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Background:  Genetic diversity of viral isolates in HIV-infected individuals varies substantially. However, it remains unclear whether HIV-related disease progresses more rapidly in patients harboring virus swarms with low or high diversity and, in the same context, whether high or low diversity is required to induce potent humoral and cellular immune responses.

Methods:  To explore whether viral diversity predicts virologic control, we studied HIV-infected patients, who received antiretroviral therapy (ART) for years before undergoing structured treatment interruptions (STI). HIV env gene diversity before initiation of ART and the ability of the patients to contain viremia after STI and final cessation of treatment was evaluated. Moreover, in vitro replication capacity, proviral DNA load in peripheral blood mononuclear cells (PBMC), HIV-specific cyctotoxic T-lymphocyte or cytotoxic T-cell (CTL) and T-helper responses, neutralizing antibody response against autologous virus, host genetic factors associated with the course of HIV disease (CCR2 [V64I], CCR5 [G-2455A], CCR5 [delta 32], CX3CR1 [T280M], interleukin (IL)-10 [C-592A], RANTES [G-403A], RANTES [C-28G], MIP-1a [T113C], SDF-1 [3’A], and  HLA types [HLA-A*02, A*6802, A*11, B*27, B*51, B*57, B*58, Cw*08 and DRB1*01, HLA- A23, B*08, B*3501, B*45, B*53, Cw*04]), and HIV genotypic drug resistance were determined.

Results:  Seven out of 21 patients contained plasma viremia at low levels after the final treatment cessation. Clonal sequences encompassing the Env C2V3C3 domain derived from plasma prior to treatment exhibited significantly lower diversity in these patients compared to those derived from patients with poor control of viremia. Viral diversity pre-ART correlated with viral replication capacity of rebounding virus isolates during STI. Neutralizing antibody activity against autologous virus was significantly higher in patients who controlled viremia and was associated with lower pre-treatment diversity. No such association was found with binding antibodies directed to gp120. In contrast, HIV- specific CD8⁺ and CD4⁺ T-cell responses did not correlate with diversity and showed no differences between controllers and non-controllers and no associations between viral diversity, control of viremia, and host genetic factors.

Conclusions:  In summary, lower pretreatment viral diversity was associated with spontaneous control of viremia, reduced viral fitness, and higher neutralizing antibody titers, suggesting a link between viral diversity, viral fitness, and neutralizing antibody activity.

Keywords: viral diversity; replication capacity; neutralizing antibodies