Systematic screening of viral and human genetic variation identifies antiretroviral resistance and immune escape link.

Background

Considering the remaining threat of drug-resistantmutations (DRMs) to antiretroviral treatment (ART) efficacy, we investigated how the selective pressure of human leukocyte antigen (HLA)-restricted cytotoxic T lymphocytes drives certain DRMs' emergence and retention.

Methods

We systematically screened DRM:HLA class I allele combinations in 3997 ART-naïve Swiss HIV Cohort Study (SHCS) patients. For each pair, a logistic regression model preliminarily tested for an association with the DRM as the outcome. The three HLA:DRM pairs remaining after multiple testing adjustment were analyzed in three ways: cross-sectional logistic regression models to determine any HLA/infection time interaction, survival analyses to examine if HLA type correlated with developing specific DRMs, and via NetMHCpan to find epitope binding evidence of immune escape.

Results

Only one pair, RT-E138:HLA-B18, exhibited a significant interaction between infection duration and HLA. The survival analyses predicted two pairs with an increased hazard of developing DRMs: RT-E138:HLA-B18 and RT-V179:HLA-B35. RT-E138:HLA-B18 exhibited the greatest significance in both analyses (interaction term odds ratio [OR] 1.169 [95% confidence interval (CI) 1.075-1.273]; p-value<0.001; survival hazard ratio 12.211 [95% CI 3.523-42.318]; p-value<0.001). The same two pairs were also predicted by netMHCpan to have epitopic binding.

Conclusions

We identified DRM:HLA pairs where HLA presence is associated with the presence or emergence of the DRM, indicating that the selective pressure for these mutations alternates direction depending on the presence of these HLA alleles.

Funding

Funded by the Swiss National Science Foundation within the framework of the SHCS, and the University of Zurich, University Research Priority Program: Evolution in Action: From Genomes Ecosystems, in Switzerland.

Informations de copyright

© 2021, Nguyen et al.

Déclaration de conflit d'intérêts

HN, CT, JF, JB, SY, MP, HH, KK, MT, MB, CK, RK No competing interests declared, MC has received research and travel grants for his institution from ViiV and Gilead. EB has received fees for his institution for participation to advisory board from MSD, Gilead Sciences, ViiV Healthcare, Abbvie and Janssen. HG HFG has received unrestricted research grants from Gilead Sciences and Roche; fees for data and safety monitoring board membership from Merck; consulting/advisory board membership fees from Gilead Sciences, Sandoz and Mepha; and travel reimbursement from Gilead.