Towards a vaccine against AIDS

International audiencen.

HIV gp41 Engages gC1qR on CD4+ T Cells to Induce the Expression of an NK Ligand through the PIP3/H2O2 Pathway

CD4+ T cell loss is central to HIV pathogenesis. In the initial weeks post-infection, the great majority of dying cells are uninfected CD4+ T cells. We previously showed that the 3S motif of HIV-1 gp41 induces surface expression of NKp44L, a cellular ligand for an activating NK receptor, on uninfected bystander CD4+ T cells, rendering them susceptible to autologous NK killing. However, the mechanism of the 3S mediated NKp44L surface expression on CD4+ T cells remains unknown. Here, using immunoprecipitation, ELISA and blocking antibodies, we demonstrate that the 3S motif of HIV-1 gp41 binds to gC1qR on CD4+ T cells. We also show that the 3S peptide and two endogenous gC1qR ligands, C1q and HK, each trigger the translocation of pre-existing NKp44L molecules through a signaling cascade that involves sequential activation of PI3K, NADPH oxidase and p190 RhoGAP, and TC10 inactivation. The involvement of PI3K and NADPH oxidase derives from 2D PAGE experiments and the use of PIP3 and H2O2 as well as small molecule inhibitors to respectively induce and inhibit NKp44L surface expression. Using plasmid encoding wild type or mutated form of p190 RhoGAP, we show that 3S mediated NKp44L surface expression on CD4+ T cells is dependent on p190 RhoGAP. Finally, the role of TC10 in NKp44L surface induction was demonstrated by measuring Rho protein activity following 3S stimulation and using RNA interference. Thus, our results identify gC1qR as a new receptor of HIV-gp41 and demonstrate the signaling cascade it triggers. These findings identify potential mechanisms that new therapeutic strategies could use to prevent the CD4+ T cell depletion during HIV infection and provide further evidence of a detrimental role played by NK cells in CD4+ T cell depletion during HIV-1 infection

Human Tick-Borne Diseases and Advances in Anti-Tick Vaccine Approaches: A Comprehensive Review

This comprehensive review explores the field of anti-tick vaccines, addressing their significance in combating tick-borne diseases of public health concern. The main objectives are to provide a brief epidemiology of diseases affecting humans and a thorough understanding of tick biology, traditional tick control methods, the development and mechanisms of anti-tick vaccines, their efficacy in field applications, associated challenges, and future prospects. Tick-borne diseases (TBDs) pose a significant and escalating threat to global health and the livestock industries due to the widespread distribution of ticks and the multitude of pathogens they transmit. Traditional tick control methods, such as acaricides and repellents, have limitations, including environmental concerns and the emergence of tick resistance. Anti-tick vaccines offer a promising alternative by targeting specific tick proteins crucial for feeding and pathogen transmission. Developing vaccines with antigens based on these essential proteins is likely to disrupt these processes. Indeed, anti-tick vaccines have shown efficacy in laboratory and field trials successfully implemented in livestock, reducing the prevalence of TBDs. However, some challenges still remain, including vaccine efficacy on different hosts, polymorphisms in ticks of the same species, and the economic considerations of adopting large-scale vaccine strategies. Emerging technologies and approaches hold promise for improving anti-tick vaccine development and expanding their impact on public health and agriculture

OA031-05. HIV escape from natural killer cytotoxicity: Nef inhibits NKp44L expression on HIV-infected CD4+ T cells

International audienc

HIV escape from natural killer cytotoxicity: nef inhibits NKp44L expression on CD4+ T cells.

International audienceOBJECTIVE: HIV infection induces a progressive depletion of CD4 T cells. We showed that NKp44L, a cellular ligand for an activating natural killer (NK) receptor, is expressed on CD4 T cells during HIV infection and is correlated with both CD4 cell depletion and increase in viral load. NKp44LCD4 T cells are highly sensitive to the NK lysis activity. In contrast, HIV-infected CD4 T cells are resistant to NK killing, suggesting that HIV-1 developed strategies to avoid detection by the host cell immunity. DESIGN: To assess whether viral protein can affect NKp44L expression, using Nef-deficient virus as well as a panel of recombinant vaccinia viruses expressing all HIV-1 viral proteins was tested. The involvement of Nef in the downmodulation of NKp44L was determined using defined mutants of Nef. Functional consequences of Nef on NK-cell recognition were evaluated by either 51Cr-release assays and degranulation assays in presence of anti-NKp44L mAb. RESULTS: We observed that during HIV-1 infection, noninfected CD4 T cells exclusively expressed NKp44L, and demonstrate that Nef mediates NKp44L intracellular retention in HIV-infected cells. This has functional consequences on HIV-infected CD4 T cells recognition by NK cells, causing a decreased susceptibility to NK cytotoxicity. Furthermore, experiments in presence of neutralizing NKp44L mAb revealed that Nef inhibitory effect on NK cytotoxicity mainly depends on the NKp44L pathway. CONCLUSION: This novel escape mechanism could explain the resistance of HIV-infected cells to NK lysis and as a result play a key role in maintaining the HIV reservoir by avoiding recognition by NK cells

