Antiretroviral therapy down-regulates innate antiviral response genes in patients with AIDS in sub-Saharan Africa

Objective: HIV pathogenesis is characterized by destructive imbalances between virus-mediated immune damage, antiviral immune responses, and immune activation. We characterized the effects of successful antiretroviral therapy (ART) to identify the breadth and patterns of HIV-associated gene expression. Methods: In a prospective observational, longitudinal cohort study of 10 ART-naive Ugandans with AIDS (median 30 CD4/μL), we measured mRNA gene profiles in peripheral blood using Affymetrix U133-Plus2.0 microarrays at 0, 2, 4, 8, and 24 weeks after ART initiation. Results: We identified 160 mRNA transcripts that were consistently down-regulated and 48 that were up-regulated after ART at each point over 24 weeks based on linear regression modeling (adjusted P < 0.05), Of these 208 transcripts, approximately half represent heretofore unrecognized ART-responsive genes and one-third have no known function. The down-regulated genes with known function encoded mediators of innate antiviral responses, including antiviral restriction factors, pattern recognition receptors, and interferon response proteins, and mediators of immune activation, cellular proliferation, and apoptosis. Conclusions: By using ART to block the viral stimulus, we identified transcripts involved in innate antiviral immunity, including antiviral restriction factors and pattern recognition receptors, that were not previously known to be induced by HIV infection.