Viral and host mediators of non-suppressible HIV-1 viremia

Abstract

Non-suppressible HIV-1 viremia (NSV) is defined as persistent low-level viremia on antiretroviral therapy (ART) without evidence of ART non-adherence or significant drug resistance. Unraveling the mechanisms behind NSV would broaden our understanding of HIV-1 persistence. Here we analyzed plasma virus sequences in eight ART-treated individuals with NSV (88% male) and show that they are composed of large clones without evidence of viral evolution over time in those with longitudinal samples. We defined proviruses that match plasma HIV-1 RNA sequences as ‘producer proviruses’, and those that did not as ‘non-producer proviruses’. Non-suppressible viremia arose from expanded clones of producer proviruses that were significantly larger than the genome-intact proviral reservoir of ART-suppressed individuals. Integration sites of producer proviruses were enriched in proximity to the activating H3K36me3 epigenetic mark. CD4+ T cells from participants with NSV demonstrated upregulation of anti-apoptotic genes and downregulation of pro-apoptotic and type I/II interferon-related pathways. Furthermore, participants with NSV showed significantly lower HIV-specific CD8+ T cell responses compared with untreated viremic controllers with similar viral loads. We identified potential critical host and viral mediators of NSV that may represent targets to disrupt HIV-1 persistence.

The histone methyltransferase SETD2 regulates HIV expression and latency

“…H3K36me3 modified histones mediate HIV integration in vitro [ 53 ], and HIV integration sites in vivo are enriched in H3K36me3 abundant regions [ 54 ]. Nevertheless, our data indicate that HIV integration is independent of H3K36me3.…”

Early antiretroviral therapy in SIV-infected rhesus macaques reveals a multiphasic, saturable dynamic accumulation of the rebound competent viral reservoir

“…Sequence analysis revealed residual plasma viremia on ART was due in each case to a single (but different) barcoded virus lineage in each of the 3 animals ( S3 Fig ). Although the current study did not include confirmatory integration site sequencing, we posit that the most plausible explanation for this residual non-suppressible viremia is that it reflects the cumulative virus production from an early established and clonally expanded infected CD4 + T cell population [ 34 , 40 ]. Interestingly, the virus in the remaining RM generated known drug resistance mutations [ 21 , 22 ] which caused a complete failure to suppress.…”

The sounds of silencing: dynamic epigenetic control of HIV latency

“…The chromatin landscape near the integration sites on HIV-1 latency can also play a role in restricting HIV reactivation. Studies of rare people with HIV (PWH) with nonsuppressible HIV-1 viremia (NSV) have shown that the integration sites of the intact producer provirus that are responsible for generating sequencing-matching plasma viruses in the circulation show significant enrichment of activating H3K36 methylation marks [ 34 ]. These findings align with a recent study showing that nucleosomes containing H3K36me3 are preferentially targeted by the HIV-1 preintegration complex [ 35 ].…”