Linkage of HIV amino acid variants to protective host alleles at CHD1L and HLA class I loci in an African population

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dc.contributor.authorSchulz, Vanessa
dc.contributor.examiningcommitteeMcKinnon, Lyle (Medical Microbiology and Infectious Diseases)
dc.contributor.examiningcommitteeOsiowy, Carla (Medical Microbiology and Infectious Diseases)
dc.contributor.supervisorMcLaren, Paul
dc.contributor.supervisorSandstrom, Paul
dc.date.accessioned2023-12-05T22:59:29Z
dc.date.available2023-12-05T22:59:29Z
dc.date.issued2023-11-08
dc.date.submitted2023-12-01T22:49:07Zen_US
dc.date.submitted2023-12-05T20:00:26Zen_US
dc.degree.disciplineMedical Microbiology and Infectious Diseasesen_US
dc.degree.levelMaster of Science (M.Sc.)
dc.description.abstractHIV viral load (VL), measured as RNA copies/mL of plasma, is a predictor of disease progression and transmission potential. Therefore, the restriction of VL is key to achieving the “Undetectable=Untransmittable” and UNAIDS “95-95-95” targets to reduce the amount of people living with HIV and AIDS. VL is variable between individuals, with host genetics, viral fitness, and the environment contributing to this variability. The HLA region has been consistently associated with HIV protection or susceptibility, based on the ability of an HLA allele to restrict HIV. However, HIV escape from HLA is well described, with some viral mutations completely abrogating the protective effect of HLA alleles. A previous genome wide association study (GWAS) of HIV VL in individuals of African ancestry identified a locus on chromosome 1, near the protein coding gene CHD1L, that has a novel association with control of HIV replication. However, not all of the individuals carrying protective alleles in this locus maintained low VL. In addition, this regions’ impact on viral evolution has not been investigated. To address this, we conducted an analysis in 174 people living with HIV (PLWH), from South Africa and Kenya, with both human and viral sequence data available. Logistic regression was used to test the association between HIV amino acid variants in reverse transcriptase (RT), protease, integrase (IN), gag, and nef with host alleles near CHD1L and in HLA. We observed associations between the CHD1L variants rs77029719, rs7519713, rs59784663 and rs73004025 with codon 248 of HIV RT. We also observed associations between the CHD1L variant rs7519713 and codons 18 and 147 of HIV gag, and codons 60 and 216 of IN. These associations are consistent with viral escape from CHD1L pressure. In addition, we observed associations between HLA B*81 and HLA C*18 with RT codon 4 and HLAB*58 with RT codon 196. Lastly, we conducted a HIV VL GWAS in 552 PLWH from South Africa, a population that has not been largely investigated, but were unable to replicate the chromosome 1 associations at genome wide significance. Here, we report on a viral escape mutation scan and GWAS, where we show evidence of selective pressure by HLA and variants near CHD1L on RT, gag, and IN. Our findings provide new insight into how genetic variability, near the CHD1L locus, contributes to viral evolution and host control in a population highly affected by HIV.
dc.description.noteFebruary 2024
dc.description.sponsorshipCanadian Institutes of Health Research, http://dx.doi.org/10.13039/501100000024, CIHR-CGSM, University of Manitoba, http://dx.doi.org/10.13039/100010318, Tri-Agency Master's Supplemental Award
dc.identifier.urihttp://hdl.handle.net/1993/37844
dc.language.isoeng
dc.rightsopen accessen_US
dc.subjectHIV
dc.subjectgenome-to-genome
dc.subjecthost-pathogen interaction
dc.subjectviral genomics
dc.subjecthost genomics
dc.subjectHLA
dc.subjectviral load
dc.titleLinkage of HIV amino acid variants to protective host alleles at CHD1L and HLA class I loci in an African population
dc.typemaster thesisen_US
local.subject.manitobano
project.funder.identifierhttp://dx.doi.org/10.13039/100011094
project.funder.namePublic Health Agency of Canada
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