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

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-1C_EA) is more pathogenic due to the evolution of a PYxE-insertion (C_PYxEi) in the gag-p6 that also could affect the therapy response.

Methods

HIV-1B (n = 112) and HIV-1C_EA (n = 128) infected individuals residing in Sweden were analysed with regard to Gag-p6 genotype and clinically monitored. Based on the Gag-p6 characteristics, three HIV-1C_EA and one HIV-1B patient derived p2-INT-recombinant virus (gag-p2/NCp7/p1/p6/pol-PR/RT/IN) were constructed to analyse 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 analyse catalytic efficiency of RT.

Results

A higher viral failure rate and lower pre-therapy CD4⁺ T-cell counts were observed in HIV-1C_EA infected patients compared to HIV-1B-infected patients. In Gag-p6, PTAP-duplication was more common in HIV-1C. HIV-1C_EA–infected patients with signature C_PYxEi, evidenced very low pre-therapy CD4⁺ T-cell counts and suboptimal gain in CD4⁺ T-cells following therapy, as compared to the non-C_PYxEi-strains indicating higher virulence. VGKs, showed a statistically significant higher replication capacity (RC) for the C_PYxEi viruses than the other two non-C_PYxEi 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-1C_EA following PYxE-insertion that is associated with suboptimal CD4⁺ T-cell gain following therapy initiation. This article is protected by copyright. All rights reserved

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