Drug Resistance Mutation Frequency of Single-Genome Amplification-Derived HIV-1 Polymerase Genomes in the Cerebrospinal Fluid and Plasma of HIV-1-Infected Individuals under Nonsuppressive Therapy

Abstract

HIV-1 evolution in the CSF and plasma may result in discordant drug-resistance mutations (DRMs) in the compartments. Single genome amplification (SGA) was used to generate partial HIV-1 polymerase genomes in paired CSF and plasma from 12 HIV-1 positive CHARTER participants classified as neurocognitively unimpaired or with various degrees of HIV-Associated Neurocognitive Disorders (HAND). Subjects were viremic on combination antiretroviral therapy (cART). HIV-1 DRMs and phylogenetic characteristics were determined using the Stanford HIVdb program and phylogenetic analyses. Individual DRMs were identified more frequently in plasma than in paired CSF (p=0.0078). Significant differences in the ratios of DRMs in CSF and plasma were found in 3 individuals with HAND (3/7=43%). 2 HAND subjects (2/7=29%) demonstrated one DRM in CSF not identified in paired plasma. Longitudinal analyses (n=4) revealed significant temporal differences in the ratios of DRMs in the compartments. Statistically significant differences in the frequency of DRMs in the CSF and plasma are readily found in those on non-suppressive cART. While compartment-based DRM discordance was largely consistent with increased drug-selective pressures in the plasma, overrepresentation of DRMs in the CNS can occur. Underlying mechanisms of HAND are complex and multifactorial. The clinical impact of DRM discordance on viral persistence and HAND pathogenesis remains unclear and warrants further investigation in larger, longitudinal cohorts. Importance: Several antiretroviral agents do not efficiently enter the CNS and independent evolution of HIV-1 viral variants in the CNS and plasma can occur. We use single genome amplification (SGA) in cross-sectional and longitudinal analyses to uniquely define both the identity and relative proportions of drug resistance mutations (DRMs) on individual HIV-1 pol genomes in the cerebrospinal fluid (CSF) and plasma in individuals with incomplete viral suppression and known neurocognitive status. Statistically significant differences in the ratio of DRMs in the CSF and plasma were readily found in those on non-suppressive cART and overrepresentation of DRMs in the CNS can occur. Although questions about the clinical significance of DRM discordance remain, in the quest for viral eradication, it is important to recognize that a significant, dynamic, compartment-based DRM ratio imbalance can exist, as it has the potential to go unnoticed in the setting of standard clinical drug resistance testing.