The clinical impact of HIV-1 dual infection has significant implications for understanding AIDS pathogenesis, virus transmission, and vaccine development. Dual infection can occur as a result of co-infection, wherein acquisition of two HIV-1 viral strains occurs during primary infection, or superinfection, wherein a second viral strain infects sometime after primary infection. Until recently, near simultaneous HIV-1 co-infection was thought to be the principle if not exclusive mode of dual infection. However, recent reports by several investigators, including our group, have shown that superinfection does indeed occur, and the circumstances under which this occurs may be instructive to understanding cellular niches for viruses and the interactions between the infecting strains. Furthermore, we have found that dual infection may be associated with more rapid disease progression. We propose in this continuing application to follow up our preliminary findings, expanding our studies of dual infection and adding considerable focus on rapid disease progression, including identification of host genes that impact these outcomes. Specifically, we propose to address the following specific aims and linked hypotheses using virologic, immunological and bioinformatics methodologies: AIM 1: Critically examine the link between dual HIV-1 infection and rapid disease progression. We will use population-based studies to assess the hypothesis that dual infection, when it occurs, is associated with accelerated disease progression. AIM 2: Determine the structure, interactions and replication fitness of dually infecting HIV-1 strains. We will test the hypotheses that viral strains in dually infected subjects differ in their replication fitness and capacity to infect distinct target cells, and that the types of viral interactions that occur is determined by the timing of infection with the second strain. AIM 3: Identify host genes that play a role in acquisition of dual infection and rapid disease progression. We will test the hypothesis that there is a strong host genetic component to susceptibility to multiple HIV infections, and that these genes are intimately associated with rapid disease progression. In summary, we will critically examine the link between dual HIV- 1 infection and rapid progression and determine viral and host genetic factors critical to that link.