Efforts to cure HIV have focused on reactivating latent proviruses to enable elimination by CD8+ cytotoxic T-cells. Clinical studies of latency reversing agents (LRA) in antiretroviral therapy (ART)-treated individuals have shown increases in HIV transcription, but without reductions in virologic measures, or evidence that HIV-specific CD8+ T-cells were productively engaged. Here, we show that the SARS-CoV-2 mRNA vaccine BNT162b2 activates the RIG-I/TLR – TNF – NFκb axis, resulting in transcription of HIV proviruses with minimal perturbations of T-cell activation and host transcription. T-cells specific for the early gene-product HIV-Nef uniquely increased in frequency and acquired effector function (granzyme-B) in ART-treated individuals following SARS-CoV-2 mRNA vaccination. These parameters of CD8+ T-cell induction correlated with significant decreases in cell-associated HIV mRNA, suggesting killing or suppression of cells transcribing HIV. Thus, we report the observation of an intervention-induced reduction in a measure of HIV persistence, accompanied by precise immune correlates, in ART-suppressed individuals. However, we did not observe significant depletions of intact proviruses, underscoring challenges to achieving (or measuring) HIV reservoir reductions. Overall, our results support prioritizing the measurement of granzyme-B-producing Nef-specific responses in latency reversal studies and add impetus to developing HIV-targeted mRNA therapeutic vaccines that leverage built-in LRA activity.
En France, le niveau atteint par les prélèvements est de plus en plus contesté. À partir d’une enquête statistique inédite, l’article montre que l’exaspération à l’égard des prélèvements est étroitement liée à un sentiment d’injustice fiscale plus ou moins marqué selon les prélèvements et selon certaines caractéristiques sociales. Toutes choses égales par ailleurs, le sentiment d’injustice est particulièrement prégnant chez les femmes, les contribuables peu diplômés, les habitants en zones rurales, et il varie fortement avec l’âge. Les membres des classes populaires se montrent particulièrement critiques tandis que les bénéficiaires de niches fiscales sont plus satisfaits. Le jugement porté sur les différents prélèvements révèle deux conceptions de la justice fiscale, l’une valorisant l’objectif de réduction des inégalités est l’apanage des fonctionnaires et des contribuables orientés à gauche, et l’autre, défendue par les cadres, les chefs d’entreprise et professions libérales privilégiant l’initiative économique.
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The increasing access to the space domain has led to the growth of the on-orbit object population, as well as the evolution of space surveillance capabilities. With the increased public attention paid to spacecraft proximity and rendezvous operations, is an opportunity to examine what and how current space surveillance capabilities can contribute to this field. This thesis examines the feasibility and challenges associated with re-purposing an existing on-orbit space surveillance capability, the NEOSSat microsatellite, to perform proximity operations. The ability of NEOSSat to collect a sufficient number of accurate optical observations to determine the relative orbit of a target spacecraft is explored. A variety of observation events are explored with a collection of spacecraft to generate relative orbits using inertial orbit determination techniques. These practical results, to the author's knowledge, are the first in the field of relative orbit determination using inertial techniques between two co-orbital Low Earth Orbit satellites. iii iv List of Tables x List of Figures xi List of Accronyms xv Chapter 1 Chapter 6 Conclusion 113
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