Exome sequencing identifies HELB as a novel susceptibility gene for non-mucinous, non-high-grade-serous epithelial ovarian cancer.

Rare, germline loss-of-function variants in a handful of genes that encode DNA repair proteins have been shown to be associated with epithelial ovarian cancer with a stronger association for the high-grade serous hiostotype. The aim of this study was to collate exome sequencing data from multiple epithelial ovarian cancer case cohorts and controls in order to systematically evaluate the role of coding, loss-of-function variants across the genome in epithelial ovarian cancer risk. We assembled exome data for a total of 2,573 non-mucinous cases (1,876 high-grade serous and 697 non-high grade serous) and 13,925 controls. Harmonised variant calling and quality control filtering was applied across the different data sets. We carried out a gene-by-gene simple burden test for association of rare loss-of-function variants (minor allele frequency < 0.1%) with all non-mucinous ovarian cancer, high grade serous ovarian cancer and non-high grade serous ovarian cancer using logistic regression adjusted for the top four principal components to account for cryptic population structure and genetic ancestry. Seven of the top 10 associated genes were associations of the known ovarian cancer susceptibility genes BRCA1, BRCA2, BRIP1, RAD51C, RAD51D, MSH6 and PALB2 (false discovery probability < 0.1). A further four genes (HELB, OR2T35, NBN and MYO1A) had a false discovery rate of less than 0.1. Of these, HELB was most strongly associated with the non-high grade serous histotype (P = 1.3×10-6, FDR = 9.1×10-4). Further support for this association comes from the observation that loss of function variants in this gene are also associated with age at natural menopause and Mendelian randomisation analysis shows an association between genetically predicted age at natural menopause and endometrioid ovarian cancer, but not high-grade serous ovarian cancer.

Human T-Cell Leukemia Virus Type 1 (HTLV-1) bZIP Factor Upregulates the Expression of ICAM-1 To Facilitate HTLV-1 Infection.

Human T-cell leukemia virus type 1 (HTLV-1) causes multiple pathological effects, ranging from a form of leukemia to a spectrum of inflammation-mediated diseases. These diseases arise from one or several infected CD4+ T cells among thousands acquiring proliferation and survival advantages and ultimately becoming pathogenic. Given the low incidence of HTLV-1-associated diseases among carriers, such cellular evolutionary processes appear to occur rarely. Therefore, infectious spread of HTLV-1 within the T-cell population may be one underlying factor influencing disease development. Free HTLV-1 virions are poorly infectious, so infection of T cells relies on direct contact between infected and target cells. Following contact, virions pass to target cells through a virological synapse or cellular conduits or are transferred to target cells within an extracellular matrix. Lymphocyte functioning antigen 1 (LFA-1) on the surface of the target cell engaging with its ligand, ICAM-1, on the surface of the infected cell (effector cell) initiates and stabilizes cell-cell contact for infection. We found that stable expression of an HTLV-1 accessory protein, HTLV-1 bZIP factor (HBZ), in Jurkat T cells increases homotypic aggregation. This phenotype was attributed to elevated ICAM-1 expression in the presence of HBZ. Using a single-cycle replication-dependent luciferase assay, we found that HBZ expression in Jurkat cells (used as effector cells) increases HTLV-1 infection. Despite this effect, HBZ could not replace the critical infection-related functions of the HTLV-1 regulatory protein Tax. However, in HTLV-1-infected T cells, knockdown of HBZ expression did lead to a decrease in infection efficiency. These overall results suggest that HBZ contributes to HTLV-1 infectivity.IMPORTANCE Human T-cell leukemia virus type 1 (HTLV-1) causes a variety of diseases, ranging from a fatal form of leukemia to immune-mediated inflammatory diseases. These diseases occur rarely, arising from one or a small subset of virally infected cells infrequently evolving into a pathogenic state. Thus, the process of HTLV-1 cell-to-cell transmission within the host helps influence the probability of disease development. HTLV-1 primarily infects T cells and initially spreads within this cell population when virally infected T cells dock to uninfected target T cells and then transfer HTLV-1 virus particles to the target cells. Here we found that the viral protein HTLV-1 bZIP factor (HBZ) promotes infectivity. HBZ accomplishes this task by increasing the surface abundance of a cellular adhesion protein known as intercellular adhesion molecule 1 (ICAM-1), which helps initiate and stabilize contact (docking) between infected and target T cells. These results define a novel and unexpected function of HBZ, diverging from its defined functions in cellular survival and proliferation.

Identification, molecular and phylogenetic analysis of poxvirus in skin lesions of southern right whale.

Poxvirus skin disease has been reported in several species of cetaceans, principally in odontocetes, and a single report in mysticetes. Southern right whales Eubalaena australis in Peninsula Valdes, Argentina, show a variety of skin lesions of unknown etiology, and the number of these lesions has increased in recent years. Samples from dead whales were taken in order to establish the etiology of these lesions. One calf and one adult presented ring-type lesions, characterized by a circumscribed and slightly raised area of skin. Lesions were histologically characterized by the presence of microvesicles and vacuolated cells in the stratum spinosum, along with hyperplasia of the stratum corneum and eosinophilic inclusion bodies in the cytoplasm of the epithelial cells. Transmission electron microscopy showed aggregations of virions with typical poxvirus morphology. PCR of cetacean poxvirus (CPV) DNA polymerase, DNA topoisomerase I and parapoxvirus DNA polymerase gene fragments was done, and confirmed the presence of poxvirus in one sample. Phylogenetic analysis showed that the detected poxvirus belongs to the CPV-2 group. This is the first confirmed report of poxvirus in southern right whales in Argentina.