Higher Genetic Diversity and Viral Evolution in Key Regions of the Envelope Gene Are Associated with Broader Neutralizing Antibody Responses: a Report of Two Chronic HIV Infected Cases

Abstract

Dozens of broadly neutralizing antibodies (bnAbs) have been identified from chronically infected HIV-1 patients, but it is still unclear what determines the acquisition of broad neutralizing activities. Two chronic HIV-1 infected cases with similar autologous neutralizing activities were followed up for two years to study the viral evolution of the envelope gene and the neutralizing activity against autologous and heterologous viruses. The neutralization activities against homologous viruses gradually increased in both patients. HA172 eventually developed a cross-clade neutralizing antibodies response, with a neutralization breadth of 88.9% (8/9) against tier 2 heterologous HIV-1. However, HA084 could only neutralize 44.4% (4/9) of the same virus panel. Higher genetic diversity of the env gene at baseline (0.027 vs. 0.002, p ＜ 0.001), stronger immune pressure on V3 (3.08 vs. 0.99, p ＜ 0.001) or V4 loops (2.63 vs. 0.62, p = 0.002), increasing length of V1V2 and V4 loops, and evolution on V1V2 and CD4-binding sites (CD4bs) were identified in HA172. The findings demonstrated that higher viral genetic diversity, viral evolution on V1V2 and CD4bs might contribute to the development of bnAbs. The findings indicate the possibility of inducing better neutralizing antibodies in immunodeficient patients and may help develop an immune therapy strategy based on bnAbs.