Tolerance has its limits: how the thymus copes with infection

The thymus is required for T cell differentiation; a process that depends on which antigens are encountered by thymocytes, the environment surrounding the differentiating cells, and the thymic architecture. These features are altered by local infection of the thymus and by the inflammatory mediators that accompany systemic infection. Although once believed to be an immune privileged site, it is now known that antimicrobial responses are recruited to the thymus. Resolving infection in the thymus is important because chronic persistence of microbes impairs the differentiation of pathogen-specific T cells and diminishes resistance to infection. Understanding how these mechanisms contribute to disease susceptibility, particularly in infants with developing T cell repertoires, requires further investigation.We thank Joana Neves and Nadine Santos for critical reading of the manuscript. This work was supported by Portuguese Foundation for Science and Technology (FCT) grant PTDC/SAU-MII/101663/2008 and individual fellowships to CN-A and CN. SMB was supported by National Institutes of Health Grant R01 R56 AI067731

Transient Nature of Long-Term Nonprogression and Broad Virus-Specific Proliferative T-Cell Responses with Sustained Thymic Output in HIV-1 Controllers

HIV-1(+) individuals who, without therapy, conserve cellular anti-HIV-1 responses, present with high, stable CD4(+) T-cell numbers, and control viral replication, facilitate analysis of atypical viro-immunopathology. In the absence of universal definition, immune function in such HIV controllers remains an indication of non-progression.CD4 T-cell responses to a number of HIV-1 proteins and peptide pools were assessed by IFN-gamma ELISpot and lymphoproliferative assays in HIV controllers and chronic progressors. Thymic output was assessed by sjTRECs levels. Follow-up of 41 HIV-1(+) individuals originally identified as "Long-term non-progressors" in 1996 according to clinical criteria, and longitudinal analysis of two HIV controllers over 22 years, was also performed. HIV controllers exhibited substantial IFN-gamma producing and proliferative HIV-1-specific CD4 T-cell responses to both recombinant proteins and peptide pools of Tat, Rev, Nef, Gag and Env, demonstrating functional processing and presentation. Conversely, HIV-specific T-cell responses were limited to IFN-gamma production in chronic progressors. Additionally, thymic output was approximately 19 fold higher in HIV controllers than in age-matched chronic progressors. Follow-up of 41 HIV-1(+) patients identified as LTNP in 1996 revealed the transitory characteristics of this status. IFN-gamma production and proliferative T-cell function also declines in 2 HIV controllers over 22 years.Although increased thymic output and anti-HIV-1 T-cell responses are observed in HIV controllers compared to chronic progressors, the nature of nonprogressor/controller status appears to be transitory

Two-component spike nanoparticle vaccine protects macaques from SARS-CoV-2 infection

Brouwer et al. present preclinical evidence in support of a COVID-19 vaccine candidate, designed as a self-assembling two-component protein nanoparticle displaying multiple copies of the SARS-CoV-2 spike protein, which induces strong neutralizing antibody responses and protects from high-dose SARS-CoV-2 challenge.The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic is continuing to disrupt personal lives, global healthcare systems, and economies. Hence, there is an urgent need for a vaccine that prevents viral infection, transmission, and disease. Here, we present a two-component protein-based nanoparticle vaccine that displays multiple copies of the SARS-CoV-2 spike protein. Immunization studies show that this vaccine induces potent neutralizing antibody responses in mice, rabbits, and cynomolgus macaques. The vaccine-induced immunity protects macaques against a high-dose challenge, resulting in strongly reduced viral infection and replication i

Stroke genetics informs drug discovery and risk prediction across ancestries

Previous genome-wide association studies (GWASs) of stroke — the second leading cause of death worldwide — were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis3, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach4, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry5. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries

ETUDE DELA PATHOGENICITE DU VIRUS DE L'IMMUNODEFICIENCE SIMIENNE SIVMAC 251 DELTA NEF CHEZ LE MACAQUE RHESU (MACACA MULATTA) ET IMPLICATIONS VACCINALES

NANTES-Ecole Nat.Vétérinaire (441092302) / SudocSudocFranceF

Contribution des modèles du macaque rhésus infecté par un SIV sauvage ou atténué à la compréhension de la dynamique lymphocytaire lors de l'infection de l'homme par le VIH (importance de l'apport thymique)

