Speaker
Description
Although antiretroviral therapy (ART) can effectively suppress HIV replication, infection cannot be eliminated due to the presence of long-lived, latently infected cells. Treatment interruption leads to the reactivation of latently infected cells and subsequent viral replication in plasma, which may replenish the population of long-lived latently infected cells. Understanding the timing of establishment, rate of turnover, and reactivation potential is key to rational targeting of the latent reservoir.
We analysed data from three cohorts of macaques that were infected with either a barcoded SIV or barcoded SHIV. Using mathematical modelling, we compared the pattern of barcodes in plasma virus at different sampling times before ART with barcodes that appeared during rebound. We found that the virus present at the time of ART initiation was the major source of the virus that rebounded during later treatment interruption. However, the analysis of cell-associated SIV DNA sampled during ART suggested that the bulk of proviral DNA is laid down at the peak of viral load in acute infection, with much smaller contributions by the virus present at the time of ART initiation. Two cohorts also resumed therapy after the first ATI and subsequently re-interrupted for a second ATI. Again, the source of the rebounding virus was primarily from virus replicating at the time of the most recent ART initiation.
Our modelling has shown that the different temporal origins of the rebounding and proviral reservoir can be explained by a higher turnover of the reactivatable reservoir compared to the total proviral DNA during the active replication of virus in plasma, possibly due to varying degrees of reactivation competency. Understanding the mechanisms of formation of the rebound competent reservoir will be critical for developing an HIV cure.
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