204 research outputs found
Understanding drivers of experimental malaria sub-unit vaccine induced immunity in Tanzania volunteers
No full textDespite being a preventable and treatable disease, Plasmodium falciparum malaria remains a major threat, especially in children and pregnant women in sub-Saharan Africa. Considerable progress has been achieved during the past decade, however, these positive trends have stalled in 2017. Efforts towards better disease control and focal elimination are hindered by development and spread of insecticide and drug resistance, leaving a malaria vaccine as a required tool to complement these approaches. RTS, S a subunit pre-erythrocyte stage vaccine is the only advanced malaria vaccine that has received approval for pilot administration in three countries in sub-Saharan Africa. This vaccine is however challenged by low efficacy and fast waning of protection. There is, therefore, an urgent need for the development of more potent malaria vaccines. WHO targets malaria elimination by 2030 and achieving this goal will depend on stopping malaria transmission. This goal will largely depend on reducing asexual blood stage Plasmodium parasites – which are not only the cause of morbidity and mortality -but also responsible for the development of gametocytes. Induction of parasite growth inhibitory antibodies has been shown to be key for protection following natural exposure and therefore, many vaccine development approaches try to follow this guidance from nature.
In order to reach this goal of a highly protective vaccine targeting asexual blood stages with acceptable longevity of duration, more research is needed understand mechanisms of optimal induction of long-lived antibody responses in a population that is also affected from other co-infections like helminths or HIV. Therefore, this thesis aimed to 1) investigate a novel blood stage sub-unit malaria vaccine candidate, P27A, for its potential to induce long-lasting antibody responses when formulated in the novel adjuvant GLA-SE in malaria pre-exposed populations, 2) understanding magnitude and cytokine production of the CD4 T cell responses induced by this novel vaccine formulation and the interaction with ongoing helminth co-infections, 3) shed more light on the mechanism of GLA-SE adjuvant being able to induce high and long-lasting antibody responses by studying follicular helper T cells in peripheral blood, 4) implement lymph node excision biopsy in rural Tanzania for detailed investigation of germinal centre responses which are crucial for production of potent antibody response.
The antigen P27A, when formulated with GLA-SE, induced a robust humoral immunity, with enhanced production of cytophilic antibodies, IgG1 and IgG3 and expansion of CD4 Th1 cells producing IL2, TNFa and IFNg, and subsequent memory development. In addition, the adjuvant GLA-SE promoted the expansion of peripheral follicular helper T cells and recruitment of T cells bearing common T cell receptors, which is essential for a vaccine intended for the general population
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Observations on the trial of Mr. Robt. Perreau ::with Mr. Perreau's defence, as spoken on his trial, in which many unaccounted-for omissions in the sessions-paper are supplied, from a copy sent to the author by Mrs. R. Perreau an address to the Jury on Mr. R. Perreau's trial and such remarks on Mr. Rudd's narrative as tend to confirm the justness of these observations : the whole prefaced with correspondence between the author & Mrs. R. Perreau.
No full textObservations on the trial of Mr. Robt. Perreau ::with Mr. Perreau's defence, as spoken on his trial, in which many unaccounted-for omissions in the sessions-paper are supplied, from a copy sent to the author by Mrs. R. Perreau an address to the Jury on Mr. R. Perreau's trial and such remarks on Mr. Rudd's narrative as tend to confirm the justness of these observations : the whole prefaced with correspondence between the author & Mrs. R. Perreau.
No full textLocation, dynamics and expression of functional proteins in the HIV viral reservoir
No full textAfter HIV infection, the virus quickly spreads throughout the body and establishes a viral reservoir. Although effective Antiretroviral therapy (ART) can inhibit viral replication, functional virus persists in CD4+ T cells and is difficult to clear in large numbers in lymphoid organs. To better characterize these CD4+ T cells carrying replication-competent viruses, we established the HIV Gag and Envelope Reactivation co-Detection Assay (GERDA) and analyzed the tissue homing properties of cells that transiently appear in circulating blood. The presence and function of HIV in key body compartments was confirmed by GERDA in combination with proviral DNA and poly-A transcripts, with low viral activity in circulating cells early after diagnosis. CD4+ T cells carrying replication-competent virus were more likely to be lymph node homing, with TN and TCM being the primary viral reservoirs. We then performed an in- depth analysis of the env regions of circulating PBMCs and T cell subsets, and we found that individual immune system function was negatively correlated with the diversity of viral reservoirs, with archived viral sequences often containing inactivating mutations and showing higher genetic diversity in TTM and TEM.
