Compound heterozygous TYK2 mutations underlie primary immunodeficiency with T-cell lymphopenia.

Complete tyrosine kinase 2 (TYK2) deficiency has been previously described in patients with primary immunodeficiency diseases. The patients were infected with various pathogens, including mycobacteria and/or viruses, and one of the patients developed hyper-IgE syndrome. A detailed immunological investigation of these patients revealed impaired responses to type I IFN, IL-10, IL-12 and IL-23, which are associated with increased susceptibility to mycobacterial and/or viral infections. Herein, we report a recessive partial TYK2 deficiency in two siblings who presented with T-cell lymphopenia characterized by low naïve CD4+ T-cell counts and who developed Epstein-Barr virus (EBV)-associated B-cell lymphoma. Targeted exome-sequencing of the siblings' genomes demonstrated that both patients carried novel compound heterozygous mutations (c.209_212delGCTT/c.691C > T, p.Cys70Serfs*21/p.Arg231Trp) in the TYK2. The TYK2 protein levels were reduced by 35% in the T cells of the patient. Unlike the response under complete TYK2 deficiency, the patient's T cells responded normally to type I IFN, IL-6, IL-10 and IL-12, whereas the cells displayed an impaired response to IL-23. Furthermore, the level of STAT1 was low in the cells of the patient. These studies reveal a new clinical entity of a primary immunodeficiency with T-cell lymphopenia that is associated with compound heterozygous TYK2 mutations in the patients.

Molecular epidemiology of HIV type 1 infection in Iran: genomic evidence of CRF35_AD predominance and CRF01_AE infection among individuals associated with injection drug use.

To understand the molecular epidemiology of HIV-1 infection in Iran, we conducted the first study to analyze the genome sequence of Iranian HIV-1 isolates. For this cross-sectional study, we enrolled 10 HIV-1-infected individuals associated with injection drug use from Tehran, Shiraz, and Kermanshah. Near full-length genome sequences obtained from their plasma samples were used for phylogenetic tree and similarity plotting analyses. Among 10 isolates, nine were clearly identified as CRF35_AD and the remaining one as CRF01_AE. Interestingly, five of our Iranian CRF35_AD isolates made two clusters with 10 Afghan CRF35_AD isolates in a phylogenetic tree, indicating epidemiological connections among injection drug users in Iran and Afghanistan. In contrast, our CRF01_AE isolate had no genetic relationship with any other CRF01_AE isolates worldwide, even from Afghanistan. This study provides the first genomic evidence of HIV-1 CRF35_AD predominance and CRF01_AE infection among individuals associated with injection drug use in Iran.

Entry from the cell surface of severe acute respiratory syndrome coronavirus with cleaved S protein as revealed by pseudotype virus bearing cleaved S protein.

Severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV) is known to take an endosomal pathway for cell entry; however, it is thought to enter directly from the cell surface when a receptor-bound virion spike (S) protein is affected by trypsin, which induces cleavage of the S protein and activates its fusion potential. This suggests that SARS-CoV bearing a cleaved form of the S protein can enter cells directly from the cell surface without trypsin treatment. To explore this possibility, we introduced a furin-like cleavage sequence in the S protein at amino acids 798 to 801 and found that the mutated S protein was cleaved and induced cell fusion without trypsin treatment when expressed on the cell surface. Furthermore, a pseudotype virus bearing a cleaved S protein was revealed to infect cells in the presence of a lysosomotropic agent as well as a protease inhibitor, both of which are known to block SARS-CoV infection via an endosome, whereas the infection of pseudotypes with an uncleaved, wild-type S protein was blocked by these agents. A heptad repeat peptide, derived from a SARS-CoV S protein that is known to efficiently block infections from the cell surface, blocked the infection by a pseudotype with a cleaved S protein but not that with an uncleaved S protein. Those results indicate that SARS-CoV with a cleaved S protein is able to enter cells directly from the cell surface and agree with the previous observation of the protease-mediated cell surface entry of SARS-CoV.