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Selectively Eliminating HIV-Latently Infected Cells Without Viral Reactivation
T-cell marker may take the "shock" out of "shock-and-kill" strategy
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CROI 2015, February 23-26, 2015, Seattle, Washington
Mark Mascolini
A newly confirmed molecular marker of latently HIV-infected memory CD4 cells may allow selective killing of those cells without reactivating HIV gene expression--taking the "shock" out of the "shock-and-kill" strategy to drain the latent T-cell reservoir [1].
Antiretroviral therapy cannot eliminate HIV because the virus survives long enough in infected CD4 cells to allow reversion to an invulnerable resting memory state, observed University of California, San Diego (UCSD) researchers who conducted this study. The proposed "shock-and-kill" strategy to dry up this reservoir would rely on reversing HIV latency in these cells, then killing the infected cells. But so far the agents used to activate HIV in resting cells have managed to wake up only a small fraction of latent virus.
Grant Campbell and UCSD colleagues noted that the X-linked inhibitor of apoptosis protein (XIAP) becomes upregulated in latently infected cell lines. They conducted this cell study to see whether they could identify XIAP in primary latently infected resting central memory CD4 cells and whether they could use this cellular flag to pinpoint and kill CD4 cells harboring latent HIV--without reactivating the virus.
The UCSD team isolated naive CD4 cells from HIV-negative people, infected them with HIV, and expanded them with IL-2 for 12 days. They isolated memory CD4 cells and exposed them to IL-7 for another 20 days. Then Campbell and colleagues used standard techniques to assess HIV integration and XIAP expression. Next they treated long-lived resting memory CD4 cells with an XIAP antagonist or an XIAP inhibitor. Finally, they used two methods to assess cell apoptosis.
After 32 days of infection, CD4 cells had a resting central memory phenotype and harbored the equivalent of 1 integrated copy of HIV DNA. XIAP expression proved significantly greater on HIV-infected resting memory CD4 cells than on uninfected CD4 cells (P < 0.05).
When the researchers targeted XIAP with an XIAP antagonist or inhibitor, they observed a significant dose-dependent increase in numbers of latently infected resting central memory CD4 cells undergoing apoptosis. They did not see the same thing in mock-infected cells. In addition, HIV p24 antigen expression did not increase in targeted CD4 cells, a finding indicating that HIV gene expression had not been turned on.
The researchers concluded that "latently infected central memory CD4 T cells have increased expression of XIAP" and that "targeting XIAP selectively eliminates HIV-infected cells without reactivation of HIV."
Reference
1. Campbel G, Bruckman R, Chu YL, Spector S. Selectively eliminating HIV latently infected cells without viral reactivation. CROI 2015. February 23-26, 2015. Seattle, Washington. Abstract 387.
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