Human immune response correlates of attenuated HIV-2 pathogenesis

Since 1985 the Kanki laboratory has maintained a prospective cohort of registered female sex workers in Dakar, Senegal that has supported multi-disciplinary research on both HIV-1 and HIV-2. Data from this cohort has demonstrated that HIV-2 is significantly less pathogenic than HIV-1 and it is presumed that host immunity largely contributes to the superior control of HIV-2 infection. In this thesis we describe novel humoral immune response correlates of attenuated HIV-2 pathogenesis. We first examined the association between anti-Tat antibody responses and disease progression in 144 HIV-2-infected individuals with up to 16 years of follow-up. Two-thirds of subjects tested positive for anti-Tat antibodies and these individuals were shown to have a significantly lower risk of disease progression than those who lacked anti-Tat antibodies. This study established anti-Tat antibodies as prognostic markers of disease progression in HIV-2. In our second study, a novel neutralizing antibody assay system was developed, and with it we found that HIV-2 infection is characterized by a broad, low magnitude neutralizing response to a panel of heterologous viruses. Further, this study demonstrated that heterologous neutralizing responses are driven by viral replication in both HIV-1 and HIV-2, as we found a significant positive association between median neutralizing antibody titers and viral loads in both groups. To examine the role of neutralizing antibody responses in HIV-2 pathogenesis, we examined long-term dynamics of neutralizing antibody responses in HIV-2-infected subjects who either remained asymptomatic or who progressed to AIDS. This longitudinal study evaluated plasma samples collected from 10 HIV-2- infected individuals at various time intervals following seroconversion for neutralizing antibody responses against a panel of heterologous primary viruses. We discovered that some HIV-2-infected subjects who progress clinically demonstrate a suppressed ability to fully develop or to sustain neutralizing responses, however, since nonprogressors and progressors had comparable responses within the first year of infection, this response is not prognostic of disease progression. In conclusion, we demonstrate that antibody responses are biologically important immune mechanisms in HIV-1 and HIV-2 infection and that qualitative and quantitative differences exist between HIV-1 and HIV-2 subjects that correlate with the reduced viremia and pathogenesis of HIV-2.