Heterogeneity in Cytokine Responses to HIV-1 Infection

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Immunological and clinical manifestations of natural and treated human immunodeficiency virus type 1 (HIV- 1) infection can vary considerably at the individual or population level. To elucidate the role of host factors that regulate variable responses to HIV-1infection, Dr. Jianming Tang, Associate Professor of Medicine at the University of Alabama at Birmingham, proposes to test several hypotheses generated by earlier and ongoing studies. The research will examine critical cytokine and chemokine pathways for which promising preliminary data collectively point to their importance in the immunopathogenesis of HIV-1infection. The primary work will rely on a historical cohort of 530 adolescents whose outcomes have already been documented through longitudinal (quarterly) measurements of viral load (virus-host equilibrium), CD8+CD38+ T-cell percentage (T-cell activation), and CD4+ T-cell counts (immunodeficiency). Highly sensitive, ELISA-based assays will be used to simultaneously quantify plasma levels of 16 cytokines and chemokines in untreated patients; products that are clearly correlated with contrasting HIV-1-related outcomes will be evaluated in patients before and after effective antiretroviral therapy. In addition, genes encoding informative cytokines, chemokines, and related products (e.g., receptors) will be targeted for high- density, bead array-based genotyping of single nucleotide polymorphisms (SNPs), supplemented and refined by TaqMan SNP assays and selective re-sequencing. Genetic associations with HIV-1-related outcomes or systemic cytokine/chemokine expression will be tested for independent and potentially interactive effects in multivariable models. The same SNP dataset can be analyzed for genetic associations with sexually transmitted infections due to two other agents (Chlamydia trachomatis and herpes simplex virus type 2) commonly seen in the adolescent cohort. Overall, these multifaceted analyses, along with secondary (confirmatory) work based on studies of 120 adults with chronic HIV-1infection, are expected to allow valuable training in biostatistical applications and provide a robust account of heterogeneous cytokine responses to HIV-1infection. The most convincing and generalizable of findings from this work should pave the way for Dr. Tang to pursue targeted experimental studies and substantially strengthen a collaborative research program that focuses on infection and immunity in immunocompromised hosts.