High Level of Pre-Treatment HIV-1 Drug Resistance and Its Association with HLA Class I-Mediated Restriction in the Pumwani Sex Worker Cohort

Abstract

Background: We analyzed the prevalence of pre-antiretroviral therapy (ART) drug resistance mutations (DRMs) in a Kenyan population. We also examined whether host HLA class I genes influence the development of pre-ART DRMs.

Methods: The HIV-1 proviral DNAs were amplified from blood samples of 266 ART-naïve women from the Pumwani Sex Worker cohort of Nairobi, Kenya using a nested PCR method. The amplified HIV genomes were sequenced using next-generation sequencing technology. The prevalence of pre-ART DRMs was investigated. Correlation studies were performed between HLA class I alleles and HIV-1 DRMs.

Results: Ninety-eight percent of participants had at least one DRM, while 38% had at least one WHO surveillance DRM. M184I was the most prevalent clinically important variant, seen in 37% of participants. The DRMs conferring resistance to one or more integrase strand transfer inhibitors were also found in up to 10% of participants. Eighteen potentially relevant (p < 0.05) positive correlations were found between HLA class 1 alleles and HIV drug-resistant variants.

Conclusions: High levels of HIV drug resistance were found in all classes of antiretroviral drugs included in the current first-line ART regimens in Africa. The development of DRMs may be influenced by host HLA class I-restricted immunity.

Keywords: antiretroviral therapy; drug-resistant mutation; human immunodeficiency virus; human leukocyte antigen; next-generation sequencing technology.

Figure 1

Pre-ART HIV DRM frequency divided by antiretroviral drug classes. Pre-ART DRMs were classified into low (dark color) or high (light color) frequency variants according to the portion of variants in the viral population (quasispecies) of each sample. Low abundant variant: the proportion of variant was <20% of the quasispecies; high abundant variant: the proportion of variant was >20% of the quasispecies. Only the clinically significant DRMs are shown. NRTI: M184I, K65ER; NNRTI: E138AK, K101ENT, G190ES, L100IV, K103NT; PI: D30N, M46I, V82A, N88S, I47V, I50V; INSTI: E138K, G118R, R263K, T66IA, Y143CH. DRMs: drug resistance mutations. NRTI: nucleos(t)ide reverse transcriptase inhibitor. NNRTI: non-nucleos(t)ide reverse transcriptase inhibitor. PI: protease inhibitor. INSTI: integrase strand transfer inhibitor.

Figure 2

Kaplan–Meier survival analysis of RT E138K mutation on HIV disease progression to CD4+ T cells. Kaplan–Meier survival analysis was carried out to estimate the effect of HLA-specific adapted escape mutation-RT E138K on the time of CD4+ T cell counts to below 200 cells/µL (diagnosis of AIDS). Log-rank test was used to compare the time of CD4+ T cells declining to <200 cells/µL of two groups: the participants harboring RT E138K mutations and those who do not have the mutations. A p-value < 0.05 is considered significant. RT: reverse transcriptase.