298 HIV Replication is Associated with High Frequencies of HIV-Specific IFN-gamma+ CD4+ T-cells with Limited In Vitro Proliferation in Chronically-infected Children Z. Scott*, C. Beaumier, M. Sharkey, M. Stevenson, K. Luzuriaga Univ of Massachusetts Med Sch, Worcester
Background: The ability of HIV-1 chronically-infected children to generate functional virus-specific CD4+ T-cell responses is poorly understood. The present study investigated the relationship between HIV-1 replication and virus (HIV-1, CMV)-specific CD4+ T-cell frequency and function in a large cohort of chronically-infected children.
Methods: HIV-1 p55 (Gag)-specific CD4+ T-cell frequencies were measured in 44 HIV-1 vertically-infected children receiving antiretroviral therapy using intracellular cytokine staining for IFN-gamma and lymphoproliferative assays. PCR amplification of HIV 2-LTR DNA circles was performed to detect recent HIV-1 replication in children with plasma HIV-1 loads < 50 copies/mL.
Results: HIV-1 p55-specific CD4+ T-cell responses were commonly detected (38/44 = 86%). In children with plasma HIV-1 RNA loads of < 50 copies/mL, the proportion of children with detectable p55-specific IFN-gamma responses (11/16 = 69%) differed significantly (Fisher’s Exact, p < 0.05) from children with active HIV replication (27/28 = 96%; median viral load: 2,295 copies/mL). The median frequency of p55-specific responses in HIV-1 suppressed individuals (0.14%) was significantly lower than that in children with plasma HIV-1 > 50 copies/mL (0.57%; Wilcoxon Rank Sum, p < 0.005). In children with plasma HIV-1 < 50 copies/mL, p55-specific CD4+ T-cells were only detected in children with detectable 2-LTR DNA circles. P55-specific proliferative responses were only detected in children with plasma HIV-1 < 50 copies/mL. Finally, CMV pp65-specific CD4+ T-cell responses were more commonly detected and at higher frequencies in CMV co-infected children with plasma HIV-1 < 50 copies/mL than in children with detectable plasma HIV-1 RNA (1.07% vs 0.07%; p < 0.05).
Conclusions: Frequencies of HIV-specific IFN-gamma+ CD4+ T-cells were higher in children with ongoing viral replication than in children with controlled viral replication; however, the in vitro proliferative capacity of HIV-specific CD4+ T-cells from children with ongoing viral replication was diminished. The lack of such proliferative responses, as well as the preservation of CMV-specific CD4+ T-cells in children with controlled HIV-1 replication suggests that interruption of therapy may have deleterious effects on the quality of HIV-1 and other virus-specific CD4+ T-cell responses. A vaccine to stimulate HIV-specific CD4+ T-cells in the context of antiretroviral therapy may improve virus-specific CD4+ T-cell function in these children.