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Retroviruses, including HIV, can activate innate immune responses, but the host sensors for retroviruses are largely unknown. Here we show that HIV infection activates cyclic guanosine monophosphate—adenosine monophosphate (cGAMP) synthase (cGAS) to produce cGAMP, which binds to and activates the adaptor protein STING to induce type I interferons and other cytokines. Inhibitors of HIV reverse transcriptase, but not integrase, abrogated interferon-β induction by the virus, suggesting that the reverse-transcribed HIV DNA triggers the innate immune response. Knockout or knockdown of cGAS in mouse or human cell lines blocked cytokine induction by HIV, murine leukemia virus, and simian immunodeficiency virus. These results indicate that cGAS is an innate immune sensor of HIV and other retroviruses.

For the past two decades, scientists from around the world, working on different aspects of foamy virus (FV) research, have gathered in different research institutions almost every two years to present their recent results in formal talks, to discuss their ongoing studies informally, and to initiate fruitful collaborations. In this report we review the 2014 anniversary conference to share the meeting summary with the virology community and hope to arouse interest by other researchers to join this exciting field. The topics covered included epidemiology, virus molecular biology, and immunology of FV infection in non-human primates, cattle, and humans with zoonotic FV infections, as well as recent findings on endogenous FVs. Several topics focused on virus replication and interactions between viral and cellular proteins. Use of FV in biomedical research was highlighted with presentations on using FV vectors for gene therapy and FV proteins as scaffold for vaccine antigen presentation. On behalf of the FV community, this report also includes a short tribute to commemorate Prof. Axel Rethwilm, one of the leading experts in the field of retrovirology and foamy viruses, who passed away 29 July 2014.

The shortage of organs for transplantation is a major barrier to the treatment of organ failure. Although porcine organs are considered promising, their use has been checked by concerns about the transmission of porcine endogenous retroviruses (PERVs) to humans. Here we describe the eradication of all PERVs in a porcine kidney epithelial cell line (PK15). We first determined the PK15 PERV copy number to be 62. Using CRISPR-Cas9, we disrupted all copies of the PERV pol gene and demonstrated a >1000-fold reduction in PERV transmission to human cells, using our engineered cells. Our study shows that CRISPR-Cas9 multiplexability can be as high as 62 and demonstrates the possibility that PERVs can be inactivated for clinical application of porcine-to-human xenotransplantation.

Porcine endogenous retroviruses (PERVs) are integrated in the genome of all pigs, and some of them are able to infect human cells. Therefore, PERVs pose a risk for xenotransplantation, the transplantation of pig cells, tissues, or organ to humans in order to alleviate the shortage of human donor organs. Up to 2021, a huge body of knowledge about PERVs has been accumulated regarding their biology, including replication, recombination, origin, host range, and immunosuppressive properties. Until now, no PERV transmission has been observed in clinical trials transplanting pig islet cells into diabetic humans, in preclinical trials transplanting pig cells and organs into nonhuman primates with remarkable long survival times of the transplant, and in infection experiments with several animal species. Nevertheless, in order to prevent virus transmission to the recipient, numerous strategies have been developed, including selection of PERV-C-free animals, RNA interference, antiviral drugs, vaccination, and genome editing. Furthermore, at present there are no more experimental approaches to evaluate the full risk until we move to the clinic.

To establish chronic infections, viruses must develop strategies to evade the host's immune responses. Many retroviruses, including mouse mammary tumor virus (MMTV), are transmitted most efficiently through mucosal surfaces rich in microbiota. We found that MMTV, when ingested by newborn mice, stimulates a state of unresponsiveness toward viral antigens. This process required the intestinal microbiota, as antibiotic-treated mice or germ-free mice did not transmit infectious virus to their offspring. MMTV-bound bacterial lipopolysaccharide triggered Toll-like receptor 4 and subsequent interleukin-6 (IL-6)—dependent induction of the inhibitory cytokine IL-10. Thus, MMTV has evolved to rely on the interaction with the microbiota to induce an immune evasion pathway. Together, these findings reveal the fundamental importance of commensal microbiota in viral infections.