HIV Tat can activate viral transcription by interacting with transactivation response element (TAR), Rev is needed for expression of late genes (eg Env, Gag). With a series of Tat and Rev mutants, we revealed a regulatory role for Rev in the early events of viral infection, and we found that premature expression of Rev in an artifact produced a dominant negative phenotype that interfered with wild-type viral production, suggesting that the non- complementary negative effects of Rev when expressed prior to HIV infection or prior to Tat expression suggest that i) Tat and Rev functions can be decoupled (Env expression without Tat) and ii) strict kinetic dependence is critical for a productive HIV infection in vitro. Our results provide an overall analysis of not only the location and dynamics of the viral reservoir but also the protein function of the virus, which provides a theoretical basis for understanding and clearing HIV latent reservoirs
Blood CXCR3+ CD4 T Cells Are Enriched in Inducible Replication Competent HIV in Aviremic Antiretroviral Therapy-Treated Individuals
No full textWe recently demonstrated that lymph nodes (LNs) PD-1+/T follicular helper (Tfh) cells from antiretroviral therapy (ART)-treated HIV-infected individuals were enriched in cells containing replication competent virus. However, the distribution of cells containing inducible replication competent virus has been only partially elucidated in blood memory CD4 T-cell populations including the Tfh cell counterpart circulating in blood (cTfh). In this context, we have investigated the distribution of (1) total HIV-infected cells and (2) cells containing replication competent and infectious virus within various blood and LN memory CD4 T-cell populations of conventional antiretroviral therapy (cART)-treated HIV-infected individuals. In the present study, we show that blood CXCR3-expressing memory CD4 T cells are enriched in cells containing inducible replication competent virus and contributed the most to the total pool of cells containing replication competent and infectious virus in blood. Interestingly, subsequent proviral sequence analysis did not indicate virus compartmentalization between blood and LN CD4 T-cell populations, suggesting dynamic interchanges between the two compartments. We then investigated whether the composition of blood HIV reservoir may reflect the polarization of LN CD4 T cells at the time of reservoir seeding and showed that LN PD-1+ CD4 T cells of viremic untreated HIV-infected individuals expressed significantly higher levels of CXCR3 as compared to CCR4 and/or CCR6, suggesting that blood CXCR3-expressing CD4 T cells may originate from LN PD-1+ CD4 T cells. Taken together, these results indicate that blood CXCR3-expressing CD4 T cells represent the major blood compartment containing inducible replication competent virus in treated aviremic HIV-infected individuals
Rotation in Multiple Correspondence Analysis: a planar rotation iterative procedure
No full textMultiple Correspondence Analysis (MCA) is a well-known multivariate method for statistical description of categorical data (see for instance Greenacre and Blasius, 2006). Similarly to what is done in Principal Component Analysis (PCA) and Factor Analysis, the MCA solution can be rotated to increase the components simplicity. The idea behind a rotation is to find subsets of variables which coincide more clearly with the rotated components. This implies that maximizing components simplicity can help in factor interpretation and in variables clustering. In PCA, the probably most famous rotation criterion is the varimax one introduced by Kaiser (1958). Besides, Kiers (1991) proposed a rotation criterion in his method named PCAMIX developed for the analysis of both numerical and categorical data, and including PCA and MCA as special cases. In case of only categorical data, this criterion is a varimax-based one relying on the correlation ratio between the categorical variables and the MCA numerical components. The optimization of this criterion is then reached by the algorithm of De Leeuw and Pruzansky (1978). In this paper, we give the analytic expression of the optimal angle of planar rotation for this criterion. If more than two principal components are to be retained, similarly to what is done by Kaiser (1958) for PCA, this planar solution is computed in a practical algorithm applying successive pairwise planar rotations for optimizing the rotation criterion. A simulation study is used to illustrate the analytic expression of the angle for planar rotation. The proposed procedure is also applied on a real data set to show the possible benefits of using rotation in MCA.categorical data, multiple correspondence analysis, correlation ratio, rotation, varimax criterion
Host Molecule Incorporation into HIV Virions, Potential Influences in HIV Pathogenesis
No full textDuring the last phase of HIV viral production, nascent HIV virions acquire a fraction of the cellular lipid membrane to create the external lipid envelope, a process by which cellular proteins present on the surface of the infected cell can be incorporated along with Env trimers. Interestingly, several studies indicated that these incorporated host molecules could conserve their biological activity and consequently contribute to HIV pathogenesis either by enhancing the infectivity of HIV virions, their tissue tropism or by affecting immune cell functions. The following review will describe the main approaches used to characterize membrane bound host molecule incorporation into HIV virions, the proposed mechanisms involved, and the role of a non-exhaustive list of incorporated molecules
Anthropologies philosophiques
No full textL’anthropologie philosophique fait depuis une dizaine d’années l’objet d’un véritable renouveau. On assiste en effet à un retour en grâce, en Allemagne comme en France ou en Italie, de la fameuse « anthropologie philosophique allemande » de l’entre-deux-guerres. Max Scheler, Arnold Gehlen, Helmuth Plessner, Paul Alsberg, autant de noms prestigieux et pourtant passablement oubliés, dont les hypothèses aventureuses (la « néoténie », la « positionnalité excentrique », « l’être lacunaire ») sont à nouveau commentées, prises au sérieux, discutées. Or il faut se souvenir qu’un tel mouvement a joué un rôle crucial, positivement ou négativement, dans l’histoire de la phénoménologie. Husserl, Heidegger, plus tard Patocka, Merleau-Ponty ou Blumenberg, eurent à prendre position, soit en assumant une certaine « phobie de l’anthropologie », constitutive de la phénoménologie historique, soit pour la surmonter et tenter alors une anthropologie « d’un point de vue phénoménologique ». Ce numéro de la revue Alter entend rouvrir ce dossier pour en explorer les différents aspects et en évaluer, à l’âge de la psychologie évolutionniste ou des spéculations sur le post-humain, toute la portée philosophique
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