This project involves a number of clinically based studies directed at delineating the pathogenic mechanisms of human immunodeficiency virus (HIV) infection and the role of immune activation in the propagation of disease and destruction of the immune system. We have demonstrated that, after tetanus toxoid booster inoculation, HIV-1 infected patients had transient increases in plasma viremia after immunization, increases in proviral burden, and increased virus within lymph nodes. HIV was more easily isolated from PBMCs from the majority of patients after immunization than before immunization. We also demonstrated an enhanced susceptibility of PBMCs to HIV infection in normal volunteers after tetanus immunization. Phylogenetic analysis of the viral bursts within plasma in most cases reflected a non-specific increase in viral replication, secondary to an expanded pool of susceptible CD4+ T cells. An exception to this was in a patient in which immunization favored the expansion of M-tropic (CCR5 utilizing) over T-tropic(CXCR4-utilizing) viruses. In one of three patients the data suggested that immune activation resulted in the appearance in plasma of virus induced from latently infected cells. A cross-sectional study was performed which evaluated the expression of CCR5 and CXCR4 in whole blood samples taken from 25 HIV-1-infected and 10 uninfected individuals. We found that co- receptor expression correlated with the level of cellular activation in vivo in both HIV-1-infected and uninfected individuals, with CXCR4 being expressed predominantly on quiescent (HLA-DR -)T cells and CCR5 being expressed predominantly on activated (HLA-DR+) T cells. Lower expression of CXCR4 and higher expression of CCR5 on CD4+ T cells correlated with advancing disease. Twenty-three individuals with various forms of acute and chronic filariasis and 10 blood bank controls were studied. We found a modest increase in susceptibility of unstimulated PBMCs taken from filariasis patients in comparison to controls. In 6 patients with filariasis, the susceptibility to infection was evaluated pre- and post-filaria treatment. In three out of six patients, anti-filarial treatment significantly decreased susceptibility to infection, whereas in the other three, it was unchanged. - Immune activation; HIV; viral quasispecies; HIV co- receptor; filariasis - Human Subjects
