Antigen-Presenting Cells Represent Targets for R5 HIV-1 Infection in the First Trimester Pregnancy Uterine Mucosa

BACKGROUND: During the first trimester of pregnancy, HIV-1 mother-to-child transmission is relatively rare despite the permissivity of placental cells to cell-to-cell HIV-1 infection. The placenta interacts directly with maternal uterine cells (decidual cells) but the physiological role of the decidua in the control of HIV-1 transmission and whether decidua could be a source of infected cells is unknown. METHODOLOGY/PRINCIPAL FINDINGS: To answer to this question, decidual mononuclear cells were exposed to HIV-1 in vitro. Decidual cells were shown to be more susceptible to infection by an R5 HIV-1, as compared to an X4 HIV-1. Infected cells were identified by flow cytometry analysis. The results showed that CD14(+) cells were the main targets of HIV-1 infection in the decidua. These infected CD14(+) cells expressed DC-SIGN, CD11b, CD11c, the Fc gamma receptor CD16, CD32 and CD64, classical MHC class-I and class-II and maturation and activation molecules CD83, CD80 and CD86. The permissivity of decidual tissue was also evaluated by histoculture. Decidual tissue was not infected by X4 HIV-1 but was permissive to R5 HIV-1. Different profiles of infection were observed depending on tissue localization. CONCLUSIONS/SIGNIFICANCE: The presence of HIV-1 target cells in the decidua in vitro and the low rate of in utero mother-to-child transmission during the first trimester of pregnancy suggest that a natural control occurs in vivo limiting cell-to-cell infection of the placenta and consequently infection of the fetus

Seminal Plasma Exposures Strengthen Vaccine Responses in the Female Reproductive Tract Mucosae

HIV-1 sexual transmission occurs mainly via mucosal semen exposures. In the female reproductive tract (FRT), seminal plasma (SP) induces physiological modifications, including inflammation. An effective HIV-1 vaccine should elicit mucosal immunity, however, modifications of vaccine responses by the local environment remain to be characterized. Using a modified vaccinia virus Ankara (MVA) as a vaccine model, we characterized the impact of HIV-1+ SP intravaginal exposure on the local immune responses of non-human primates. Multiple HIV-1+ SP exposures did not impact the anti-MVA antibody responses. However, SP exposures revealed an anti-MVA responses mediated by CD4+ T cells, which was not observed in the control group. Furthermore, the frequency and the quality of specific anti-MVA CD8+ T cell responses increased in the FRT exposed to SP. Multi-parameter approaches clearly identified the cervix as the most impacted compartment in the FRT. SP exposures induced a local cell recruitment of antigen presenting cells, especially CD11c+ cells, and CD8+ T cell recruitment in the FRT draining lymph nodes. CD11c+ cell recruitment was associated with upregulation of inflammation-related gene expression after SP exposures in the cervix. We thus highlight the fact that physiological conditions, such as SP exposures, should be taken into consideration to test and to improve vaccine efficacy against HIV-1 and other sexually transmitted infections

Modelling the response to vaccine in non-human primates to define SARS-CoV-2 mechanistic correlates of protection

The definition of correlates of protection is critical for the development of next-generation SARS-CoV-2 vaccine platforms. Here, we propose a model-based approach for identifying mechanistic correlates of protection based on mathematical modelling of viral dynamics and data mining of immunological markers. The application to three different studies in non-human primates evaluating SARS-CoV-2 vaccines based on CD40-targeting, two-component spike nanoparticle and mRNA 1273 identifies and quantifies two main mechanisms that are a decrease of rate of cell infection and an increase in clearance of infected cells. Inhibition of RBD binding to ACE2 appears to be a robust mechanistic correlate of protection across the three vaccine platforms although not capturing the whole biological vaccine effect. The model shows that RBD/ACE2 binding inhibition represents a strong mechanism of protection which required significant reduction in blocking potency to effectively compromise the control of viral replication.Initiative for the creation of a Vaccine Research InstituteInfrastructure nationale pour la modélisation des maladies infectieuses humaine

