Multiple Mechanisms of HIV-1 Resistance to PGT135 in a Chinese Subtype B' Slow Progressor

We investigated HIV-1 immune evasion mechanisms in a slow progressor (CBJC515) by constructing pseudoviruses expressing autologous Env proteins. Intriguingly, all pseudoviruses exhibited resistance to the broadly neutralizing antibody (bNAb) PGT135. Using site-directed mutagenesis and chimeric Env construction, we identified distinct escape mechanisms: early 2005 strains lost the N332 glycan site, while 2006/2008 strains retained key epitopes but developed resistance through structural modifications in the V1/V4/C2 regions or acquired novel N-glycosylation sites (N398/N611). These findings provide insights into how HIV-1 can escape from N332-directed bNAb responses without altering the epitope itself. Furthermore, chimeric experiments also elucidated regional co-evolution and functional maintenance: the V1V2 region broadly interfered with envelope protein function, while the V3 region may exhibit compensatory activity, restoring functionality and mitigating deleterious polymorphisms in other regions to keep Env antigenic diversity. These results offer valuable mechanistic clues that may inform the development of next-generation HIV-1 vaccines.