Normalization of immune activation in lymphoid tissue following highly active antiretroviral therapy

Although significant progress has been made in understanding immune reconstitution in peripheral blood following highly active antiretroviral therapy (HAART), less is known about immune changes in lymphoid tissue. Here, the expression of cytokine proteins (interferon gamma [IFN-gamma], interleukin [IL]-2, IL-4, IL-10, IL-1 alpha, and IL-1 beta) and surface antigens (CD4, CD8, CD1a, CD68) as well as cellular proviral HIV-I DNA were determined in sequential tonsil biopsies before and at 4, 12, and 48 to 56 weeks posttherapy by quantitative in situ image analysis and fluorescent in situ 5'-nuclease assay (FISNA). Despite plasma virus suppression, a fraction of tonsil cells harbored pro-viral DNA for up to 1 year. A fourfold to eightfold increase in CD8(+) T cells in tissue compared with seronegative controls and an increased frequency of CD1a(+) dendritic cells prior to HAART reached control levels at week 56. The frequency of IFN-gamma expressing cells was 10- to 15-fold higher than controls before therapy and was comparable with findings in seronegative controls by week: 56. Elevated baseline expression of IL-1 alpha and IL-1 beta was reduced by week 4 but IL-1 alpha levels remained elevated in 1 of 3 patients at week 56. These findings suggest that with effective viral suppression the immune system in tissue may return to a more resting state.