HAART reduces death ligand but not death receptors in lymphoid tissue of HIV-infected patients and simian immunodeficiency virus-infected macaques

Abstract

Objective: To determine how antiretroviral therapy (ART) or HAART affects the expression of apoptotic ligands and their death receptors in the blood and lymphoid tissues of HIV-infected patients and simian immunodeficiency virus-infected macaques.

Methods: We analyzed the mRNA expression of death molecules [tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and FasL] and their receptors (DR5 and Fas) in blood and tonsils from HIV-infected patients (HIV positive), HIV-infected patients receiving HAART and HIV-uninfected (HIV negative) donors in a cross-sectional study. We comparatively analyzed mRNA expression of TRAIL and DR5 in blood and lymph nodes collected longitudinally from simian immunodeficiency virus-infected macaques before and after ART.

Results: Expression of TRAIL, FasL, DR5 and Fas was elevated in circulating CD4 T cells from a group of HIV-positive patients as compared with that from both HIV-negative donors and HAART patients. In a different study group, TRAIL, FasL, DR5 and Fas were increased in tonsils of HIV-positive patients as compared with HIV-negative donors and HAART patients. However, tonsils from HAART patients showed reduced expression of TRAIL and FasL but not DR5 and Fas as compared with HIV-positive patients. Similarly, data obtained in a longitudinal study of simian immunodeficiency virus-infected macaques showed that ART reduced both TRAIL and DR5 in peripheral blood but only TRAIL and not DR5 in lymph nodes from the same animals.

Conclusion: These findings suggest that HAART or ART is ineffective in reducing the expression of apoptotic death receptors in lymphoid tissue. However, analysis limited to blood leukocytes may not reveal such a defect. Our results highlight the persistence of an underlying immunologic condition that may prevent therapy-induced restoration of CD4 T cells in lymphoid tissue.

Fig. 1.

Plasma TRAIL, IFN-α and mRNA for apoptotic ligands and receptors in blood and tonsils. (A) left: Plasma TRAIL in HIV− donors, (n=45), HIV+ patients (n=45) and HAART patients (n=45). (A) right: IFN-α detected by immunohistochemistry in T cell-rich areas of tonsils from HIV− donors, HIV+ patients and HAART patients. mRNA expression for TRAIL (B), FasL (C), DR5 (D) and Fas (E) in isolated blood CD4⁺ cells (left) and in whole tonsil tissue (right) from HIV− donors, HIV+ patients and HAART patients. Data of B-E were compared by the Mann-Whitney test; NS = not significant (P>0.05). Horizontal bars: median values; upper and lower limits of boxes are 75^th and 25^th percentiles; vertical lines indicate 90^th and 10^th percentiles.

Fig. 2.

TRAIL and DR5 mRNA expression in leukocytes harvested from blood and axillary lymph nodes of 5 macaques before (Pre-ART) and 10 weeks after receiving therapy (ART). (A) Verification of ART-induced decrease in viral load, and clinical information of macaques in the study. (B) Comparison of TRAIL expression Pre-ART and ART in blood (left) and lymph nodes (right). (C) Comparison of DR5 expression Pre-ART and ART in blood (left) and lymph nodes (right). Horizontal bars indicate mean values of TRAIL and DR5