'Modeling' relationships among HIV-1 replication, immune activation and CD4+T-cell losses using adjusted correlative analyses

Objective: To model the relationships among HIV-1 replication, immune activ ation and CD4+ T-cell losses in HIV-1 infection. Methods: Cross-sectional analysis of baseline data from the Viral Activatio n by Transfusion Study. Comparisons of unadjusted and adjusted correlative analyses to establish models for mechanisms of cell loss in AIDS. Results: Using these analyses, significant correlations were found among pl asma levels of tumor necrosis factor alpha (TNF alpha) and its type two rec eptor (TNFrII), interleukin-6 (IL-6), beta(2)-microglobulin, expression of CD38 and HLA-DR on CD8+ T lymphocytes and plasma levels of HIV-1 RNA. When correlations among these indices were adjusted for possible intermediary co rrelations, the relationship between HIV-1 RNA levels and all plasma marker s of immune activation could be accounted for by the correlation between pl asma HIV-1 RNA and plasma TNFrII levels. In addition, the negative correlat ions that both HIV-1 RNA levels and TNFrII levels had with CD4+ T-cell coun ts were partially accounted for by the correlations of HIV-1 RNA and TNFrII with CD38 expression on CD8+ T cells. In persons with advanced disease (CD 4+ T cells < 50 x 10(6)/l) IL-6 levels were inversely correlated with CD4T-cell counts. Conclusions: This analysis is consistent with a model wherein HIV-1 replica tion induces TNF alpha expression that induces multiple other indices of im mune activation. In this model, HIV-1 replication and TNF alpha expression induce CD4+ T-cell losses at least in part through mechanisms reflected in heightened CD38 expression. (C) 2000 Lippincott Williams & Wilkins.