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Early evolution of human leucocyte antigen-associated escape mutations in variable Gag proteins predicts CD4+ decline in HIV-1 subtype C-infected women.

ABSTRACT: HIV-1 escape from cytotoxic T-lymphocytes results in the accumulation of human leucocyte antigen (HLA)-associated mutations in the viral genome. To understand the contribution of early escape to disease progression, this study investigated the evolution and pathogenic implications of cytotoxic T-lymphocyte escape in a cohort followed from infection for 5 years.Viral loads and CD4 cell counts were monitored in 78 subtype C-infected individuals from onset of infection until CD4 cell count decline to less than 350 cells/?l or 5 years postinfection. The gag gene was sequenced and HLA-associated changes between enrolment and 12 months postinfection were mapped.HLA-associated escape mutations were identified in 48 (62%) of the participants and were associated with CD4 decline to less than 350?cells/?l (P?=?0.05). Escape mutations in variable Gag proteins (p17 and p7p6) had a greater impact on disease progression than escape in more conserved regions (p24) (P?=?0.03). The association between HLA-associated escape mutations and CD4 decline was independent of protective HLA allele (B57, B58?:?01 and B81) expression.The high frequency of escape contributed to rapid disease progression in this cohort. Although HLA-adaption in both conserved and variable Gag domains in the first year of infection was detrimental to long-term clinical outcome, escape in variable domains had greater impact.

SUBMITTER: Chopera DR

PROVIDER: S-EPMC5177455 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Early evolution of human leucocyte antigen-associated escape mutations in variable Gag proteins predicts CD4+ decline in HIV-1 subtype C-infected women.

Chopera Denis R DR Ntale Roman R Ndabambi Nonkululeko N Garrett Nigel N Gray Clive M CM Matten David D Abdool Karim Quarraisha Q Abdool Karim Salim S Williamson Carolyn C

AIDS (London, England) 20170101 2

<h4>Objective</h4>HIV-1 escape from cytotoxic T-lymphocytes results in the accumulation of human leucocyte antigen (HLA)-associated mutations in the viral genome. To understand the contribution of early escape to disease progression, this study investigated the evolution and pathogenic implications of cytotoxic T-lymphocyte escape in a cohort followed from infection for 5 years.<h4>Methods</h4>Viral loads and CD4 cell counts were monitored in 78 subtype C-infected individuals from onset of infec ...[more]

PMID: 27755110

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Project description:BACKGROUND:Despite the extensive genetic diversity of HIV-1, viral evolution in response to immune selective pressures follows broadly predictable mutational patterns. Sites and pathways of Human Leukocyte-Antigen (HLA)-associated polymorphisms in HIV-1 have been identified through the analysis of population-level data, but the full extent of immune escape pathways remains incompletely characterized. Here, in the largest analysis of HIV-1 subtype B sequences undertaken to date, we identify HLA-associated polymorphisms in the three HIV-1 proteins most commonly considered in cellular-based vaccine strategies. Results are organized into protein-wide escape maps illustrating the sites and pathways of HLA-driven viral evolution. METHODOLOGY/PRINCIPAL FINDINGS:HLA-associated polymorphisms were identified in HIV-1 Gag, Pol and Nef in a multicenter cohort of >1500 chronically subtype-B infected, treatment-naïve individuals from established cohorts in Canada, the USA and Western Australia. At q< or =0.05, 282 codons commonly mutating under HLA-associated immune pressures were identified in these three proteins. The greatest density of associations was observed in Nef (where close to 40% of codons exhibited a significant HLA association), followed by Gag then Pol (where approximately 15-20% of codons exhibited HLA associations), confirming the extensive impact of immune selection on HIV evolution and diversity. Analysis of HIV codon covariation patterns identified over 2000 codon-codon interactions at q< or =0.05, illustrating the dense and complex networks of linked escape and secondary/compensatory mutations. CONCLUSIONS/SIGNIFICANCE:The immune escape maps and associated data are intended to serve as a user-friendly guide to the locations of common escape mutations and covarying codons in HIV-1 subtype B, and as a resource facilitating the systematic identification and classification of immune escape mutations. These resources should facilitate research in HIV epitope discovery and host-pathogen co-evolution, and are relevant to the continued search for an effective CTL-based AIDS vaccine.

Project description:BackgroundMutations within the "a" determinant region (position 124-147) that is present in the major hydrophilic region (MHR, position 99-160) of the hepatitis B surface antigen (HBsAg) are associated with vaccine-escape, lack of diagnosis, and failure to hepatitis B immunoglobulin (HBIG) therapy. Data regarding the amino acid changes of "a" determinant region of HBsAg are limited in Egypt. The prevalence and mutations in this region among chronic HBV (CHB)-infected patients in Upper Egypt are not known.Material and methodsBlood samples were collected from HBsAg-positive CHB-infected patients (n=123) admitted to Assiut University Hospitals. Serum samples were screened for HBsAg, HBeAg, anti-HBs and anti-HBe antibodies using commercially available ELISA kits. Viral load was determined by qPCR. In addition, mutational analysis was carried out targeting the HBV surface gene to determine the HBV genotype and vaccine escape mutations.ResultsSequencing analysis of HBV DNA revealed that genotype D is the major circulating type (81.3%), followed by genotype E (18.7%). Analysis of the HBV genome revealed that 103/123 (83.7%) patients showed wild-type sequences and 20/123 (16.3%) showed mutations in the HBsAg gene. Mutation in seventeen patients (17/20, 85%) showed only one mutation, and three patients showed two mutations (3/20, 15%) in the "a" determinant region. The observed mutations were T115S (3/20, 15%), P120T/S (3/20, 15%), T126S (1/20, 5%), Q129R (2/20, 10%), M133T (2/20, 10%), S143L (5/20, 25%), D144E/A (3/20, 15%), and G145R/A (4/20, 20%). Mutations in the "a" determinant region were detected in genotype D isolates only.ConclusionWe described for the first time the prevalence and characterization of vaccine escape mutants in CHB patients in Upper Egypt. Mutational analysis of the "a" determinant region revealed the presence of a wide spectrum of mutants in the circulating HBV isolates that could be a potential threat to HBV diagnosis, therapy success, and HBV vaccination program in Upper Egypt.

Dataset Information

Early evolution of human leucocyte antigen-associated escape mutations in variable Gag proteins predicts CD4+ decline in HIV-1 subtype C-infected women.

Publications

Early evolution of human leucocyte antigen-associated escape mutations in variable Gag proteins predicts CD4+ decline in HIV-1 subtype C-infected women.

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