Longitudinal Analysis of Cerebrospinal Fluid and Plasma HIV-1 Envelope Sequences Isolated From a Single Donor with HIV Asymptomatic Neurocognitive Impairment

Objective: Combined antiretroviral treatment (cART) has changed the clinical presentation of HIV-associated neurocognitive disorders (HAND) to that of the milder forms of the disease. Asymptomatic neurocognitive impairment (ANI) is now more prevalent and is associated with increased morbidity and mortality risk in HIV-1-infected people. HIV-1 envelope (env) genetic heterogeneity has been detected within the central nervous system (CNS) of individuals with ANI. Changes within env determine co-receptor use, cellular tropism, and neuropathogenesis. We hypothesize that compartmental changes are associated with HIV-1 env C2V4 during ANI and sought to analyze paired HIV-1 env sequences from plasma and cerebrospinal fluid (CSF) of a female subject undergoing long-term cART.

Methods: Paired plasma and CSF samples were collected at 12-month intervals and HIV-1 env C2V4 was cloned and sequenced.

Results: Phylogenetic analysis of paired samples consistently showed genetic variants unique to the CSF. Phenotypic prediction showed CCR5 (R5) variants for all CSF-derived sequences and showed minor X4 variants (or dual-tropic) in the plasma at later time points. Viral compartmentalization was evident throughout the study, suggesting that the occurrence of distinctive env strains may contribute to the neuropathogenesis of HAND.

Conclusions: Our study provides new insights about the genetic characteristics within the C2V4 of HIV-1 env that persist after long-term cART and during the course of persistent ANI.