"Characterizing the effect of HIV-1 superinfection on the development of antibody breadth: gaining insight into the elicitation of broadly neutralizing antibodies"
The identification of naturally-occurring neutralizing antibodies (NAbs) that are cross-reactive against all global subtypes of HIV-1 and determining how they can be elicited in humans are both critical steps in the development of an antibody-based vaccine. While only a fraction of HIV-1-infected individuals are thought to elicit broadly NAbs, it has been established that NAb breadth is strongly associated with viral diversity. Therefore, I am proposing to examine the NAb responses of HIV-1-infected individuals with elevated levels of viral diversity, as observed in those who are superinfected. HIV-1 superinfection occurs when an individual with an established primary HIV-1 infection later becomes reinfected with an additional virus from a different source partner.
I hypothesize that superinfected individuals develop a broader NAb response compared to singly-infected individuals as a result of the antigenic stimulation associated with increased viral diversity. To test this hypothesis, I will compare the NAb breadth from 12 superinfected and 36 matched singly-infected women 5 years post-initial infection so that the NAb response will have had time to develop. These data will be among the first to elucidate the comparative magnitude of NAb breadth observed in superinfected women in the years following superinfection. I also plan to identify the two superinfected women with the greatest NAb breadth and isolate individual HIV-specific NAb-producing B cells to determine their antibodies’ relative contribution to the overall NAb response. In doing so, I will ascertain whether their breadth is mediated by a few monoclonal antibodies targeted to a single epitope or by a collective effort of many different NAbs involved in a polyclonal response.
Thus far, preliminary data supports my main hypothesis, showing that superinfected women in our cohort do exhibit a broader NAb response compared to singly-infected women. This implies that if initial HIV-1 infection is analogous to a “natural immunization,” superinfection can likewise be thought of as a “boost” in terms of the antibody response. Close examination of the NAb breadth and specificity conferred by the genetically diverse viruses in these women may in the future be informative on vaccine design in terms of timing as well as antigenic and immunogenic components.