In a 2019 Pan-European Study, Portugal exhibited the highest prevalence of Feline Leukemia Virus (FeLV) infection (8.8%). Following the coronavirus disease 2019 (COVID-19) pandemic, it is crucial to evaluate how the prevalence of FeLV has evolved. FeLV infection is associated with the highest morbidity rates, primarily due to the increased incidence of diseases that compromise the health of cat populations, which varies according to the lifestyle and background of the cats studied. This study aimed (1) to estimate the prevalence and temporal trends of FeLV and FIV infections among cats presented to a university veterinary hospital in the Lisbon metropolitan area, and (2) to evaluate the clinical associations between FeLV infection, health status, and FeLV-related conditions in cats. Conducted over 4.5 years, from January 2019 to July 2023, this cross-sectional study took place at a teaching hospital and involved 1,124 cats that were tested serologically and/or by qPCR and RT-qPCR for FeLV. Information was gathered on the intrinsic and extrinsic characteristics of the cats, their health status, and any related diseases. The overall prevalence of FeLV was found to be 11.3% (95% CI: 9.5%−13.3%), with 1.8% (95% CI: 1.1%−2.7%) of cats co-infected with FIV, and it peaked in 2020 at 14.1% (95% CI: 7.5%−23.4%), with 2.4% (95% CI: 0.03%−8.2%) co-infected with FIV. Over the 4.5-year period, an increasing number of cats were tested, and more quantification of proviral and viral loads was performed. This indicated a more progressive course in 47.0% (31/66), of sick FeLV-infected cats, who exhibited a higher incidence of FeLV-related diseases. Although there was no significant difference in the average age between positive and negative cats, FeLV-positive cats demonstrated a higher rate of sickness (74.8%, n = 95). To the best of the authors’ knowledge, this study represents the largest cross-sectional investigation of FeLV infection prevalence and its health implications conducted in Portugal. Overall, the available data suggest a possible increase in FeLV prevalence in Portugal, concurrent with a declining vaccination rate from 14.2% to 5.0%. The results also highlight notable differences in clinical status between progressive and regressive disease courses, reinforcing the necessity of staging the course of infection at diagnosis to ensure an informed medical approach and realistic prognosis. Efforts should focus on improving vaccination and screening activities, promoting neutering of indoor and outdoor cats, and isolating infected cats.

This study aimed to characterize the clinical presentations and effects of progressive and regressive outcomes of feline leukemia virus (FeLV) infection on the life expectancy of cats. In total, 176 cats were selected: 116 with progressive infection (FeLV + P), 30 with regressive infection (FeLV + R), and 30 FeLV-negative cats (Control). The cats underwent testing using ELISA to detect the FeLV p27 antigen and nested polymerase chain reaction to identify U3-LTR region and gag proviral DNA. The cats were clinically monitored until their death or for a period ranging 12–54 months. Survival analysis was performed using Kaplan–Meier analysis and Cox regression. The median survival time following FeLV diagnosis was 30 days for the FeLV + P group. The median survival time was not reached for the other groups. The cats’ health status (sick) at the time of inclusion in the study and the progression status of the FeLV infection led to a 4–5-fold increase in the Hazard Ratio (HR) for death in the general population. The primary causes of death among cats in the FeLV + P group were lymphoma, leukemia, anemia, and other diseases. In the FeLV + R group, the causes of death included leukemia, anemia, and other diseases. Progressive FeLV infection reduced life expectancy, whereas regressive FeLV infection had no direct impact on the survival curve.

