HIV infection of lung cells is believed to be central to pulmonary pathogenesis in AIDS through immune dysfunction, alveolitis, and other effects. The mechanisms that regulate HIV replication and activation within the lung are poorly understood. Macrophages are the principal cell type infected in lung and HIV strains isolated from lung are generally macrophage (M)- tropic, but few lung-derived HIV isolates have been carefully characterized. M-tropic strains are often thought of as homogeneous, but the investigators have shown that M-tropic viruses may be very diverse in replication kinetics, cytopathogenicity and tropism. Recent reports also suggest that lung isolates may also demonstrate diverse features, and these characteristics may change over time. The hypothesis is that there are intrinsic biological and genetic differences among M-tropic HIV-1 variants in the lung that contribute to local virus activation and replication, and that evolution over time may result in the emergence of variants with enhanced replicative and pathogenic capacity in the lung. To better understand the viral determinants that underlie accelerated HIV replication and pathogenesis in the lung and mechanism(s) involved in emergence of these strains, the investigators will: (1) Identify primary HIV isolates that emerge over time in the lung, by generating a panel of lung- and blood-derived HIV-1 primary isolates from a cohort of individuals sampled serially; (2) Define the biological characteristics of pulmonary variants that contribute to enhanced replication and pathogenesis, using relevant primary cell types to analyze evolution from latent to productive infection, kinetics, selective tropism for lung versus blood cells, cytopathogenicity and macrophage cytokine induction, and; (3) Determine the viral genetic basis for these differences, by constructing chimeras to map determinants of accelerated kinetics, lung cell tropism, and others identified in Aim 2. In addition, the investigators will analyze sequences over time to determine whether changes result from compartmentalized evolution or from recruitment of virus or infected cells from circulation. The investigators anticipate that these studies will lead to increased understanding of how intrinsic virual factors lead to increased HIV replication within the lung and disease progression. In addition, the investigators believe that they will provide insight into the relationship between localized and systemic processes involved in HIV pathogenesis.
