| Human immunodeficiency virus Type 1 (HIV-1) resides in a wide variety of tissues including the brain, blood, lung, spleen, lymph nodes, and genital tract within infected individuals. Each anatomical niche is characterized by region-specific immunological surveillance, host cell characteristics, and antiretroviral drug penetration. Several reports suggest that the trafficking of virus between anatomic compartments is minimal and infrequent. Therefore, it is expected that HIV should evolve independently in each anatomic compartment, adapting to local immunologic, cellular, and pharmacokinetic characteristics.; The goal of this dissertation is to assess the degree of viral compartmentalization between tissues, and furthermore, to identify viral genetic characteristics that are specific to particular cell types and organs. The first chapter is a brief introduction to the basic biology of HIV, focusing on epidemiology and evolution. The second chapter is an exploration of the genetic determinants underlying differential HIV-1 chemokine receptor usage (CCR5 vs. CXCR4), which largely defines a strain's cellular tropism. In chapter three, the extent of natural selection on CCR5- and CXCR4-using HIV-1 strains is assessed using a variety of analytical techniques, focusing mainly on the deficiencies of the recently described "codon volatility" method. The fourth chapter investigates the biology of HIV-1 transmission by systematically comparing the population genetics of semen- and blood plasma-derived HIV variants, using previously published HIV-1 envelope RNA sequences. In chapter five, HIV neurotropism and neurovirulence are explored by generating and analyzing several hundred envelope sequences representing cerebrospinal fluid- (CSF) and plasma-derived viruses from paired CSF and plasma samples of eighteen chronically infected donors with available neuropsychiatric data. Finally, in chapters six and seven, the in vitro phenotypic correlates of HIV neurotropism are examined by comparing the effects of CSF- and plasma-derived HIV-1 Nef proteins on major histocompatibility class I (MHC-I) expression in the host cell. In addition, preliminary data on the in vitro infection of fetal brain aggregates are presented, as a model for studying HIV neuropathogenesis in a controlled laboratory setting.; In summary, the data presented within this dissertation support the theory that distinct viral genetic and evolutionary characteristics are associated with compartment-specific HIV-1 populations. |
