Genetic characterization of viral blips in patients following suppressive HIV ART.
Jhamba, Lindiwe Amanda.
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Antiretroviral therapy (ART) has resulted in the decline of HIV-related mortality worldwide. On initiating treatment, most patients can suppress plasma viral RNA to undetectable levels (<20 copies/mL). Patients on ART frequently experience intermittent viremia (viral blips), however the genetic nature and source of these rebounding viruses while on suppressive ART remains unclear. The study of these genetic characteristics would be essential in the development of targeted vaccines and adjunct treatments. We identified four HIV-1 subtype C infected women from the Females Rising through Education, Support and Health (FRESH) acute infection cohort who experienced viral blips following suppressive ART (median 584 days). Two participants initiated treatment during the chronic infection phase (~625 days post detection) and the other two initiated treatment immediately upon first HIV-1 RNA detection. RNA was extracted from stored plasma samples of participants’ transmitter/founder (T/F) virus (~3 days post detection), pre-treatment initiation and during viral blips (>2,000 copies/mL). Gag and env genes were amplified by single genome amplification followed by sequencing. The protease and reverse transcriptase region of the pol gene were also amplified and bulk sequenced. Phylogenetic relatedness and genetic differences were visualized using Maximum-likelihood trees and Highlighter plots respectively (Los Alamos HIV-1 database). The gag and env blip sequences of the acute-treated participants were similar to those of the T/F, while those of the chronic-treated participants were genetically distinct from the T/F but similar to the pre-treatment initiation virus (PreART). In the acute-treated participants, all transmitted HLA-associated gag cytotoxic CD8+ T lymphocyte (CTL) escape identified was retained in the blip-derived sequences, however the chronic-treated participants experienced an increase of ~0.8% CTL escape at the blip time point. This increase coupled with development of a reduced replication capacity mutation (HLA-B*57:01/58:01 T242N), may be indicative of immune pressure prior to ART initiation. Mutations associated with bnAb escape in the CD4 binding, gp120/gp41 and V1V2 sites were identified only in the PreART and blip sequences of the chronic-treated participants, whereas the acute-treated retained the same amino acid residues at T/F and blip. With the exception of one chronic-treated participant who developed mutations associated with resistance to efavirenz, the viral blips were not associated with mutations linked to drug resistance. This data suggests that those who initiate treatment late are less likely to benefit from an immune response-inducing vaccine or bnAb therapy.