Progressive transformation of the HIV-1 reservoir cell profile over two decades of antiviral therapy

HIV-1 establishes a life-long reservoir of virally infected cells which cannot be eliminated by antiretroviral therapy (ART). Here, we demonstrate a markedly altered viral reservoir profile of long-term ART-treated individuals, characterized by large clones of intact proviruses preferentially integrated in heterochromatin locations, most prominently in centromeric satellite/micro-satellite DNA. Longitudinal evaluations suggested that this specific reservoir configuration results from selection processes that promote the persistence of intact proviruses in repressive chromatin positions, while proviruses in permissive chromosomal locations are more likely to be eliminated. A bias toward chromosomal integration sites in heterochromatin locations was also observed for intact proviruses in study participants who maintained viral control after discontinuation of antiretroviral therapy. Together, these results raise the possibility that antiviral selection mechanisms during long-term ART may induce an HIV-1 reservoir structure with features of deep latency and, possibly, more limited abilities to drive rebound viremia upon treatment interruptions.

Automated summary

Long-term antiretroviral therapy (ART) in HIV-1 infected individuals leads to significant changes in the viral reservoir profile, with intact proviruses preferentially integrated in heterochromatin locations. These intact proviruses are more likely to persist and avoid elimination compared to proviruses in permissive chromosomal locations. This altered viral reservoir structure may contribute to deep latency and reduced rebound viremia upon treatment interruptions.