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Therapeutic HIV vaccinations may alter the size of the resting memory CD4+ T-cell latent HIV reservoir as HIV establishes latency when memory responses are formed, including those toward HIV. Alternatively, latently infected CD4+ T cells maybe killed, while exiting the reservoir upon activation.The effect of therapeutic immunization with modified vaccinia Ankara and Fowlpox-based HIV vaccines on the latent reservoir was examined in 19 young adults who were receiving effective antiretroviral therapy. Correlations between size of the reservoir [measured in infectious units per million (IUPM)] resting CD4+ T cells and HIV-specific immune responses, including immune activation were examined. Decay of the reservoir was assessed using random-effects model.A modest transient decrease in the size of the reservoir was observed at week 40 [mean −0.31 log10 IUPM (95% confidence interval: −0.60 to −0.03; P = 0.03] following HIV vaccinations. The estimated half-life (T1/2) of the reservoir during the 40 weeks following vaccination was 9.8 months and statistically different from zero (P = 0.02), but 35.3 months and not different from zero (P = 0.21) over 72 weeks of study. Latent reservoir size at baseline was not correlated with HIV-specific CD4+, CD8+ responses or immune activation, but became correlated with CD4+ IFNγ (r = 0.54, P = 0.02) and IL-2 responses at 6 weeks after immunization (r = 0.48, P = 0.04).Therapeutic HIV vaccinations led to a transient increase in decay of latently infected CD4+ T cells. Further studies of therapeutic HIV vaccines may provide important insights into facilitating decay of the latent reservoir.