Elimination of the Latent Reservoir for HIV-1 Requires Induction of Cytolytic T Lymphocyte Responses
Liang Shan*, K Deng, C Durand, A Rabi, J Blankson, and R Siliciano
Johns Hopkins Univ, Baltimore, MD, US
Background: HAART suppresses HIV-1 replication but cannot eliminate the virus because HIV-1 establishes latent infection, predominantly in resting memory CD4+ T cells. Interruption of HAART leads to rapid rebound of viremia from this and possibly other stable reservoirs. Life-long ART is therefore required. Efforts to purge the latent reservoir have focused on reactivating latent proviruses without inducing global T cell activation. However, the killing of the infected host cells after virus reactivation, which is essential for elimination of the reservoir, has not been assessed. If the reactivation latent HIV-1 does not cause the death of the infected host cells, this eradication strategy will fail.
Methods: In this study, we generated latently infected resting CD4+ T cells in vitro from primary CD4+ T cells from patients on HAART. Latently infected resting CD4+ T cells were treated with suberoylanilide hydroxamic acid (SAHA), an HDAC inhibitor that reactivates latent HIV-1 without inducing global T cell activation. Death of infected CD4+ T cells was monitored with or without the presence of autologous CD8+ T cells from patients on HAART.
Results: After reversal of latency, infected resting CD4+ T cells survived despite viral cytopathic effects (CPE), even in the presence of autologous CD8+ T cells from most patients on HAART. Killing of infected cells was observed only at high E:T ratios after a longer period of co-culture. Antigen-specific stimulation of CD8+ T cells before co-culture partially restored the cytolytic T lymphocyte (CTL) functions and led to efficient killing of latently infected cells.
Conclusions: Resting CD4+ T cells latently infected with HIV-1 will not be killed by either viral CPE, or host CTL responses after virus reactivation. Stimulating HIV-1-specific CTL prior to reactivating latent HIV-1 may be essential for successful eradication efforts and should be considered in future clinical trials.