The replication-competent HIV-1 latent reservoir is primarily established near the time of therapy initiation

Abstract

Although antiretroviral therapy (ART) is highly effective at suppressing HIV-1 replication, the virus persists as a latent reservoir in resting CD4+ T cells during therapy. This reservoir forms even when ART is initiated early after infection, but the dynamics of its formation are largely unknown. The viral reservoirs of individuals who initiate ART during chronic infection are generally larger and genetically more diverse than those of individuals who initiate therapy during acute infection, consistent with the hypothesis that the reservoir is formed continuously throughout untreated infection. To determine when viruses enter the latent reservoir, we compared sequences of replication-competent viruses from resting peripheral CD4+ T cells from nine HIV-positive women on therapy to viral sequences circulating in blood collected longitudinally before therapy. We found that, on average, 71% of the unique viruses induced from the post-therapy latent reservoir were most genetically similar to viruses replicating just before ART initiation. This proportion is far greater than would be expected if the reservoir formed continuously and was always long lived. We conclude that ART alters the host environment in a way that allows the formation or stabilization of most of the long-lived latent HIV-1 reservoir, which points to new strategies targeted at limiting the formation of the reservoir around the time of therapy initiation.

Limited evolution despite years of measurable viremia in a cART-treated seronegative HIV-1 positive individual

“…The first of these features is rapid activation of the latent reservoir prior to effective viral suppression. As such, our findings supports the theory presented recently by Abrahams et al [6] of rapid reservoir turnover prior to effective viral suppression. What is more, our findings elucidate this new theory by indicating that the rate of latent cell activation is the key component in this proposed rapid turnover.…”

“…By comparing these dynamics to those observed in typical, seropositive HIV-1 individuals [4][5][6][7][8][9][10], this study provides a rare glimpse into the role that antibodies play in controlling HIV-1 infection. Furthermore, it allows us to explore the dynamics that underpin the formation and maintenance of the HIV-1 reservoir.…”

“…Furthermore, both ultrasensitive measures of HIV-1 RNA in the plasma of patients on long term cART [8] and the fact that years of cART are insufficient for a cure, indicate that the reservoir decays very slowly indeed. Recent work however, has challenged these perceptions, [5,6] revealing that the makeup of the latent reservoir typically matches viral strains that are circulating just prior to therapy. Only in a minority of individuals are the strains representative of those circulating throughout HIV-1 infection, pre-cART [6].…”

“…Recent work however, has challenged these perceptions, [5,6] revealing that the makeup of the latent reservoir typically matches viral strains that are circulating just prior to therapy. Only in a minority of individuals are the strains representative of those circulating throughout HIV-1 infection, pre-cART [6].…”

“…To explain these evolutionary findings, Abrahams et al [6] propose that cART alters the host environment in a way that allows the formation or stabilization of most of the long-lived latent HIV-1 reservoir. Furthermore, they describe how a mathematical model in which the turnover of latently infected cells is much faster prior to cART than during cART can explain how viral strains matching those circulating just prior to therapy are overrepresented in the reservoir.…”