HIV rebounds from latently infected cells, rather than from continuing low-level replication

Abstract

Rapid rebound of plasma viremia in patients after interruption of long-term combination antiretroviral therapy (cART) suggests persistence of low-level replicating cells or rapid reactivation of latently infected cells. To further characterize rebounding virus, we performed extensive longitudinal clonal evolutionary studies of HIV env C2-V3-C3 regions and exploited the temporal relationships of rebounding plasma viruses with regard to pretreatment sequences in 20 chronically HIV-1-infected patients having undergone multiple 2-week structured treatment interruptions (STI). Rebounding virus during the short STI was homogeneous, suggesting mono-or oligoclonal origin during reactivation. No evidence for a temporal structure of rebounding virus in regard to pretreatment sequences was found. Furthermore, expansion of distinct lineages at different STI cycles emerged. Together, these findings imply stochastic reactivation of different clones from long-lived latently infected cells rather than expansion of viral populations replicating at low levels. After treatment was stopped, diversity increased steadily, but pretreatment diversity was, on average, achieved only >2.5 years after the start of STI when marked divergence from preexisting quasispecies also emerged. In summary, our results argue against persistence of ongoing lowlevel replication in patients on suppressive cART. Furthermore, a prolonged delay in restoration of pretreatment viral diversity after treatment interruption demonstrates a surprisingly sustained evolutionary bottleneck induced by punctuated antiretroviral therapy.HIV-1 ͉ latent reservoir ͉ structured treatment interruption ͉ viral diversity ͉ coreceptor usage

Predicting the outcomes of treatment to eradicate the latent reservoir for HIV-1

“…Studies of treatment intensification (44,45), viral evolution during ART (46,47), and in vitro antiviral efficacy (48,49) all support this assumption. Moreover, HIV persistence is widely believed to result solely from the long lifespan or proliferative ability of latently infected cells (3,50).…”

Paired quantitative and qualitative assessment of the replication-competent HIV-1 reservoir and comparison with integrated proviral DNA

“…Arguments against persistent low-level viral replication include the observation that further intensification of ART has no measurable effect (34,35). In addition, there is little evidence for viral evolution even after prolonged periods of ART (36). In contrast, the idea that the reservoir is maintained, at least in part, by the proliferation of latently infected cells is supported by the observation of increasing proportions of identical proviral sequences in circulating CD4 + T cells (15).…”

HIV Pathogenesis: Dynamics and Genetics of Viral Populations and Infected Cells

“…Their origin is unknown, but it can be speculated that they may arise from a very small fraction of infected cells that is capable of dividing and releasing virus but that do not die as a result of the expansion. Such clonal populations of virus can also be seen in the blood of patients who have stopped suppressive therapy after long-term suppression (Joos et al 2008), although the two phenomena have not yet been firmly connected. It seems likely that the last, apparently stable, phase of viremia on therapy reflects clonal viral populations, but this point remains to be established.…”