Effects on immune system and viral reservoir of a short-cycle antiretroviral therapy in virologically suppressed HIV-positive patients.

BACKGROUND: Atripla dose reduction decreases subclinical toxicity and maintains viral suppression in HIV+ individuals but the virological efficacy and immunological safety of this strategy needs to be further confirmed. METHODS: Virologically suppressed HIV-infected adults on Atripla once-daily were randomized 1 : 1 to reduce therapy to 3 days a week (3W, n = 30) or to maintain it unchanged (once-daily, n = 31). HIV-1 reservoir (total and integrated HIV-1 DNA in CD4 cells) and immunological cell activation (CD38 and HLA-DR), senescence (CD57 and CD28), apoptosis (annexinV) as well as T-naive, effector memory (TEM) (CCR7, CD45RA) and stem cell memory (TSCM) (CD954 and CD27) populations were measured at baseline, 24 and 48 weeks. RESULTS: No differences on activation, senescence or apoptosis of both CD4 and CD8 T cells were observed on follow-up. Nave CD4 T-cell proportion showed a significant decrease in the 3W group (mean ±â€ŠSD): 24.6 ±â€Š13.7 vs. 20.5 ±â€Š12.9 (P = 0.002). No differences in both plasma viral load and HIV reservoir were detected on follow-up. CD4 TSCM levels at 48 weeks correlated with basal integrated HIV-1 DNA in the 3W group but not in the once-daily group. A post hoc analysis of data prior to the study entry revealed a higher viral load zenith and a trend to lower CD4 nadir in 3W vs. once-daily group. CONCLUSION: No significant immunological or viral changes were induced in the 3W group confirming the virological efficacy and immunogical safety of this strategy. In-depth virological and immunological analyses are useful in providing additional information in antiretroviral switching studies (Clinical Trials.gov: NCT01778413).

Cytomegalovirus m154 hinders CD48 cell-surface expression and promotes viral escape from host natural killer cell control.

Receptors of the signalling lymphocyte-activation molecules (SLAM) family are involved in the functional regulation of a variety of immune cells upon engagement through homotypic or heterotypic interactions amongst them. Here we show that murine cytomegalovirus (MCMV) dampens the surface expression of several SLAM receptors during the course of the infection of macrophages. By screening a panel of MCMV deletion mutants, we identified m154 as an immunoevasin that effectively reduces the cell-surface expression of the SLAM family member CD48, a high-affinity ligand for natural killer (NK) and cytotoxic T cell receptor CD244. m154 is a mucin-like protein, expressed with early kinetics, which can be found at the cell surface of the infected cell. During infection, m154 leads to proteolytic degradation of CD48. This viral protein interferes with the NK cell cytotoxicity triggered by MCMV-infected macrophages. In addition, we demonstrate that an MCMV mutant virus lacking m154 expression results in an attenuated phenotype in vivo, which can be substantially restored after NK cell depletion in mice. This is the first description of a viral gene capable of downregulating CD48. Our novel findings define m154 as an important player in MCMV innate immune regulation.