Systematic screening of viral and human genetic variation identifies antiretroviral resistance and immune escape link. eLive
Nguyen et al. assessed whether certain human leukocyte antigen (HLA) class I alleles play a role in the development of HIV drug resistance mutations among untreated people with HIV.
SHCS participants with available HIV drug resistance testing and information on HLA were systematically screened for significant associations between HLA class I alleles and the development of drug resistance mutations using three types of analyses: logistic regression, Cox regression and a mechanistic model. Only data prior to the start of antiretroviral therapy was considered.
The study included 3’997 patients contributing 5’561 possible combinations between HLA-I alleles and drug resistance mutations. Of those, 255 combinations were sufficiently powered to warrant further analyses. Authors found significant associations between HLA-I alleles and the development of NNRTI drug resistance mutations, specifically between HLA-B18 and E138 (OR 3.78, 95% CI 2.27-6.19), between HLA-A24 and E138 (OR 1.72, 1.01-2.84), and between HLA-B35 and V179 (OR 2.14, 1.08 – 4.11). Two of these associations (HLA-B18:E138 and HLA-B35:V179) were significant in longitudinal Cox regression, and two associations (HLA-B18:E18 and HLA-B35:V179) showed clear relationships in the mechanistic model.
In summary, this study shows that immune escape conveyed by the interaction between HLA-I alleles and the virus play a role for the intrapatient development of HIV drug resistance. In addition to the transmission of resistant viruses and to the selection of drug resistance during antiretroviral therapy, these findings provide compelling evidence for a novel mechanism of HIV drug resistance development.