While complement plays an important role in immune resistance to many infectious organisms, its role in HIV disease is not well understood. Recent studies indicate that complement, along with antibody, neutralizes HIV by virolysis while other studies show that under conditions of low complement activity, infection of cells can be enhanced. These alternatives would have significantly different effects on HIV disease progression. Determining the factors involved in the susceptibility of HIV to lysis by complement is important in light of evidence that complement is activated in even asymptomatic persons. The major goals of this proposal are to define the ways in which HIV activates complement, to determine the subsequent results of complement activation and determine mechanisms that could be involved in avoidance of activation or neutralization. Although the study of complement is emphasized, the role of anti-HIV antibody in activating complement is also analyzed. Activation of complement by HIV will be assessed by iC3b generation and complement-mediated enhancement of infection. Destruction of HIV will be assessed in neutralization assays and by release of reverse transcriptase from the virion during lysis. Experiments are proposed to investigate several factors which would have significant effects on the sensitivity of HIV to complement activation or lysis. Differential susceptibility of viral strains will be determined by obtaining HIV isolates from plasma and lymphocytes, as well as during disease progression and comparing complement sensitivity. HIV isolates will also be produced in different cell types to assess the effect of host cell factors that would become incorporated into the virus. The effect of phenotypic mixing between viruses on complement activation and lysis will also be studied. This study will also determine whether HIV that has interacted with complement (opsonized) can be cleared by different complement-receptor positive cell types since this may represent an important means of viral inactivation. Finally, changes in complement activating anti-HIV antibody during disease progression will be assessed in neutralization and lysis assays using both standard HIV isolates and sequential HIV isolates. The results obtained in this study will have important implications for vaccine development, plasma virus studies and animal models for HIV research.