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

Rôle de l’immunité innée maternelle dans le contrôle de la transmission mère-enfant in utero du VIH-1

More than 25 years after the discovery of the Human Immunodeficiency Virus, there is still no effective vaccine against it. Since HIV-1 is transmitted primarily via the sexual pathway, an effective vaccine will need to provide mucosal protection. A better understanding of innate and mucosal immunity is therefore necessary for the development of a future protective vaccine against HIV-1. The uterine mucosa during pregnancy (the decidua) appears to be a relevant model of protection, since mother-to-child transmission of HIV-1 is rare in utero, especially during the first trimester of pregnancy. We hypothesised that the innate immunity of the decidua would be involved in the early stages of controlling transmission of the virus from mother to child. The objectives of this thesis work were to set up a model for studying human decidua in order to study HIV-1 infection and to identify the control mechanisms that may be present in this tissue. During the course of this thesis, we set up and validated an in vitro and ex vivo model for studying human decidual tissue using products from voluntary terminations of pregnancy carried out in the first trimester.Using this model, we showed that the decidua was permissive to in vitro infection by HIV-1 and preferentially by viruses with R5 tropism. For the first time, we identified the main viral target cells within this mucosa. These cells are CD14+ antigen-presenting cells expressing the CD11b+, CD11c+, DC-SIGN+, CD16+, CD32+, CD64+, HLA-DR+, HLA-ABC+, CD4+, CCR5+, CXCR4+, CD80+, CD86+/-, CD83+/-, IL-10+, IL-6+ and IL-1ra+ phenotypes. They therefore share properties with M2 macrophages and tolerogenic dendritic cells. The balance of soluble pro- and anti-inflammatory factors present in the decidua plays a part in controlling viral dissemination, notably via the production of β-chimokines by CD14+ cells and NK cells in the decidua. Following previous studies showing a protective role for peripheral NK cells against HIV-1 infection, we hypothesised that NK cells, the majority leukocyte population in the decidua during the first trimester, could play a role in controlling HIV-1 transmission. The phenotype of NK cells in the decidua is unique and we have shown in particular that the DNAM-1 receptor is not expressed by these cells, unlike their counterparts in the peripheral blood. We have also shown that the phenotype of decidua NK cells varies during the first trimester, with NKp30, NKp44, CD85j, CD158a and CD158b receptors decreasing with term, while the CD85j-NKG2D+ subpopulation increases. These cells could be involved in controlling HIV-1 dissemination at the maternal-foetal interface.Further work, in particular the establishment of a co-culture system between infected cells and NK cells, is underway to characterise in detail the control mechanisms within the decidua. These mechanisms will provide important information for consideration in the development of new protective vaccine strategies against HIV-1.Plus de 25 ans après la découverte du virus de l’Immunodéficience Humaine, il n’existe toujours pas de vaccin efficace contre ce virus. Le VIH-1 se transmettant avant tout par voies sexuelles, un vaccin efficace devra apporter une protection au niveau des muqueuses. Une meilleure compréhension de l’immunité innée et muqueuse est donc nécessaire à la mise en place d’un futur vaccin protecteur contre le VIH-1. La muqueuse utérine pendant la grossesse (la décidua) apparaît comme un modèle pertinent de protection puisque la transmission mère-enfant du VIH-1 est rare in utero surtout pendant le premier trimestre de grossesse. Nous avons émis l’hypothèse que l’immunité innée de la décidua interviendrait dans les premières étapes de contrôle de la transmission du virus de la mère à l’enfant. Les objectifs de ce travail de thèse étaient de mettre en place un modèle d’étude de la décidua humaine afin d’étudier l’infection VIH-1 et d’identifier les mécanismes de contrôle pouvant être présent au sein de ce tissu. Au cours de cette thèse, nous avons mis en place et validé un modèle d’étude in vitro et ex vivo du tissu décidual humain à partir de produits d’interruptions volontaires de grossesse réalisées au premier trimestre. Grâce à ce modèle, nous avons montré que la décidua était permissive à l’infection in vitro par le VIH-1 et préférentiellement par les virus de tropisme R5. Pour la première fois, nous avons identifié les principales cellules cibles du virus au sein de cette muqueuse. Ces cellules sont des cellules présentatrices d’antigène CD14+ exprimant le phénotype CD11b+, CD11c+, DC-SIGN+, CD16+, CD32+, CD64+, HLA-DR+, HLA-ABC+, CD4+, CCR5+, CXCR4+, CD80+, CD86+/−, CD83+/−, IL-10+, IL-6+ et IL-1ra+. Elles partagent donc des propriétés des macrophages M2 et des cellules dendritiques tolérogéniques. La balance des facteurs solubles pro- et anti-inflammatoires présents dans la décidua participe au contrôle de la dissémination virale notamment via la production de β-chimiokines par les cellules CD14+ et les cellules NK de la décidua. Suite aux précédentes études montrant un rôle protecteur des cellules NK de la périphérie contre l’infection VIH-1, nous avons émis l’hypothèse que les cellules NK, population leucocytaire majoritaire dans la décidua au premier trimestre, pourrait intervenir dans le contrôle de la transmission du VIH-1. Le phénotype des cellules NK de la décidua est unique et nous avons notamment montré que le récepteur DNAM-1 n’est pas exprimé par ces cellules contrairement à leurs homologues du sang périphérique. Nous avons également montré que le phénotype des cellules NK de la décidua varie au cours du premier trimestre puisque les récepteurs NKp30, NKp44, CD85j, CD158a et CD158b diminuent avec le terme alors que la sous-population CD85j-NKG2D+ augmente. Ces cellules pourraient être impliquées dans le contrôle de la dissémination du VIH-1 à l’interface materno-foetale. Des travaux complémentaires, et notamment la mise en place d’un système de co-culture entre cellules infectées et cellules NK, sont en cours afin de caractériser en détail les mécanismes de contrôle au sein de la décidua. Ces mécanismes donneront des éléments d’informations importantes à prendre en considération pour l’élaboration de nouvelles stratégies vaccinales protectrices contre le VIH-1

