and colleagues reported that humanized mice given genetically engineered CCR5-deleted stem cells and then exposed to HIV showed little CD4 cell loss or disease progression.
In a related human study described in the June 16, 2010, edition of Science Translational Medicine, John Zaia and colleagues at City of Hope Medical Center tested a similar technique in four HIV positive people undergoing stem cell transplants to treat lymphoma.
Patients' stem cells were removed and altered in three different ways to make them resistant to HIV. After cancer chemotherapy destroyed the remaining immune cells in the body, the altered stem cells were reintroduced. The modified cells were successfully engrafted and no adverse side effects were seen. This particular approach, however, remains too risky for people who do not require such drastic therapy for a life-threatening condition.
This past June the National Institutes of Health announced the creation of a new public/private collaboration, named after Project Inform founder Martin Delaney, that will support research on HIV persistence and eradication. An initiative to fund cure research was also recently launched by amfAR.
Liz Highleyman (email@example.com) is a freelance medical writer based in San Francisco.
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