Distinct amino acid signatures and neutralization sensitivity of plasma- and CSF-derived HIV-1 subtype C clones

Abstract

Abstract Background Broadly neutralizing antibodies (bnAbs) offer a promising alternative for HIV prevention and treatment, with the potential to cross the blood–brain barrier. However, the extent to which viral genetic variation between the peripheral blood and central nervous system impacts bnAb sensitivity remains insufficiently characterized. This study investigates sequence differences and neutralization profiles of matched plasma- and cerebrospinal fluid (CSF)-derived HIV-1 subtype C (HIV-1C) variants in patients coinfected with cryptococcal meningitis. Methods Matched plasma and CSF samples were obtained from seven participants with HIV-cryptococcal meningitis coinfection in Durban, KwaZulu-Natal, South Africa. HIV-1C env was amplified, cloned into a vector, and sequenced by Sanger sequencing. Amino acid sequences within bnAb epitopes were compared between plasma- and CSF-derived clones. Additionally, we generated Env-pseudotyped viruses and assessed their neutralisation sensitivity using eight bnAbs targeting five known bnAb epitopes on HIV-1 Env. Results Discordant bnAb escape mutations and variations in neutralization sensitivity between plasma and CSF were observed in the CD4 binding site, V2 Apex and the V3 glycan supersite. Despite these variations, VRC07-523LS demonstrated broad neutralisation activity, with no significant differences in sensitivity across plasma and CSF variants. However, only minor neutralization sensitivity variations were observed in the MPER and gp120-gp41 interface between plasma and CSF compartments. Conclusions These findings highlight potential differences in amino acid signatures and neutralisation sensitivity between matched plasma- and CSF-derived HIV-1C variants. Our findings show that bnAb targeting the CD4-binding site (VRC07-523LS) maintain cross-compartment efficacy and have a potential in the clearance of viral reservoirs.