CD4 T-cell hyperactivation and susceptibility to cell death determine poor CD4 T-cell recovery during suppressive HAART

Abstract

The failure to increase CD4 T-cell counts in some HAART-treated HIV-infected patients with satisfactory virological responses has been related to low CD4 T-cell production, high turnover and death. However, the relative contribution of these factors is still unclear, strongly limiting the definition of appropriate therapeutic strategies for these patients. A cross-sectional study was designed to evaluate the contribution of thymic activity, microbial translocation, cellular activation and death to CD4 T-cell recovery. We included 230 HIV-infected individuals on suppressive HAART (>2 years); 95 of them were considered 'discordant' (CD4 T-cell count <350 cells/mul) and 135 were considered 'concordant'. Comparative and logistic regression analyses were performed. Discordant patients showed higher levels of activated [human leukocyte antigen (HLA)-DRCD95 and CD38CD45RA] cells in both the CD8 and CD4 T-cell compartments. Notably, the most significant differences were observed in CD4 T cells. Discordant patients showed lower naive CD4 T-cell production (CD45RACD31 cells), higher spontaneous ex-vivo CD4 T-cell death and higher plasma levels of soluble CD14. Multivariate analysis showed that activation and death of CD4 T cells, along with nadir CD4 T-cell counts, were the only predictive factors for poor immune recovery. Moreover, the low correlations found between CD4 T-cell activation or death with thymic output and bacterial translocation suggest that additional factors modulate cellular activation and death and, in turn, CD4 T-cell recovery. CD4 T-cell repopulation during HAART is determined by CD4 T-cell activation and death. Therefore, strategies aimed to reduce these parameters should be envisaged to treat discordant patients.