VIRUS AND IMMUNE RESPONSE CHANGES IN AIDS PROGRESSION

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In most individuals, HIV infection provokes a relatively effective immune response, including neutralizing antibody and cellular immunity which eliminates most but not all virus replication. Paradoxically, the remaining low-level chronic infection leads inexorable to immune system degeneration, AIDS and death at rates that vary substantially from one individual to the next. It is becoming increasingly clear that this variable natural history of infection is due to a complex interaction of multiple factors (e.g. immune response, viral burden, non-specific immune activation, etc.) which vary independently between and within infected individuals. The disease process is also accompanied by relatively rapid emergence of viral variants, or quasispecies, which present an ongoing challenge to the immune system and provide the opportunity for the evolution of viruses with increased pathogenic potential. The overall purpose of the proposed study is to perform an extensive analysis of the interactions between longitudinal changes in; the diversity of the quasispecies swarm, the humoral immune response, viral phenotype, viral burden, and the rate of HIV disease progression in well characterized individuals, beginning at infection and throughout an extended period of clinical follow-up. While each of these components of host-virus variation has, and continues to be, studied independently, the systematic comparison of multiple factors in the same individuals should provide new insights into the complex multi-component mechanism by which HIV destroys the immune system. We will characterize 20 subjects who seroconverted in the first 18 months of an ongoing prospective study, including some who developed AIDS in 3-6 years and others who have remained asymptomatic, with over 800 CD4+ T- cells, for over 78 months. We will employ newly developed heteroduplex gel shift (HGSA) and homoduplex tracking analyses (HTA) and selective nucleotide sequencing to characterize temporal changes in the virus swarms. Neutralizing and V3 PND binding antibody will also be evaluated throughout follow-up using heterologous and autologous viruses. Finally, the pathogenic potential of viral isolates, reflected by in vitro tropism and cytopathology, will be assessed at each examination. The intercorrelation of these factors will be used to test alternative hypothesis for the biological significance of the emergence of neutralization resistant quasispecies and/or those with increased cytopathic potential. If escape mutants occur because of clonal dominance we should observe restricted specificity in neutralization despite the evolution of virus heterogeneity. If the problem is exhaustion of the immunologic repertoire, after exposure to an excessive number of new antigens, we should observe broadening of neutralizing specificities prior to the escape of more virulent strains. In either case, the emergence of more pathogenic quasispecies would be associated with rapid progression or precede accelerated progression. Alternatively, cytopathic variants may be a late consequence of prior immune system collapse which is either independent of viral phenotype or caused by particular quasispecies despite their presence as minor variants.