Increased replication capacity following evolution of PYxE insertion in Gag‐p6 is associated with enhanced virulence in HIV‐1 subtype C from East Africa. Issue 1 (6th July 2016) - Aralaguppe, Shambhu G.
Abstract : Background: A lower virulence of HIV‐1 subtype C (HIV‐1C) is suggested to be related to the global dominance of HIV‐1C. In this observational study, combining in vivo (clinical monitoring) and in vitro (genotypic, biochemical, and phenotypic assays), we explored whether HIV‐1C from East Africa (HIV‐1CEA ) is more pathogenic due to the evolution of a PYxE‐insertion (CPYxEi ) in the gag‐p6 that also could affect the therapy response. Methods: HIV‐1B (n = 112) and HIV‐1CEA (n = 128)‐infected individuals residing in Sweden were analyzed with regard to Gag‐p6 genotype and clinically monitored. Based on the Gag‐p6 characteristics, three HIV‐1CEA and one HIV‐1 B patient‐derived p2‐INT‐recombinant virus (gag‐p2/NCp7/p1/p6/pol‐PR/RT/IN) were constructed to analyze viral growth kinetics (VGKs) and drug sensitivity assays. Reverse transcriptase (RT) from the same samples was cloned into the heterodimer expression plasmid (pRT6H‐PROT) to analyze catalytic efficiency of RT. Results: A higher viral failure rate and lower pre‐therapy CD4 + T‐cell counts were observed in HIV‐1CEA ‐infected patients compared to HIV‐1B‐infected patients. In Gag‐p6, PTAP‐duplication was more common in HIV‐1C. HIV‐1CEA ‐infected patients with signature CPYxEi, evidenced very low pre‐therapy CD4 + T‐cell counts and suboptimal gain in CD4 + T‐cells following therapy, as compared to the non‐CPYxEi ‐strains indicating higher virulence. VGKs showed a statistically significant higher replication capacity (RC) for the CPYxEi viruses than the other two non‐CPYxEi strains. No statistically significant difference was observed in the catalytic efficiency among HIV‐1C RTs. Conclusions: This is the first evidence of polymerase independent increased virulence and RC in HIV‐1CEA following PYxE‐insertion that is associated with suboptimal CD4 + T‐cell gain following therapy initiation. J. Med. Virol. 89:106–111, 2017 . © 2016 Wiley Periodicals, Inc.