Increased replication capacity following evolution of PYxE insertion in Gag‐p6 is associated with enhanced virulence in HIV‐1 subtype C from East Africa
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-1B 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..
| Medienart: |
Artikel |
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| Erscheinungsjahr: |
2017 |
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| Erschienen: |
2017 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:89 |
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| Enthalten in: |
Journal of medical virology - 89(2017), 1, Seite 106-111 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Aralaguppe, Shambhu G [VerfasserIn] |
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| Links: |
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| BKL: | |
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| Themen: |
East Africa |
| RVK: |
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| doi: |
10.1002/jmv.24610 |
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| Förderinstitution / Projekttitel: |
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OLC1987073347 |
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| 245 | 1 | 0 | |a 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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| 520 | |a 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-1B 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. | ||
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