Increased replication capacity following evolution of PYxE insertion in Gag-p6 is associated with enhanced virulence in HIV-1 subtype C from East Africa

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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.
Funding Information
  • Karolinska Institutet Research Foundation (2014fobi41250)
  • Swedish Physicians Against AIDS Research Foundation (FOb2015-0009)
  • Swedish Research Council (2012-3476)
  • Stockholm County Council (20130042)
  • CWRU/UH Center for AIDS Research (P30 AI036219)
  • University of Missouri

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