Studies on Potency and breadth of HIV-1, HIV-2 and SIV neutralizing antibody responses

Abstract: Even though the relative contribution of neutralizing antibodies (Nab) to prevent progression to AIDS during HIV-1 infection is still unclear, the induction of broadly NAb directed against HIV-1 through vaccination is considered to represent an important goal for the development of HIV-1 vaccines. Factors contributing to the induction of NAb may include the strength and duration of antigenic stimulation, the preservation of CD4+ T and B cells, the conformation of the HIV-1 envelope glycoprotein complex (Env), and the evolution of Env during infection. To understand these relationships, the experimental model of pathogenic SIV infection in cynomolgus macaques and comparison of HIV-1 and HIV-2 infections in humans were used in this thesis. In the macaque model we studied in parallel the appearance of NAb and evolution of Env. For the preservation of SIV-specific cellular immune responses, early anti-retroviral treatment was provided. The main finding from this study was that the macaques that controlled viral load after treatment discontinuation displayed limited virus population genetic diversity and divergence, and had an early broad NAb response. On the other hand, the macaques with no or transient control of viremia showed greater virus diversity and divergence, and potent NAb response during the early period of infection. We propose that the early phase of viral evolution and the antigenic stimulation contributes to the development of NAb and control of viremia. In humans, HIV-2 is known to be less transmissible and less pathogenic than HIV-1. Therefore, valuable insight can be gained into HIV immunopathogenesis from studies of HIV-2 cohorts with their high proportion of long-term non-progressors. In order to analyze differences in NAb in these infections, we compared, side by side, the breadth and potency of neutralizing activity (NAc) in plasma of HIV-1, HIV-2, and dually HIV-1/2 (HIV-D) infected individuals from Guinea-Bissau against HIV-1 and HIV-2 virus panels. The striking finding was that NAc in HIV-2 plasma against HIV-2 isolates was broader and more potent than NAc in HIV-1 plasma against HIV-1 isolates. Moreover, HIV-D positive individuals had broader and more potent NAc against HIV-2 isolates than HIV-1 isolates, indicating distinct immunogenicity and/or antigenicity of HIV-2 compared to HIV-1. We next analyzed the relative role of IgG and IgA for NAc in HIV-1, HIV-2 and HIV-D plasma. Similarly to the plasma NAc, IgG neutralizing antibodies were found to be more potent in HIV-2 plasma against HIV-2 compared to IgG from HIV-1 plasma against HIV-1. Interestingly, while HIV-2 neutralizing IgA was frequently detected in plasma of HIV-2 infected individuals, HIV-1 neutralizing IgA could rarely be demonstrated in HIV-1 plasma. To study humoral immunity in HIV-1 and HIV-2 infections further, we investigated the role of complement (C’) in antibody-dependent complement-mediated inactivation. Here results showed that the C’ effect on antiviral activity against HIV-2 was more pronounced in HIV-2 plasma than the C’ effect on HIV-1 plasma against HIV-1. Analysis of HIV-D plasma corroborated that the antibody-dependent complement-mediated inactivation was more efficient against HIV-2. This finding suggests that antibody binding to HIV-2 Env facilitates efficient use of C’. In summary, this thesis may provide insights into the nature of broad and potent neutralizing humoral immune responses.