Effects of Different Drug Combinations in Immunodeficient Mice Infected with an Influenza A/H3N2 Virus

The prolonged treatment of immunosuppressed (IS) individuals with anti-influenza monotherapies may lead to the emergence of drug-resistant variants. Herein, we evaluated oseltamivir and polymerase inhibitors combinations against influenza A/H3N2 infections in an IS mouse model. Mice were IS with cyclophosphamide and infected with 3 × 103 PFU of a mouse-adapted A/Switzerland/9715293/2013 (H3N2) virus. Forty-eight hours post-infection, the animals started oseltamivir, favipiravir or baloxavir marboxil (BXM) as single or combined therapies for 10 days. Weight losses, survival rates and lung viral titers (LVTs) were determined. The neuraminidase (NA) and polymerase genes from lung viral samples were sequenced. All untreated animals died. Oseltamivir and favipiravir monotherapies only delayed mortality (the mean day to death (MDD) of 21.4 and 24 compared to 11.4 days for those untreated) while a synergistic improvement in survival (80%) and LVT reduction was observed in the oseltamivir/favipiravir group compared to the oseltamivir group. BXM alone or in double/triple combination provided a complete protection and significantly reduced LVTs. Oseltamivir and BXM monotherapies induced the E119V (NA) and I38T (PA) substitutions, respectively, while no resistance mutation was detected with combinations. We found that the multiple dose regimen of BXM alone provided superior benefits compared to oseltamivir and favipiravir monotherapies. Moreover, we suggest the potential for drug combinations to reduce the incidence of resistance

SARS-CoV-2 infection-induced immunity reduces rates of reinfection and hospitalization caused by the Delta or Omicron variants

ABSTRACTDuring a pandemic, effective vaccines are typically in short supply, particularly at onset intervals when the wave is accelerating. We conducted an observational, retrospective analysis of aggregated data from all patients who tested positive for SARS-CoV-2 during the waves caused by the Delta and Omicron variants, stratified based on their known previous infection and vaccination status, throughout the University of Texas Medical Branch (UTMB) network. Next, the immunity statuses within each medical parameter were compared to naïve individuals for the effective decrease of occurrence. Lastly, we conducted studies using mice and pre-pandemic human samples for IgG responses to viral nucleocapsid compared to spike protein toward showing a functional component supportive of the medical data results in relation to the immunity types. During the Delta and Omicron waves, both infection-induced and hybrid immunities were associated with a trend of equal or greater decrease of occurrence than vaccine-induced immunity in hospitalizations, intensive care unit admissions, and deaths in comparison to those without pre-existing immunity, with hybrid immunity often trending with the greatest decrease. Compared to individuals without pre-existing immunity, those vaccinated against SARS-CoV-2 had a significantly reduced incidence of COVID-19, as well as all subsequent medical parameters. Though vaccination best reduces health risks associated with initial infection toward acquiring immunity, our findings suggest infection-induced immunity is as or more effective than vaccination in reducing the severity of reinfection from the Delta or Omicron variants, which should inform public health response at pandemic onset, particularly when triaging towards the allotment of in-demand vaccinations

Human and Livestock Surveillance Revealed the Circulation of Rift Valley Fever Virus in Agnam, Northern Senegal, 2021

The mosquito-borne disease caused by the Rift Valley Fever Virus (RVFV) is a viral hemorrhagic fever that affects humans and animals. In 1987, RVFV emerged in Mauritania, which caused the first RVFV outbreak in West Africa. This outbreak was shortly followed by reported cases in humans and livestock in Senegal. Animal trade practices with neighboring Mauritania suggest northern regions of Senegal are at high risk for RVF. In this study, we aim to conduct a molecular and serological survey of RVFV in humans and livestock in Agnam (northeastern Senegal) by RT-PCR (reverse transcription real-time polymerase chain reaction) and ELISA (Enzyme-Linked Immunosorbent Assay), respectively. Of the two hundred fifty-five human sera, one (0.39%) tested RVFV IgM positive, while fifty-three (20.78%) tested positive for RVFV IgG. For animal monitoring, out of 30 sheep recorded and sampled over the study period, 20 (66.67%) showed seroconversion to RVFV IgG antibodies, notably during the rainy season. The presence of antibodies increased significantly with age in both groups (p < 0.05), as the force of RVF infection (FOI), increased by 16.05% per year for humans and by 80.4% per month for livestock sheep. This study supports the usefulness of setting up a One Health survey for RVF management