Dans le modèle du macaque rhésus infecté par un SIV pathogène de type sauvage, nous avons éprouvé l'hypothèse de l'épuisement des capacités prolifératives comme cause possible du déclin du nombre de lymphocytes T CD4-K Dans une seconde étude, nous avons évalué la pathogénicité à long-terme d'un virus atténué, ainsi que la dynamique lymphocytaire au cours d'une telle infection. Nous montrons qu'au cours de l'infection, le nombre de lymphocytes T CD8+ activés augmente progressivement dans le sang et dans les ganglions des animaux infectés par un SIV sauvage. Cette augmentation est corrélée avec la replication virale et l'évolution vers un SIDA. En revanche, nous n'observons aucune augmentation du nombre de lymphocytes T CD4+ en cycle. Ainsi, ces résultats mettent en évidence des comportements distincts des populations lymphocytaires T CD4+ et CD8+ suite à une activation, Lors de l'infection du macaque par un SIV atténué, nous montrons qu'en dépit d'une réplication virale très faible, ce virus conserve des propriétés pathogènes. La réplication virale, ainsi que l'activation de lymphocytes T CD8+ corrèlent positivement avec la vitesse d'évolution vers la maladie. Alors que l'apport thymique en lymphocytes T CD8+ est globalement augmenté, une relation très significative existe entre l'apport thymique en lymphocytes T CD4+ dans le sang périphérique et la non-progression vers la maladie. Globalement, nos données suggèrent que l'apport thymique en nouveaux lymphocytes T serait un facteur déterminant dans l'immunopathologie qui mène au SIDA.PARIS7-Bibliothèque centrale (751132105) / SudocSudocFranceF

Simian Immunodeficiency Virus Promoter Exchange Results in a Highly Attenuated Strain That Protects against Uncloned Challenge Virus

Among the many simian immunodeficiency virus (SIV) immunogens, only live attenuated viral vaccines have afforded strong protection to a natural pathogenic isolate. Since the promoter is crucial to the tempo of viral replication in general, it was reasoned that promoter exchange might confer a novel means of attenuating SIV. The core enhancer and promoter sequences of the SIV macaque 239nefstop strain (NF-κB/Sp1 region from −114 bp to mRNA start) have been exchanged for those of the human cytomegalovirus immediate-early promoter (CMV-IE; from −525 bp to mRNA start). During culture of the resulting virus, referred to as SIVmegalo, on CEMx174 or rhesus macaque peripheral blood mononuclear cells, deletions arose in distal regions of the CMV-IE sequences that stabilized after 1 or 2 months of culture. However, when the undeleted form of SIVmegalo was inoculated into rhesus macaques, animals showed highly controlled viremia during primary and persistent infection. Compared to parental virus infection in macaques, primary viremia was reduced by >1,000-fold to undetectable levels, with little sign of an increase of cycling cells in lymph nodes, CD4(+) depletion, or altered T-cell activation markers in peripheral blood. Moreover, in contrast to wild-type infection in most infected animals, the nef stop mutation did not revert to the wild-type codon, indicating yet again that replication was dramatically curtailed. Despite such drastic attenuation, antibody titers and enzyme-linked immunospot reactivity to SIV peptides, although slower to appear, were comparable to those seen in a parental virus infection. When animals were challenged intravenously at 4 or 6 months with the uncloned pathogenic SIVmac251 strain, viremia was curtailed by ∼1,000-fold at peak height without any sign of hyperactivation in CD4(+)- or CD8(+)-T-cell compartment or increase in lymph node cell cycling. To date, there has been a general inverse correlation between attenuation and protection; however, these findings show that promoter exchange constitutes a novel means to highly attenuate SIV while retaining the capacity to protect against challenge virus

Use of a Novel Chimeric Mouse Model with a Functionally Active Human Immune System To Study Human Immunodeficiency Virus Type 1 Infection

The goal of this study was to develop a small-animal model to study human immunodeficiency virus type 1 (HIV-1) pathogenesis in blood and primary and secondary lymphoid organs. Rag2(−/−)γ(c)(−/−) mice that are neonatally injected with human CD34(+) cells develop a functional human immune system (HIS), with human hematopoietic cells being found in the thymuses, peripheral blood, spleens, and bone marrow of the animals (hereafter these animals are referred to as HIS-Rag2(−/−)γ(c)(−/−) mice). HIS-Rag2(−/−)γ(c)(−/−) mice were infected with small amounts of CCR5-tropic HIV-1. Viral replication and immunophenotypic changes in the human cells in peripheral blood and lymphoid organs were examined. The productive infection of human cells in peripheral blood, thymus and spleen tissue, and bone marrow was detected. Ratios of CD4(+) T cells to CD8(+) T cells in the infected animals declined. Although no specific anti-HIV-1 immune responses were detected, immunoglobulin M (IgM) and IgG antibodies to an unidentified fetal calf serum protein present in the virus preparation were found in the inoculated animals. Thus, we have shown that the HIS-Rag2(−/−)γ(c)(−/−) mouse model can be used for infection with low doses of CCR5-tropic HIV-1, which is most commonly transmitted during primary infections. HIS-Rag2(−/−)γ(c)(−/−) mice can serve as a small-animal model for investigating HIV-1 pathogenesis and testing potential HIV-1 therapies, and studies with this model may replace some long and costly studies with nonhuman primates