Characterization of Cellular and Viral Factors that Define the Stability of the Latent HIV-1 Reservoir

Abstract

Human immunodeficiency virus (HIV) infection is a chronic viral illness that requires lifelong management due to the early formation of a latent viral reservoir within the patient’s CD4+ T cells. These latent infection events lay dormant within infected cells and reactivate stochastically or during periods of T cell activation presenting a major hurdle to the development of an HIV cure. As our understanding of the factors that contribute to HIV latency has evolved, we have started to appreciate latency as more than a chromatin regulation phenotype, due to the vast number of cellular factors that have been described to impact the establishment of latent infection. Additionally, the heterogeneity of described molecular changes in latently infected cells has further complicated analysis of HIV latency. Therefore, it is important to develop an understanding of the interactions of host cell and virus that ultimately lead to the establishment of a latent infection event. To this end, we characterized the host cell phenotype during latency, and the impact of viral proteins on the establishment of latent infections. Using this approach, we found that responsiveness of latent HIV infections to activating stimuli was directly linked to transcriptomic and proteomic changes within the infected cell, and that modulation of these changes could alter responsiveness of latent HIV proviruses to T cell activating stimuli. Additionally, we found that HIV Nef was able to modulate the establishment of latent infection, in a lineage dependent fashion, with HIV-1 Nef promoting active infection and HIV-2 Nef promoting latency establishment. Together these findings support the concept that HIV latency is established and maintained through alterations to the host cell that may occur during the initial infection event, although further work must be done to link these mechanisms. Therefore, it will be critical for future HIV cure strategies to account for alterations to the host cell phenotype during attempts to reverse HIV latency or enhance viral silencing. This additional step, modulation of the host cell phenotype, will be necessary to address the HIV latent reservoir and presents an exciting new direction in HIV cure research.