Mechanisms of HIV-1 Persistence and Post-Treatment Control
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CitationSharaf, Radwa. 2019. Mechanisms of HIV-1 Persistence and Post-Treatment Control. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences.
AbstractThe typical course following HIV-1 infection has been well-documented throughout numerous research studies. In this thesis, we focus on the mechanistic understanding of two atypical contrasting phenotypes that have not been well-studied; namely post-treatment control and persistent low-level viremia. The former, post-treatment control, was demonstrated in treated individuals who interrupt therapy, yet maintain viral suppression. We explored their proviral landscape and determined that levels of total, as well as intact, proviral genomes are significantly lower in post-treatment controllers, compared to non-controllers. Interestingly, the proportion of various proviral classes did not significantly differ between the two groups. We identified total proviral genomes as a biomarker to predict post-treatment control before therapy is interrupted. Additionally, to determine whether limited treatment interruptions led to an irreversible increase in the viral reservoir, we measured levels of integrated HIV-1 DNA before and after interruption and found that levels of integrated HIV-1 DNA returned to pre-treatment interruption levels after therapy was resumed. Furthermore, we studied the mechanism underlying persistent low-level viremia, which occurs in a subset of treated individuals with documented high levels of adherence, absence of drug-resistant viral variants and inability to suppress the viremia by treatment intensification. We found that plasma viremia is largely clonal and identified the matching proviral clone. Integration site analysis showed that transcriptional interference from the host gene into which the provirus was inserted regulated expression of the viral transcripts. Future studies of post-treatment controllers and individuals with persistent low-level viremia are needed to further our understanding of the mechanisms underlying HIV persistence and virologic control.
Citable link to this pagehttp://nrs.harvard.edu/urn-3:HUL.InstRepos:42029717
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