Viral Evolution and Humoral Immune Response to Dual HIV-1 Infection

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PROJECT SUMMARY/ABSTRACT In regions of the world like West-Central Africa where multiple HIV-1 groups and subtypes co-circulate, the rate of dual infection - the concomitant or sequential infection with two or more genetically distinct HIV-1 strains - is frequent, and recombinant viruses are common. A key characteristic of HIV-1 is its ability to recombine following dual infection, providing the virus with the opportunity for major evolutionary leaps and creating major challenges for diagnosis, treatment, vaccine design, and vaccine trials. Despite the fact that dual infection is common, information on how dual infection impacts on the host's anti-viral humoral immune responses is limited. Studying the impact of dual infection by discordant HIV-1 strains should increase our knowledge of the humoral immune response to diverse viruses. Therefore, the occurrence of dual infection provides a unique opportunity to investigate immune responses to multiple viral antigens and to study whether the host immune response is broadened when challenged with multiple, diverse antigens representing distinct viral subtypes and recombinant viruses. In the West-Central African country of Cameroon, multiple HIV-1 subtypes co-circulate, dual infection is common, and we have identified several individuals dually infected with diverse viruses who have remained asymptomatic and drug-na¿ve for over 3-4 years. The occurrence of dual infections in these drug-na¿ve individuals provides an opportunity to study virus evolution, to examine and compare the effect of infection by single and multiple subtypes on the host immune system in generating neutralizing antibodies, and to study whether such antibodies exhibit differences in their potency and breadth to autologous and/or heterologous viruses. These kinds of studies will shed light on the emergence of new viral subtypes and recombinants and contribute to the design of vaccines that will induce the most potent and broadly neutralizing antibodies to protect against diverse HIV-1 subtypes. We therefore propose studies in: AIM 1: To examine the potency and breadth of neutralization against autologous and heterologous HIV-1 viruses by sequential plasma specimens from either individuals infected with single HIV-1 strains or dually infected with inter- or intra-subtype strains; AIM 2: To study the genetic evolution and emergence of recombinant viruses in the blood of dually (inter-subtype) infected subjects whose serum neutralizing antibodies display different patterns of breadth and potency; and AIM 3: To study the neutralization sensitivity of the recombinant viruses isolated from individuals with inter-subtype dual infections.