Pathogenesis and Treatment of HIV Infection

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications, trials & patents

Abstract

The Strategic Timing of AntiRetroviral Treatment (START) trial demonstrated that patients with HIV infection treated early (CD4+ >500 cells/L) with combination antiretroviral therapy (cART) did better than patients treated late (CD4+ <350 cells/L or AIDS) with respect to development of AIDS-related and serious non-AIDS related illnesses. In the present study we investigated associations of biomarkers of inflammation, coagulation, and vascular injury biomarkers with clinical manifestations of disease progression (AIDS and serious non-AIDS illnesses) or death, and the impact of early initiation of cART on these biomarkers. Biomarkers were measured from stored plasma prior to randomization and at month 8. Associations of baseline biomarkers with event risk were estimated with Cox regression, pooled across groups, adjusted for age, gender, and treatment group, and stratified by region. Mean changes over 8 months were estimated and compared between the immediate and deferred ART arms using analysis of covariance models, adjusted for levels at entry. Baseline biomarker levels were measured on 4299 START participants (92% of the entire cohort). Mean follow-up was 3.2 years. Higher levels of IL-6 and D-dimer were the only biomarkers associated with the combined risk for AIDS, serious non-AIDS illnesses or death, as well as the individual components of AIDS and serious non-AIDS events (HRs ranged 1.37-1.41 per 2-fold increase in either marker). This finding was independent of baseline CD4+ count, HIV-RNA level, and other biomarkers. At month 8, biomarker levels were lower in the immediate arm by 12%-21%. These data demonstrate that IL-6 and D-dimer consistently predict clinical risk across a broad spectrum of CD4 counts for those both ART-nave and treated and identify IL-6 and D-dimer as potential therapeutic targets. The peripheral blood represents only a small fraction of the total number of lymphocytes in the body. To develop a more thorough understanding of T cell dynamics, including the effects of SIV/SHIV/HIV infection on immune cell depletion and immune reconstitution following combination antiretroviral therapy (cART), one needs to utilize approaches that allow direct visualization of lymphoid tissues. In the present study, noninvasive in vivo imaging of the CD4+ T cell pool using a labelled and-CD4 antibody fragment has revealed that at 4 weeks following initiation or interruption of cART, the changes observed in peripheral blood (PB) are primarily related to changes in the whole-body CD4 pool rather than changes in lymphocyte trafficking. The timing of lymph node tissue reconstitution was found to be random among clusters of lymph nodes within the same host and lymph nodes did not reconstitute to the same level seen in healthy controls. In contrast, a statistically significant increase in the size of the splenic CD4+T cell pool was consistently seen as early as 4 weeks after the initiation of cART and splenic CD4 pools appeared similar between treated, infected animals and healthy controls. Overall, our data suggest that the dynamics of the CD4+ cell pool following initiation or interruption of ART in SIV-infected NHPs are only approximated by the dynamics observed in peripheral blood CD4 counts. In a related study, using FDG PET imaging of the brain, discontinuation of cART was associated with increased brain glucose metabolism in association with increased levels of pro-inflammatory cytokines in the spinal fluid.