NCT02067962; Results.

The intensity of expression of the chemokine receptor CCR5 is involved in in vitro cell infectability by human immunodeficiency virus (HIV)-1 R5 isolates. Because CCR5 expression varies among individuals, the hypothesis that this expression could determine virus load in HIV-1-infected persons was tested. The mean number of CCR5 molecules per cell was measured on peripheral blood CD4+ T lymphocytes (CCR5 density) from HIV-1-infected, asymptomatic, nontreated adults. There was a strong correlation between HIV RNA plasma level and CCR5 density (P=.009) that was independent of cell activation and was not due to an HIV-induced CCR5 up-regulation. These data are compatible with the hypothesis that CCR5 density is a key factor governing cell infectability and in vivo virus production and explain the protective effect of the Delta32CCR5 deletion, which results in low CCR5 expression. CCR5 density might be of critical predictive value in HIV infection.

BACKGROUND Combined immunodeficiency (CID) is characterized by severe recurrent infections with normal numbers of T and B lymphocytes, but deficient cellular and humoral immunity. Most cases are sporadic, but autosomal recessive inheritance has been described. In the majority of cases, the cause of CID remains unknown. OBJECTIVE To identify the genetic cause of CID in two siblings, the products of a first-cousin marriage, who suffered from recurrent bacterial and candidal infections with bronchiectasis, growth delay, and early death. METHODS We performed immunologic, genetic, and biochemical studies in the two siblings, their family members and healthy controls. Reconstitution studies were performed using T cells from Malt1−/− mice. RESULTS The numbers of circulating T and B lymphocytes were normal, but T cell proliferation to antigens and antibody responses to vaccination were severely impaired in both patients. Whole genome sequencing (WGS) of one patient and her parents, followed by DNA sequencing of family members and healthy controls, revealed the presence in both patients of a homozygous missense mutation in MALT1 that resulted in loss of protein expression. Analysis of T cells that were available on one of the patients revealed severely impaired IκBα degradation and IL-2 production after activation, two events that depend on MALT1. In contrast to wild type human MALT1, the patients' MALT1 mutant failed to correct defective NF-κB activation and IL-2 production in MALT1 deficient mouse T cells. CONCLUSIONS An autosomal recessive form of CID is associated with homozygous mutations in MALT1. Should future patients found to be similarly affected they should be considered as candidates for allogeneic hematopoietic cell transplantation.

The development of multidrug-resistant viruses compromises antiretroviral therapy efficacy and limits therapeutic options. Therefore, it is an ongoing task to identify new targets for antiretroviral therapy and to develop new drugs. Here, we show that an indole derivative (IDC16) that interferes with exonic splicing enhancer activity of the SR protein splicing factor SF2/ASF suppresses the production of key viral proteins, thereby compromising subsequent synthesis of full-length HIV-1 pre-mRNA and assembly of infectious particles. IDC16 inhibits replication of macrophage- and T cell–tropic laboratory strains, clinical isolates, and strains with high-level resistance to inhibitors of viral protease and reverse transcriptase. Importantly, drug treatment of primary blood cells did not alter splicing profiles of endogenous genes involved in cell cycle transition and apoptosis. Thus, human splicing factors represent novel and promising drug targets for the development of antiretroviral therapies, particularly for the inhibition of multidrug-resistant viruses.