Speaker
Description
The latent viral reservoir (LVR) consists of transcriptionally-inactive HIV-1 proviruses within long-lived resting CD4+ T-cells, in which proviruses can persist even under fully-suppressive antiretroviral therapy (ART). The presence of this reservoir is the primary reason for viral resurgence upon ART interruption. Gaining a deeper understanding of proviral dynamics in the LVR is critical for the development of HIV cure strategies. We have developed a probabilistic framework to characterize clonal expansion as a key factor driving the expansion and maintenance of the LVR.
The common assumption that identical proviral sequences with unknown integration sites are clonal overlooks the possibility that they may represent independent integration events and remain identical by chance. Clonality is a pairwise attribute, not an intrinsic attribute of each provirus as implied by traditional measures of clonality. The probability that a pair of genetically identical proviruses ($I$) are clonal ($C$) can be written as $P(C \mid I) = \frac{P(I \mid C) P(C)}{P(I)}.$ Ignoring somatic mutation of integrated proviruses, we assume $P(I \mid C)=1.$ $P(I)$ is decomposed into $P(C) + P(I \mid \neg C) P(\neg C),$ where $P(C)$ and $P(\neg C)$ are determined by the coalescence — i.e., effective population size ($N_e$) and generation time — of cellular lineages in the LVR, and $P(I \mid \neg C)$ by the coalescence and mutation of viral lineages pre-ART. The relative contributions of these terms is determined by the proviral integration date, which we estimate by root-to-tip regression.
Analytically, we found that $P(C \mid I)$ was substantially lower for proviruses with integration dates closer to ART initiation. $P(C \mid I)$ increases with viral mutation rate, sequence length and viral $N_e$. These results imply that the role of clonal expansion may be overestimated in some contexts. We are presently applying this framework to proviral data from the RHSP and CAPRISA cohorts.
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