To date, the most beneficial treatment for an HIV-infected person is a powerful combination of drugs called HAART (highly active antiretroviral therapy). Although lifelong HAART decreases HIV in the blood to nearly undetectable levels, it does not eliminate the virus.
HIV is thought to have numerous sanctuaries or hiding places in the body, notably a small pool of white blood cells in the body known as resting CD4+ T cells. A recent study led by NIAID grantee Hui Zhang, M.D., Ph.D., from Jefferson Medical College of Thomas Jefferson University, implicates microRNAs (miRNAs, small RNAs that impair protein synthesis) in HIV’s ability to hide in resting CD4+ T cells. Researchers hope to manipulate the inhibitory effects of miRNAs on HIV and thus devise strategies to bring the virus out of hiding, making it vulnerable to drugs as well as to the body’s immune system.
When HIV hides in resting CD4+ T cells and does not multiply, the condition is called HIV latency. According to Opendra Sharma, Ph.D., a program officer in the NIAID Division of AIDS, “Latency is one of the main challenges in getting rid of the virus, because the virus becomes stably integrated in the human genomic DNA but does not replicate. In this state, HIV can evade both the immune system and antiretroviral drugs.”
The precise molecular mechanisms used by the virus to remain latent are still unknown, but Dr. Zhang and his colleagues have identified a cluster of miRNAs that interact with a region of the HIV genome. This interaction shuts off viral gene expression and protein production. As a result, HIV-infected cells do not display the antigenic proteins that make them visible to the immune system and to certain antiviral drugs, thereby maintaining viral latency.
“HAART only eliminates virus that comes out of these cells, it can not eliminate the latent HIV gene that is in resting CD4+ T cells,” says Diana Finzi, Ph.D., a program officer in NIAID’s Division of AIDS.
When Dr. Zhang and his colleagues treated resting CD4+ T cells taken from patients on HAART with specific inhibitors of miRNAs, 10 times more HIV was generated from these cells—HIV that in turn could be killed by HAART.
Researchers are hopeful that interfering with the function of these miRNAs might lead to new ways to flush HIV out of hiding. But little is known about miRNAs and how they function or influence human cell function. Also, HIV latency poses another problem. “In people on HAART, only one in one million cells have the latent virus,” notes Dr. Finzi. “Catching those rare cells is like trying to find a needle in a haystack. Inhibitors of the miRNAs will have to penetrate every single cell to get to the latently infected virus, and now that’s a very difficult prospect,” she adds.
Their research has uncovered another layer of complexity in the life cycle of HIV. Dr. Zhang and his team continue to study the role of miRNA in HIV latency and are hopeful that with continued work, miRNA inhibitors may be developed into a new therapeutic approach against the virus.
Zhang H et al. Cellular microRNAs contribute to HIV-1 latency in resting primary CD4+ T lymphocytes. Nature Medicine DOI: 10.1038/nm 639 (2007).
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Last Updated September 10, 2008