Biology subjects

Monceaux, V.

Publications and source records attributed to Monceaux, V..

3 recordsLinked to original sources

bioRxiv2026

Modeling how memory CD8 T cells can elicit post-treatment control of HIV infection

While most people living with HIV suffer progressive disease following cessation of antiretroviral therapy, a small fraction elicits lasting post-treatment control. Understanding the mechanisms underlying this control is key to devising effective HIV remission strategies. Although recent studies implicate memory CD8 T cells, how these cells establish lasting viremic control remains unknown. Here, we combine mathematical modeling and analysis of data from SIV-infected non-human primates to elucidate the underlying mechanisms. We recognized that sustained antigenic stimulation leads to heritable epigenetic remodeling of the CD8 T cell pool, impairing memory cell survivability. Antiretroviral therapy rapidly suppresses viremia, thereby arresting antigenic stimulation and preserving memory potential. The greater this preservation is, the better would be the memory recall response following viral rebound post-treatment. Our mathematical model based on this hypothesis predicts that post-treatment control is an alternative steady state to progressive infection, realized by strong memory-driven recall responses. Our model fits longitudinal virological data spanning the pre-, during-, and post-antiretroviral treatment phases of infection, and recapitulates the outcomes of progressive disease and long-term remission realized, the latter predominantly with early treatment initiation. It shows, consistently with data, that memory CD8 T cells could drive post-treatment control independently of the size of the latent reservoir, explaining how such control may be realized more widely than estimated with prevalent hypotheses. Our model further explains the existence of a window of treatment initiation times that maximizes the chances of post-treatment control. Finally, model predictions inform interventions targeting memory CD8 T cells for HIV remission.

immunology↗

bioRxiv2020

Anti-apoptotic clone 11 derived peptides induce in vitro death of CD4+ T cells susceptible to HIV-1 infection

HIV-1 successfully establishes long-term infection in its target cells despite viral cytotoxic effects. We have recently shown that cell metabolism is an important factor driving CD4+ T-cell susceptibility to HIV-1 and the survival of infected cells. We show here that expression of anti-apoptotic clone 11 (AAC-11), an anti-apoptotic factor upregulated in many cancers, increased with progressive CD4+ T cell memory differentiation in association with the expression of cell cycle, activation and metabolism genes and correlated with susceptibility to HIV-1 infection. Synthetic peptides based on the LZ domain sequence of AAC-11, responsible for its interaction with molecular partners, were previously shown to be cytotoxic to cancer cells. Here we observed that these peptides also blocked HIV-1 infection by inducing cell death of HIV-1 susceptible primary CD4+ T-cells across all T-cell subsets. The peptides targeted metabolically active cells and had the greatest effect on effector and transitional CD4+ T cell memory subsets. Our results suggest that AAC-11 survival pathway is potentially involved in the survival of HIV-1 infectable cells and provide a proof of principle that some cellular characteristics can be targeted to eliminate the cells offering the best conditions to sustain HIV-1 replication. IMPORTANCEAlthough antiretroviral treatment efficiently blocks HIV multiplication, it cannot eliminate the cells already carrying integrated proviruses. In the search for a HIV cure the identification of new potential targets to selectively eliminate infected cells is of the outmost importance. We show here that peptides derived from the anti-apoptotic clone 11 (AAC-11), which expression levels correlated with susceptibility to HIV-1 infection of CD4+ T-cells, induced cytotoxicity in CD4+ T-cells showing the highest levels of activation and metabolic activity, conditions known to favor HIV-1 infection. Accordingly, CD4+ T-cells that survived the cytotoxic action of the AAC-11 peptides were resistant to HIV-1 replication. Our results identify a new potential molecular pathway to target HIV-1 infection.

microbiology↗

bioRxiv2019

Optimal maturation of the SIV-specific CD8+ T-cell response after primary infection is associated with natural control of SIV. ANRS SIC study

Highly efficient virus-specific CD8+ T-cells are associated with immune control of HIV infection, but it remains unclear how these cells are generated and maintained over time. We used a macaque model of spontaneous control of SIVmac251 infection to monitor the development and evolution of potent antiviral CD8+ T-cell responses. SIV-specific CD8+ T-cells emerged during primary infection in all animals. However, the ability of CD8+ T cells to suppress SIV replication was low in early stages but increased after a period of maturation, temporally linked with the establishment of sustained low-level viremia in controller macaques. SIV-specific CD8+ T-cells with a central memory phenotype expressed higher levels of survival markers in controllers versus non-controllers. In contrast, a persistently skewed differentiation phenotype was observed among central memory SIV-specific CD8+ T-cells in non-controllers since primary infection, typified by relatively high expression levels of T-bet. Collectively, these data show that the phenotype of SIV-specific CD8+ T-cells defined early after SIV infection favor the gain of antiviral potency as a function of time in controllers, whereas SIV-specific CD8+ T-cell responses in non-controllers fail to gain antiviral potency due to early defects imprinted in the central memory pool.

immunology↗