{"id":315716,"date":"2016-11-03T20:11:52","date_gmt":"2016-11-04T03:11:52","guid":{"rendered":"https:\/\/cm-edgetun.pages.dev\/en-us\/research\/?post_type=msr-research-item&#038;p=315716"},"modified":"2018-10-16T20:07:13","modified_gmt":"2018-10-17T03:07:13","slug":"early-selection-gag-protective-hla-alleles-contributes-reduced-hiv-1-replication-capacity-may-largely-compensated-chronic-infection","status":"publish","type":"msr-research-item","link":"https:\/\/cm-edgetun.pages.dev\/en-us\/research\/publication\/early-selection-gag-protective-hla-alleles-contributes-reduced-hiv-1-replication-capacity-may-largely-compensated-chronic-infection\/","title":{"rendered":"Early Selection in Gag by Protective HLA Alleles Contributes to Reduced HIV-1 Replication Capacity That May Be Largely Compensated for in Chronic Infection"},"content":{"rendered":"<p>Mutations that allow escape from CD8 T-cell responses are common in HIV-1 and may attenuate pathogenesis by reducing viral fitness. While this has been demonstrated for individual cases, a systematic investigation of the consequence of HLA class I-mediated selection on HIV-1 <em>in vitro<\/em> replication capacity (RC) has not been undertaken. We examined this question by generating recombinant viruses expressing plasma HIV-1 RNA-derived Gag-Protease sequences from 66 acute\/early and 803 chronic untreated subtype B-infected individuals in an NL4-3 background and measuring their RCs using a green fluorescent protein (GFP) reporter CD4 T-cell assay. In acute\/early infection, viruses derived from individuals expressing the protective alleles HLA-B*57, -B*5801, and\/or -B*13 displayed significantly lower RCs than did viruses from individuals lacking these alleles (<em>P<\/em> < 0.05). Furthermore, acute\/early RC inversely correlated with the presence of HLA-B-associated Gag polymorphisms (<em>R<\/em> = \u22120.27; <em>P<\/em> = 0.03), suggesting a cumulative effect of primary escape mutations on fitness during the first months of infection. At the chronic stage of infection, no strong correlations were observed between RC and protective HLA-B alleles or with the presence of HLA-B-associated polymorphisms restricted by protective alleles despite increased statistical power to detect these associations. However, RC correlated positively with the presence of known compensatory mutations in chronic viruses from B*57-expressing individuals harboring the Gag T242N mutation (<em>n<\/em> = 50; <em>R<\/em> = 0.36; <em>P<\/em> = 0.01), suggesting that the rescue of fitness defects occurred through mutations at secondary sites. Additional mutations in Gag that may modulate the impact of the T242N mutation on RC were identified. A modest inverse correlation was observed between RC and CD4 cell count in chronic infection (<em>R<\/em> = \u22120.17; <em>P<\/em> < 0.0001), suggesting that Gag-Protease RC could increase over the disease course. Notably, this association was stronger for individuals who expressed B*57, B*58, or B*13 (<em>R<\/em> = \u22120.27; <em>P<\/em> = 0.004). Taken together, these data indicate that certain protective HLA alleles contribute to early defects in HIV-1 fitness through the selection of detrimental mutations in Gag; however, these effects wane as compensatory mutations accumulate in chronic infection. The long-term control of HIV-1 in some persons who express protective alleles suggests that early fitness hits may provide lasting benefits.<\/p>\n","protected":false},"excerpt":{"rendered":"<p>Mutations that allow escape from CD8 T-cell responses are common in HIV-1 and may attenuate pathogenesis by reducing viral fitness. While this has been demonstrated for individual cases, a systematic investigation of the consequence of HLA class I-mediated selection on HIV-1 in vitro replication capacity (RC) has not been undertaken. We examined this question by [&hellip;]<\/p>\n","protected":false},"featured_media":0,"template":"","meta":{"msr-url-field":"","msr-podcast-episode":"","msrModifiedDate":"","msrModifiedDateEnabled":false,"ep_exclude_from_search":false,"_classifai_error":"","msr-author-ordering":null,"msr_publishername":"","msr_publisher_other":"","msr_booktitle":"","msr_chapter":"","msr_edition":"Journal of Virology","msr_editors":"","msr_how_published":"","msr_isbn":"","msr_issue":"22","msr_journal":"Journal of 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