A major hurdle to curing people of HIV infection is the way the virus hides in a reservoir composed primarily of dormant immune cells. It is generally believed that HIV does not replicate in these cells because the virus depends on active cellular machinery to do so. Now, two new papers by NIAID grantees propose that the virus itself--not cells--controls whether HIV is replicating, and that periods of latency paradoxically give the virus a survival advantage. The findings may explain why HIV cure strategies to awaken cells in the latent reservoir have not succeeded.
In the first paper, scientists at the Gladstone Institutes in San Francisco led by Leor S. Weinberger, Ph.D., demonstrated that HIV remains active as the cells it has infected transition to rest, suggesting the two processes are independent. Through computer modeling, the scientists identified the HIV protein Tat as the controller of the virus' on/off switch and found that manipulating Tat levels consistently changed the state of the virus. Conversely, modifying the state of a host cell had little to no impact on viral latency. To confirm their findings, the researchers applied synthetic biology to effectively decouple the virus and the cell and directly manipulate Tat. They found that altering Tat levels was sufficient to turn the virus on or off, but relaxing or activating the host cell had no effect on virus replication.
In the second paper, Gladstone scientists collaborated with the Wyss Institute at Harvard University to explain why HIV might have developed the capacity for latency. HIV usually enters people at mucosal surfaces, where there are relatively few target cells to infect. If HIV infected and killed the few available target cells there, it would die out. However, if HIV becomes latent in some mucosal tissue cells, it can remain latent until those cells migrate to other tissue with more target cells, boosting the odds for successful infection. Using mathematical models based on patient data, the researchers found that latency benefitted the virus overall, resulting in higher infection rates.
Materials provided by NIH/National Institute of Allergy and Infectious Diseases. Note: Content may be edited for style and length.
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