Biology and Molecular Biology of the Evolution of Macrophage-Tropic HIV-1

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Project Abstract The biology, evolution, and pathogenesis of macrophage-tropic HIV-1 is poorly understood. Historically, all R5 (CCR5-tropic) HIV-1 strains were considered macrophage-tropic. We now know that the wild type/normal form of HIV-1 requires a high density of CD4 for entry, thus directing infections to CD4+ T cells, which express high densities of CD4, and avoiding infection of macrophages, which express low densities of CD4. Macrophage tropism represents an evolutionary path along which the virus evolves the ability to more efficiently use a low density of CD4 for entry, allowing myeloid cells to now become targets for replication. This evolutionary path is followed most commonly within the CNS, where CD4+ T cells are rare, and evolution of this phenotype is associated with HIV-associated dementia. Several attempts have been made to map genetic determinants of macrophage tropism and paradoxically these have often been identified as the consensus amino acid in the R5 T-tropic virus population. Also, other than inferring better binding to CD4, nothing is known about the molecular mechanisms of how the Env protein evolves to become macrophage-tropic. Similarly, how HIV-1 colonizes the brain to establish a compartmentalized infection is largely obscure. Little is known about how selective pressures within myeloid cells may select for additional evolution beyond the entry phenotype, where such pressure may have selected for Vpx in other primate lentiviruses. Answers to these questions will inform the search for a latent reservoir in the CNS, which may ultimately be important for a successful HIV-1 cure. In this application we provide extensive preliminary data that start to address these questions and describe a body of work that will significantly advance our knowledge of this most pathogenic evolutionary variant of HIV-1.