EARLY REDUCTION OF IMMUNE ACTIVATION IN LYMPHOID-TISSUE FOLLOWING HIGHLY-ACTIVE HIV THERAPY

Objective: To evaluate immune reconstitution within HIV-infected lymph oid tissue during highly active antiretroviral therapy (HAART). Design and methods: In situ cellular responses were studied in sequential to nsil!ar biopsies in three asymptomatic HIV-infected (CD4 cells greater than 400 x 10(6)/l) antiretroviral treatment-naive volunteers enrolle d in a clinical trial to determine the early effect of HAART. Computer ized image analysis was used to study immunohistochemically stained se quential tonsil sections for the patterns of local cytokine production , chemokine receptor expression and cellular distribution. Replicate q uantitative assessments of samples before and after 4 weeks of therapy were used for the evaluation oi drug effects and compared with four u ninfected controls. Tonsillar HIV proviral-DNA was determined by fluor escent in situ 5'-nuclease assay. Results: HIV-infected tonsil tissue was characterized by extensive pro-inflammatory and type 1 cytokine ex pression. A five- to 15-fold elevation of interleukin (IL)-1 alpha, IL -12, IL-2 and interferon (IFN)-gamma protein expression was found comp ared with controls, and each encompassed a mean of at least 4.5% of th e tissue compartment. This was reduced by 20-90% in all individuals af ter 4 weeks of HAART. In contrast, type 2 cytokine expression (IL-4, I L-10), plus tumour necrosis factor (TNF)-alpha, remained low throughou t the study. HAART reduced, by 40%, the expression of HIV co-receptors , CCR5 and CXCR4, which initially were elevated four to six times over the control values. In addition, the myelomonocytic inflammatory prot eins, CD68 and calprotectin, diminished by 26-83% after therapy. The H IV RNA was reduced to undetectable levels in plasma by HAART. However, a large pool of tonsil cells (2-7%), remained HIV DNA positive after 4 weeks oi therapy. Conclusions: Although immune activation may be the direct consequence of HIV replication, HAART-associated reconstitutio n begins with a reduction in inflammatory cytokine production which pr ecedes the elimination of local proviral reservoirs. (C) 1998 Lippinco tt-Raven Publishers.