Natural killer (NK) cells are important early responders against viral infections. Changes in metabolism are crucial to fuel NK cell responses, and altered metabolism is linked to NK cell dysfunction in obesity and cancer. However, very little is known about the metabolic requirements of NK cells during acute retroviral infection and their importance for antiviral immunity. Here, using the Friend retrovirus mouse model, we show that following infection NK cells increase nutrient uptake, including amino acids and iron, and reprogram their metabolic machinery by increasing glycolysis and mitochondrial metabolism. Specific deletion of the amino acid transporter Slc7a5 has only discrete effects on NK cells, but iron deficiency profoundly impaires NK cell antiviral functions, leading to increased viral loads. Our study thus shows the requirement of nutrients and metabolism for the antiviral activity of NK cells, and has important implications for viral infections associated with altered iron levels such as HIV and SARS-CoV-2. Metabolic alterations control the fate and function of immune cells in response to infections, but the function of NK cell metabolism in the context of acute viral infections is unclear. Here the authors show that acute NK cell responses to Friend retrovirus involve increased glycolysis and mitochondrial metabolism and require amino acid transport as well as iron sufficiency.

Tight regulation of immune responses is not only critical for preventing autoimmune diseases but also for preventing immunopathological damage during infections in which overactive immune responses may be more harmful for the host than the pathogen itself. Regulatory T cells (Tregs) play a critical role in this regulation, which was discovered using the Friend retrovirus (FV) mouse model. Subsequent FV studies revealed basic biological information about Tregs, including their suppressive activity on effector cells as well as the molecular mechanisms of virus-induced Treg expansion. Treg suppression not only limits immunopathology but also prevents complete elimination of pathogens contributing to chronic infections. Therefore, Tregs play a complex role in the pathogenesis of persistent retroviral infections. New therapeutic concepts to reactivate effector T-cell responses in chronic viral infections by manipulating Tregs also came from work with the FV model. This knowledge initiated many studies to characterize the role of Tregs in HIV pathogenesis in humans, where a complex picture is emerging. On one hand, Tregs suppress HIV-specific effector T-cell responses and are themselves targets of infection, but on the other hand, Tregs suppress HIV-induced immune hyperactivation and thus slow the infection of conventional CD4+ T cells and limit immunopathology. In this review, the basic findings from the FV mouse model are put into perspective with clinical and basic research from HIV studies. In addition, the few Treg studies performed in the simian immunodeficiency virus (SIV) monkey model will also be discussed. The review provides a comprehensive picture of the diverse role of Tregs in different retroviral infections and possible therapeutic approaches to treat retroviral chronicity and pathogenesis by manipulating Treg responses.

Background: Although ∼20% of human cancers are caused by microorganisms, only suspicion exists for a microbial cause of lung cancer. Potential infectious agents were investigated in non-small cell lung cancer (NSCLC) and non-neoplastic lung. Methods: Seventy NSCLC tumours (33 squamous cell carcinomas, 17 adenocarcinomas, 10 adenocarcinomas with lepidic spread, and 10 oligometastases) and 10 non-neoplastic lung specimens were evaluated for molecular evidence of microorganisms. Tissues were subjected to the Lawrence Livermore Microbial Detection Array, an oncovirus panel of the International Agency for Research on Cancer, and human papillomavirus (HPV) genotyping. Associations were examined between microbial prevalence, clinical characteristics, and p16 and EGFR expression. Results: Retroviral DNA was observed in 85% squamous cell carcinomas, 47% adenocarcinomas, and 10% adenocarcinomas with lepidic spread. Human papillomavirus DNA was found in 69% of squamous cell carcinomas with 30% containing high-risk HPV types. No significant viral DNA was detected in non-neoplastic lung. Patients with tumours containing viral DNA experienced improved long-term survival compared with patients with viral DNA-negative tumours. Conclusions: Most squamous cell carcinomas and adenocarcinomas contained retroviral DNA and one-third of squamous cell carcinomas contained high-risk HPV DNA. Viral DNA was absent in non-neoplastic lung. Trial results encourage further study of the viral contribution to lung carcinogenesis.