Neutralizing antibody responses in HIV-2: role in disease progression and protection from subsequent HIV-1 coinfection.

Natural infection with many viruses results in the production of antibodies which help clear the virus and protect us from subsequent reinfection. Eliciting such an antibody response is the basis of many effective vaccines, but unfortunately little is understood about protective antibody responses in HIV, which has hindered HIV vaccine design. Despite sharing many similarities with HIV-1, most patients with HIV-2 do not develop AIDS (although a minority do) and the reason for this is not entirely clear. This project proposes to compare antibody responses in HIV-1 and HIV-2 infected patients and explore whether stronger antibody responses are found in HIV-2 infected patients who do not progress to AIDS, when compared to those who do, and HIV-1 infected patients; at a stage where the immune system is relatively well preserved. Early studies also suggested that HIV-2 antibodies could render HIV-1 non-functional and we also propose to compare this ability in patients who are HIV-2 infected and go on acquire HIV-1 superinfection, with those who have remained HIV-2 mono-infected despite possible exposure to HIV-1. Such information could provide vital clues to how the HIV surface interacts with antibodies and the importance of eliciting an antibody response in future HIV vaccines.

Understanding the molecular basis of a broad and potent neutralizing antibody (NAb) response in natural HIV infection is a gap that if filled could provide critical information relevant to HIV vaccine design. Exploring a potential role for protective humoral immunity in the majority of HIV-2 infected individuals who behave as non-progressors warrants further study, as does the possibility that in some HIV-2 infected individuals NAb responses may be cross-reactive and protect against subsequent HIV-1 infection. A more potent NAb response in HIV-2 infection when compared to HIV-1 would provide support for the importance of a strong humoral component in future vaccines, as well as providing clues to HIV envelope structure and interaction with NAb that are vital in achieving such a response. Alternatively, if in fact some HIV-2 infected individuals have a higher chance of HIV-1 acquisition than uninfected controls, complement-mediated antibody-dependent enhancement of HIV-1 by HIV-2 sera is a possible mechanism that is yet unexplored. Thus the primary aims and objectives are to:

1) Compare contemporaneous autologous NAb responses in HIV-1 and HIV-2 infected individuals with asymptomatic HIV infection and preserved CD4 counts; with HIV-2 infected individuals stratified into those who progress to advanced immunosuppression and those who remain long term non-progressors.

2) Compare HIV-1 cross-neutralizing and enhancing antibody responses in HIV-2 infected patients who subsequently go on to acquire HIV-1 coinfection, with those who remain HIV-2 mono-infected, matched as best possible for HIV-1 exposure.

NAb responses will largely be assessed using a recombinant pseudovirus reporter assay and neutralization measured as a function of reductions in luciferase reporter gene expression after a single round of infection with molecularly cloned Env-pseudotyped strains bearing HIV-1 or HIV-2 envelope proteins in TZM-bl cells.

The study will be performed on stored plasma and serum samples from two cohorts currently followed by the MRC Gambia services: Comparison of NAb responses in HIV-1 and HIV-2 will be done on the patients from the MRC Fajara GUM clinic cohort and will be a cross-sectional analysis; comparing samples from 3 groups of patients with CD4% ? 28% at baseline: HIV-1, HIV-2 patients who subsequently behave as progressors and those who behave as non-progressors. To compare HIV-1 cross-neutralization or enhancement by HIV-2, subjects from the Caio community cohort will be used; with individuals who are HIV-2 infected and acquire subsequent HIV-1 matched in a retrospective case-control study to those who remain HIV-2 mono-infected despite possible exposure to HIV-1.