Combination antiretroviral therapy (ART) has resulted in a major decrease in morbidity and mortality in HIV- infection. However, ART does not eradicate virus or restore HIV-specific immune responses capable of controlling viral replication once therapy is interrupted. Development of interventions that could generate immune responses capable of maintaining HIV suppression after cessation of ART and improve efficacy of vaccine candidates would be a crucial clinical advance. Evidence suggests that effective HIV-specific CD4 T cells will be required to achieve this goal, yet these cells remain seriously understudied. The lack of restoration of effective HIV-specific CD4 T helper responses in spite of extended ART raised the possibility that these responses are irreversibly crippled. However, the results we have generated during the first four years of this grant support a striking conclusion: that CD4 T cell impairment in HIV-infection is to a significant extent under control of inhibitory mechanisms that can be reverted by manipulation of regulatory networks. Data suggest that one of these pathways, PD-1, also plays an important role in the maintenance of HIV reservoirs, making it a very attractive therapeutic target. In this competing renewal we propose to build on the major progress made during the initial funding period and to utilize combined approaches of cellular biology, molecular immunology and advanced cell imaging to pinpoint critical events that regulate effective and inefficient HIV-specific CD4 T cell responses. We also propose to investigate another neglected area of HIV-research: the impact that ineffective HIV-specific CD4 T cell responses have on antigen-presenting cell functions.
In Aim 1, we will identify critical gene signatures of functional and exhausted HIV-specific CD4 T cells. We will determine the master transcription factors that are regulated by PD-1 in HIV-specific CD4 T cells and define their role in the control of exhausted CD4 T cell functions. We will examine the potential for HIV-specific CD4 T cell functional plasticity by overexpressing or silencing these master genes in primary cells.
In Aim 2 we will use advanced live imaging to determine the dynamics of immunological synapses built by functional and exhausted HIV- specific CD4 T cells. We will define the role of individual co-inhibitors and determine whether optimized co- stimulatory signaling can prevent this defective synapse formation and function.
In Aim 3 we will define specific defects in licensing of antigen-presenting cells by HIV-specific CD4 T cells, and specific mechanisms of APC impairment. We will determine whether APC present inappropriate responses to stimulatory signals. By selectively blocking molecules expressed by dysfunctional CD4 T cells, we will determine events causally involved in the perturbation of APC functions. We will also define how the interplay between regulatory pathways leads to the observed defects. This proposal will provide novel understanding of the molecular basis for functional differences between protective and ineffective HIV-specific CD4 T cells and will identify new therapeutic targets to generate effective HIV-specific immunity in ART-treated and uninfected persons.
Antiviral therapy (ART) that blocks replication of HIV has resulted in a dramatic improvement in the quality of life for people living with HIV/AIDS. However, specific white cells that recognize HIV, called T cells, remain incapable of effectively fighting the virus on their own. As current treatments do not eliminate HIV, the virus therefore quickly multiplies again if treatment is interrupted. In these studies, we propose to identify the mechanisms that prevent proper T cell responses against HIV in infected persons, and to look for ways to rescue the ability of these T cells to control HIV.
|Prévost, Jérémie; Zoubchenok, Daria; Richard, Jonathan et al. (2017) Influence of the Envelope gp120 Phe 43 Cavity on HIV-1 Sensitivity to Antibody-Dependent Cell-Mediated Cytotoxicity Responses. J Virol 91:|
|Baxter, Amy E; Niessl, Julia; Fromentin, Rémi et al. (2017) Multiparametric characterization of rare HIV-infected cells using an RNA-flow FISH technique. Nat Protoc 12:2029-2049|
|Reiss, Samantha; Baxter, Amy E; Cirelli, Kimberly M et al. (2017) Comparative analysis of activation induced marker (AIM) assays for sensitive identification of antigen-specific CD4 T cells. PLoS One 12:e0186998|
|Richard, Jonathan; Prévost, Jérémie; von Bredow, Benjamin et al. (2017) BST-2 Expression Modulates Small CD4-Mimetic Sensitization of HIV-1-Infected Cells to Antibody-Dependent Cellular Cytotoxicity. J Virol 91:|
|Levast, Benoît; Barblu, Lucie; Coutu, Mathieu et al. (2017) HIV-1 gp120 envelope glycoprotein determinants for cytokine burst in human monocytes. PLoS One 12:e0174550|
|Baxter, Amy E; Niessl, Julia; Morou, Antigoni et al. (2017) RNA flow cytometric FISH for investigations into HIV immunology, vaccination and cure strategies. AIDS Res Ther 14:40|
|Lee, Wen Shi; Richard, Jonathan; Lichtfuss, Marit et al. (2016) Antibody-Dependent Cellular Cytotoxicity against Reactivated HIV-1-Infected Cells. J Virol 90:2021-30|
|Alsahafi, Nirmin; Ding, Shilei; Richard, Jonathan et al. (2016) Nef Proteins from HIV-1 Elite Controllers Are Inefficient at Preventing Antibody-Dependent Cellular Cytotoxicity. J Virol 90:2993-3002|
|Baxter, Amy E; Niessl, Julia; Fromentin, Rémi et al. (2016) Single-Cell Characterization of Viral Translation-Competent Reservoirs in HIV-Infected Individuals. Cell Host Microbe 20:368-380|
|Gandhi, Rajesh T; Kwon, Douglas S; Macklin, Eric A et al. (2016) Immunization of HIV-1-Infected Persons With Autologous Dendritic Cells Transfected With mRNA Encoding HIV-1 Gag and Nef: Results of a Randomized, Placebo-Controlled Clinical Trial. J Acquir Immune Defic Syndr 71:246-53|
Showing the most recent 10 out of 38 publications