Barriers to Infection of Human Cells by Feline Leukemia Virus: Insights into Resistance to Zoonosis.

The human genome displays a rich fossil record of past gammaretrovirus infections, yet no current epidemic is evident, despite environmental exposure to viruses that infect human cells in vitro Feline leukemia viruses (FeLVs) rank high on this list, but neither domestic nor workplace exposure has been associated with detectable serological responses. Nonspecific inactivation of gammaretroviruses by serum factors appears insufficient to explain these observations. To investigate further, we explored the susceptibilities of primary and established human cell lines to FeLV-B, the most likely zoonotic variant. Fully permissive infection was common in cancer-derived cell lines but was also a feature of nontransformed keratinocytes and lung fibroblasts. Cells of hematopoietic origin were generally less permissive and formed discrete groups on the basis of high or low intracellular protein expression and virion release. Potent repression was observed in primary human blood mononuclear cells and a subset of leukemia cell lines. However, the early steps of reverse transcription and integration appear to be unimpaired in nonpermissive cells. FeLV-B was subject to G→A hypermutation with a predominant APOBEC3G signature in partially permissive cells but was not mutated in permissive cells or in nonpermissive cells that block secondary viral spread. Distinct cellular barriers that protect primary human blood cells are likely to be important in protection against zoonotic infection with FeLV.IMPORTANCE Domestic exposure to gammaretroviruses such as feline leukemia viruses (FeLVs) occurs worldwide, but the basis of human resistance to infection remains incompletely understood. The potential threat is evident from the human genome sequence, which reveals many past epidemics of gammaretrovirus infection, and from recent cross-species jumps of gammaretroviruses from rodents to primates and marsupials. This study examined resistance to infection at the cellular level with the most prevalent human cell-tropic FeLV variant, FeLV-B. We found that blood cells are uniquely resistant to infection with FeLV-B due to the activity of cellular enzymes that mutate the viral genome. A second block, which appears to suppress viral gene expression after the viral genome has integrated into the host cell genome, was identified. Since cells derived from other normal human cell types are fully supportive of FeLV replication, innate resistance of blood cells could be critical in protecting against cross-species infection.

Neurectomy versus Nerve Sparing in Open Inguinal Hernia Repair: A Randomised Controlled Trial.

OBJECTIVE:  To determine the effect of neurectomy in reducing the frequency of chronic inguinodynia after mesh hernioplasty in open inguinal hernia repair. STUDY DESIGN: Single blind randomised controlled-trial. PLACE AND DURATION OF STUDY: Surgical Unit-I, Department of General Surgery, Services Hospital, Lahore, Pakistan from September 2018 to September 2019. METHODOLOGY: All male patients undergoing open groin hernia surgery were included in the study. A total of 100 patients were randomly categorised into group A (neurectomy group) and group B (nerve sparing group). Patients were followed up for three months for the development of chronic inguinodynia. Signifiance was determined at p <0.05 using Chi-square and Fisher's exact tests. RESULTS: Out of 100 patients, 50 patients were enrolled in group A, while 50 were enrolled in group B. Mean age of patients was 42.1 ± 17.5 years. The median (IQR) acute pain score in neurectomy group was 3.0 (2.0-4.0), while median (IQR) acute pain score was 4.0 (3.0-6.0) in nerve sparing group with statistically significant difference (z = -3.256, p = 0.001). The frequency of chronic inguinodynia was significantly less in group A compared to group B [3 (6%) vs. 13 (26%), p = 0.012]. CONCLUSION: Excision of ilioinguinal and iliohypogastric nerve in inguinal mesh hernioplasty reduces the frequency of chronic inguinodynia. Ilioinguinal neurectomy may be practised routinely in patients undergoing Lichtenstein mesh hernioplasty.   Key Words: Inguinal neurectomy, Inguinal hernia, Chronic inguinodynia, Lichtenstein mesh hernioplasty.

Gamma-Retrovirus Integration Marks Cell Type-Specific Cancer Genes: A Novel Profiling Tool in Cancer Genomics.

Retroviruses have been foundational in cancer research since early studies identified proto-oncogenes as targets for insertional mutagenesis. Integration of murine gamma-retroviruses into the host genome favours promoters and enhancers and entails interaction of viral integrase with host BET/bromodomain factors. We report that this integration pattern is conserved in feline leukaemia virus (FeLV), a gamma-retrovirus that infects many human cell types. Analysis of FeLV insertion sites in the MCF-7 mammary carcinoma cell line revealed strong bias towards active chromatin marks with no evidence of significant post-integration growth selection. The most prominent FeLV integration targets had little overlap with the most abundantly expressed transcripts, but were strongly enriched for annotated cancer genes. A meta-analysis based on several gamma-retrovirus integration profiling (GRIP) studies in human cells (CD34+, K562, HepG2) revealed a similar cancer gene bias but also remarkable cell-type specificity, with prominent exceptions including a universal integration hotspot at the long non-coding RNA MALAT1. Comparison of GRIP targets with databases of super-enhancers from the same cell lines showed that these have only limited overlap and that GRIP provides unique insights into the upstream drivers of cell growth. These observations elucidate the oncogenic potency of the gamma-retroviruses and support the wider application of GRIP to identify the genes and growth regulatory circuits that drive distinct cancer types.

Frequent infection of human cancer xenografts with murine endogenous retroviruses in vivo.

Infection of human cancer xenografts in mice with murine leukemia viruses (MLVs) is a long-standing observation, but the likelihood of infection in vivo and its biological consequences are poorly understood. We therefore conducted a prospective study in commonly used xenograft recipient strains. From BALB/c nude mice engrafted with MCF7 human mammary carcinoma cells, we isolated a virus that was virtually identical to Bxv1, a locus encoding replication-competent xenotropic MLV (XMLV). XMLV was detected in 9/17 (53%) independently isolated explants. XMLV was not found in primary leukemias or in THP1 leukemia cells grown in Bxv1-negative NSG (NOD/SCID/γCnull) mice, although MCF7 explants harbored replication-defective MLV proviruses. To assess the significance of infection for xenograft behavior in vivo, we examined changes in growth and global transcription in MCF7 and the highly susceptible Raji Burkitt lymphoma cell line chronically infected with XMLV. Raji cells showed a stronger transcriptional response that included up-regulation of chemokines and effectors of innate antiviral immunity. In conclusion, the risk of de novo XMLV infection of xenografts is high in Bxv1 positive mice, while infection can have positive or negative effects on xenograft growth potential with significant consequences for interpretation of many xenograft studies.

Chylothorax in a case of Non-Hodgkin's lymphoma.

A case of asymptomatic 60 years old male diagnosed as Non-Hodgkin's lymphoma (angioimmunoblastic T-cell type) invading thoracic duct leading to chylothorax is presented. Generally, patients with this moderately aggressive lymphoma are adults who exhibit generalized lymphadenopathy, B-symptoms, polyclonal hypergammaglobulinemia, skin rash and various autoimmune phenomena.