HIV-2/SIV Vpx antagonises NF-κB activation by targeting p65.

BACKGROUND: The NF-κB family of transcription factors and associated signalling pathways are abundant and ubiquitous in human immune responses. Activation of NF-κB transcription factors by viral pathogen-associated molecular patterns, such as viral RNA and DNA, is fundamental to anti-viral innate immune defences and pro-inflammatory cytokine production that steers adaptive immune responses. Diverse non-viral stimuli, such as lipopolysaccharide and cytokines, also activate NF-κB and the same anti-pathogen gene networks. Viruses adapted to human cells often encode multiple proteins targeting the NF-κB pathway to mitigate the anti-viral effects of NF-κB-dependent host immunity. RESULTS: In this study we have demonstrated using a variety of assays, in a number of different cell types including primary cells, that plasmid-encoded or virus-delivered simian immunodeficiency virus (SIV) accessory protein Vpx is a broad antagonist of NF-κB signalling active against diverse innate NF-κB agonists. Using targeted Vpx mutagenesis, we showed that this novel Vpx phenotype is independent of known Vpx cofactor DCAF1 and other cellular binding partners, including SAMHD1, STING and the HUSH complex. We found that Vpx co-immunoprecipitated with canonical NF-κB transcription factor p65, but not NF-κB family members p50 or p100, preventing nuclear translocation of p65. We found that broad antagonism of NF-κB activation by Vpx was conserved across distantly related lentiviruses as well as for Vpr from SIV Mona monkey (SIVmon), which has Vpx-like SAMHD1-degradation activity. CONCLUSIONS: We have discovered a novel mechanism by which lentiviruses antagonise NF-κB activation by targeting p65. These findings extend our knowledge of how lentiviruses manipulate universal regulators of immunity to avoid the anti-viral sequelae of pro-inflammatory gene expression stimulated by both viral and extra-viral agonists. Importantly our findings are also relevant to the gene therapy field where virus-like particle associated Vpx is routinely used to enhance vector transduction through antagonism of SAMHD1, and perhaps also through manipulation of NF-κB.

Clinical features and management of individuals admitted to hospital with monkeypox and associated complications across the UK: a retrospective cohort study.

BACKGROUND: The scale of the 2022 global mpox (formerly known as monkeypox) outbreak has been unprecedented. In less than 6 months, non-endemic countries have reported more than 67 000 cases of a disease that had previously been rare outside of Africa. Mortality has been reported as rare but hospital admission has been relatively common. We aimed to describe the clinical and laboratory characteristics and outcomes of individuals admitted to hospital with mpox and associated complications, including tecovirimat recipients. METHODS: In this cohort study, we undertook retrospective review of electronic clinical records and pathology data for all individuals admitted between May 6, and Aug 3, 2022, to 16 hospitals from the Specialist and High Consequence Infectious Diseases Network for Monkeypox. The hospitals were located in ten cities in England and Northern Ireland. Inclusion criteria were clinical signs consistent with mpox and MPXV DNA detected from at least one clinical sample by PCR testing. Patients admitted solely for isolation purposes were excluded from the study. Key outcomes included admission indication, complications (including pain, secondary infection, and mortality) and use of antibiotic and anti-viral treatments. Routine biochemistry, haematology, microbiology, and virology data were also collected. Outcomes were assessed in all patients with available data. FINDINGS: 156 individuals were admitted to hospital with complicated mpox during the study period. 153 (98%) were male and three (2%) were female, with a median age of 35 years (IQR 30-44). Gender data were collected from electronic patient records, which encompassed full formal review of clincian notes. The prespecified options for data collection for gender were male, female, trans, non-binary, or unknown. 105 (71%) of 148 participants with available ethnicity data were of White ethnicity and 47 (30%) of 155 were living with HIV with a median CD4 count of 510 cells per mm3 (IQR 349-828). Rectal or perianal pain (including proctitis) was the most common indication for hospital admission (44 [28%] of 156). Severe pain was reported in 89 (57%) of 156, and secondary bacterial infection in 82 (58%) of 142 individuals with available data. Median admission duration was 5 days (IQR 2-9). Ten individuals required surgery and two cases of encephalitis were reported. 38 (24%) of the 156 individuals received tecovirimat with early cessation in four cases (two owing to hepatic transaminitis, one to rapid treatment response, and one to patient choice). No deaths occurred during the study period. INTERPRETATION: Although life-threatening mpox appears rare in hospitalised populations during the current outbreak, severe mpox and associated complications can occur in immunocompetent individuals. Analgesia and management of superimposed bacterial infection are priorities for patients admitted to hospital. FUNDING: None.

A multi-centre observational study of HIV, tuberculosis and risk of chronic lung disease in urban West Africa.

OBJECTIVE: HIV and tuberculosis (TB) are risk factors for non-communicable chronic lung disease (CLD). Despite the high prevalence of these infections in West Africa, there are no studies that compare CLD between people with HIV and HIV-negative populations in this setting. This study sought to quantify the contribution of HIV and TB infection in addition to conventional CLD risk factors, such as tobacco and biofuel exposure, to CLD in urban West Africa. DESIGN: A multi-centre cross-sectional study was conducted in three community clinics in Lagos, Nigeria between 2018 and 2019. METHODS: Spirometry, questionnaires and clinical records were used to estimate prevalence of CLD and association with risk factors. RESULTS: In total, 148 HIV-negative individuals and 170 HIV-positive individuals completed the study. Current cigarette (11 of 318, 3.5%) and lifetime domestic biofuel (6 of 318, 1.8%) exposures were low. Airway obstruction (33 of 170, 19.4% vs. 12 of 148, 8.1%, P  = 0.004) and CLD (73 of 170, 42.9% vs. 34 of 148, 23%, P  < 0.0001) were more prevalent in people with HIV compared with the HIV-negative group. HIV infection [odds ratio 2.35 (1.33, 4.17), P  = 0.003] and history of TB [odds ratio 2.09 (1.04, 4.20), P  = 0.038] were independently associated with increased risk of CLD. CONCLUSION: HIV and TB far outweigh conventional risk factors, including tobacco and domestic biofuel exposure, as drivers of non-communicable CLD in urban West Africa. Current global policy for CLD may have limited impact on CLD in this setting. Enhanced prevention, diagnosis and management strategies for incident HIV and TB infections are likely to have a significant impact on long-term lung health in sub-Saharan Africa.

Liver transplantation for acute liver failure due to efavirenz hepatotoxicity: the importance of routine monitoring.

We present the first case report in the UK of acute liver failure caused by efavirenz therapy culminating in liver transplantation. A 26-year-old Zimbabwean woman commenced emtricitabine, tenofovir and efavirenz (Atripla) in December 2011. Her liver function tests at baseline and at 20 days after initiating antiretroviral therapy were normal. At three months of therapy her blood tests haemolysed and were not processed. She had previously missed follow-up appointments and on this occasion failed to return for repeat tests. She was not seen again until after six months of antiretroviral therapy when she presented to her general practitioner with acute liver failure. Her condition deteriorated and she required liver transplantation. She recovered well and re-started antiretroviral therapy to good effect. The case illustrates the value of routine monitoring after initiating antiretroviral therapy and the fundamental importance of engaging patients in long-term management to ensure safe treatment.