Vaccine-induced human antibodies specific for the third variable region of HIV-1 gp120 impose immune pressure on infecting viruses

To evaluate the role of V3-specific IgG⁺ antibodies (Abs) in the RV144 clinical HIV vaccine trial, which reducedHIV-1 infection by 31.2%, the anti-V3 Ab response was assessed. Vaccinees' V3 Abs were highly cross-reactivewith cyclic V3 peptides (cV3s) from diverse virus subtypes. Sieve analysis of CRF01_AE breakthrough virusesfrom 43 vaccine- and 66 placebo-recipients demonstrated an estimated vaccine efficacy of 85% against viruseswith amino acids mismatching the vaccine at V3 site 317 (p= 0.004) and 52% against virusesmatching the vaccineat V3 site 307 (p = 0.004). This analysis was supported by data showing that vaccinees' plasma Abs wereless reactive with I³⁰⁷ when replaced with residues foundmore often in vaccinees' breakthrough viruses. Simultaneously, viruses with mutations at F³¹⁷ were less infectious, possibly due to the contribution of F³¹⁷ to optimalformation of the V3 hydrophobic core. These data suggest that RV144-induced V3-specific Abs imposed immunepressure on infecting viruses and inform efforts to design an HIV vaccine.