Rôle de l'immunité innée maternelle dans le contrôle de la transmission mère-enfant in utero du VIH-1

PARIS7-Bibliothèque centrale (751132105) / SudocSudocFranceF

Decidual soluble factors participate in the control of HIV-1 infection at the maternofetal interface

International audienceBackgroundMaternofetal transmission (MFT) of HIV-1 is relatively rare during the first trimester of pregnancy despite the permissivity of placental cells for cell-to-cell HIV-1 infection. Invasive placental cells interact directly with decidual cells of the uterine mucosa during the first months of pregnancy, but the role of the decidua in the control of HIV-1 transmission is unknown.ResultsWe found that decidual mononuclear cells naturally produce low levels of IL-10, IL-12, IL-15, TNF-α, IFN-α, IFN-γ and CXCL-12 (SDF-1), and large amounts of CCL-2 (MCP1), CCL-3 (MIP-1α), CCL-4 (MIP-1β), CCL-5 (Rantes), CXCL-10 (IP-10), IL-6 and IL-8. CCL-3 and CCL-4 levels were significantly upregulated by in vitro infection with R5 HIV-1 but not X4. Decidual CD14+ antigen presenting cells were the main CCL-3 and CCL-4 producers among decidual leukocytes. R5 and X4 HIV-1 infection was inhibited by decidual cell culture supernatants in vitro. Using HIV-1 pseudotypes, we found that inhibition of the HIV-1 entry step was inhibited by decidual soluble factors.ConclusionOur findings show that decidual innate immunity (soluble factors) is involved in the control of HIV-1 infection at the maternofetal interface. The decidua could thus serve as a mucosal model for identifying correlates of protection against HIV-1 infection