Epigenetic Mechanisms of HIV-1 Persistence

Abstract

Eradicating HIV-1 in infected individuals will not be possible without addressing the persistence of the virus in its multiple reservoirs. In this context, the molecular characterization of HIV-1 persistence is key for the development of rationalized therapeutic interventions. HIV-1 gene expression relies on the redundant and cooperative recruitment of cellular epigenetic machineries to cis-regulatory proviral regions. Furthermore, the complex repertoire of HIV-1 repression mechanisms varies depending on the nature of the viral reservoir, although, so far, few studies have addressed the specific regulatory mechanisms of HIV-1 persistence in other reservoirs than the well-studied latently infected CD4⁺ T cells. Here, we present an exhaustive and updated picture of the heterochromatinization of the HIV-1 promoter in its different reservoirs. We highlight the complexity, heterogeneity and dynamics of the epigenetic mechanisms of HIV-1 persistence, while discussing the importance of further understanding HIV-1 gene regulation for the rational design of novel HIV-1 cure strategies.

Keywords: HIV-1 latency; HIV-1 persistence; epigenetics; reservoirs.

Figure 1

Fates of unintegrated HIV-1 DNA and respective contribution to viral persistence. Adapted from [38]. Following retrotranscription, the nuclear linear HIV-1 DNA can be integrated into the host genome as a provirus, can be degraded or can recombine or exploit host DNA repair machinery to generate functional 1-LTR or 2-LTR episomal circles from which transcription arises.

Figure 2

The 5′LTR is heterochromatized in HIV-1 latently infected CD4⁺ T cells. A multitude of interrelated epigenetic mechanisms cooperatively maintain the HIV-1 promoter in a heterochromatic architecture in latently infected CD4⁺ T cells. These include the position of repressive nucleosomes on the 5′LTR, the presence of repressive histone marks such as hypoacetylation or H3K9me3, the hypermethylation of two CpG islands surrounding the transcription start site and the involvement of lncRNA-like epigenetic mechanisms.

Figure 3

The multiple modes of CTIP2-mediated repression of HIV-1 gene expression in microglial cells. CTIP2 presents pleiotropic functions in HIV-1 gene repression in microglial cells. (A) CTIP2 and LSD1 bind the Sp1 sites in the 5′LTR. CTIP2 recruits sequentially HDACs and the HMT SUV39H1 that catalyzes H3K9me3. This mark is recognized by HP1 that recruits more units of SUV39H1 that spread the heterochromatic mark. In parallel, LSD1 recruits the hCOMPASS complex, containing notably the HMT SET1 that stimulates H3K4me3. (B) CTIP2 associated with HMGA1 stabilizes the inactive P-TEFb complex (composed of the small nuclear 7SK RNA, HEXIM-1 and LARP7 and MeCP2). (C) HIC1, CTIP2 and HMGA1 form a tripartite repressive complex that may be due to SIRT1 HDAC activity.