Raltegravir intensification shows differing effects on CD8 and CD4 T cells in HIV-infected HAART-suppressed individuals with poor CD4 T-cell recovery

Abstract

Immunodiscordant HIV-infected patients show viral suppression during antiretroviral therapy but fail to recover CD4 T cells. Immunodiscordance is characterized by partial CD4 T-cell immunodeficiency and increased inflammation, activation and immunosenescence in both CD4 and CD8 T cells. A randomized, controlled, 48-week intensification study to assess the effect of raltegravir on immunological parameters in immunodiscordant patients (CD4 cell counts <350 cells/μl; viral load <50 copies/ml for >2 years). Patients were randomized (2 : 1) to intensify therapy with raltegravir (intensified arm, n = 30) or continue with the same therapy (control arm, n = 14). Both groups showed similar immunological baseline characteristics. CD4 T-cell counts increased faster in the intensified arm (P = 0.01, week 12). However, no differences between groups were observed at week 48. Additionally, no changes in thymic output (CD45RA(+)CD31(+) cells), activation (HLA-DR(+)CD95(+) cells) or ex-vivo cell death were observed in CD4 T cells at any time point intergroups or intragroups. Conversely, intensified arm showed significant decreases in the expression of the CD8 T-cell activation marker CD38 at weeks 24-48, which were more evident in memory cells. Despite this, the levels of HLA-DR expression in CD8 T cells and plasma soluble CD14 remained stable in both arms overtime. Long-term (48-week) raltegravir intensification failed to counterbalance CD4 T-cell deficiency and its associated features: hyperactivation and death of CD4 T cells. However, raltegravir induced a specific reduction of CD38 expression in CD8 T cells, suggesting a beneficial effect on CD8 T-cell hyperactivation, which has been linked with HIV-associated comorbidities.