[R01] Early interventions at ART initiation to reduce the HIV-1 reservoir and enhance adaptive immune responses
Ente: National Institute of Allergy and Infectious Diseases
Scadenza: 2029-07-31
Importo max: $545,816
Paese: US
Descrizione
Increasing efforts are being made to understand whether early intervention after HIV-1 infection can enable long-
term viral control and reduction of the viral reservoir through the preservation of HIV-1-specific immune
responses. Recently, the pioneering eCLEAR phase 1b/2a clinical trial led by MPI SØgaard, found that
administration of the HIV-Env specific broadly neutralizing antibody (bNAb) 3BNC117 at antiviral therapy (ART)
initiation enhanced CD8+ T cell viral immunity and enabled viral control amongst participants harboring
3BNC117-sensitive viruses. However, the mechanisms underlying this outcome remain largely unknown.
Understanding The goal of this collaborative R01 (M Betts, UPenn, B Jones, Weill-Cornell University, and
O. SØgaard, Aarhus University) is to define the mechanisms underlying this protective outcome in order
to inform future development of targeted immunotherapy at ART initiation as an HIV cure strategy. We
hypothesize that the partial success of eCLEAR can be defined in terms of both specific mechanisms of
efficacious CD8+ T-cell responses and of the features selected in remaining reservoir-harboring cells. We will
address this hypothesis in three integrated Aims using samples directly from the eCLEAR study. In Aim 1, we
will define phenotypic, functional, and transcriptomic features of the adaptive T cell immune responses that are
modulated by bNAb treatment at ART initiation (SØgaard). In Aim 2, we will define how the HIV reservoir is
differentially modulated after prolonged ART treatment and within post-therapy viral controllers vs. non-
controllers who received 3BNC117 (Betts). In Aim 3, we will define the ability of CD8+ T cells from eCLEAR
participants who did or did not exhibit post-ART control to mediate viral control in vivo using a novel humanized
mouse model. In addition, we will modulate CD8+ T cell functions within this system to uncover specific control
mechanisms. The anticipated outcomes of our project are i) A comprehensive characterization of the
immunologic and reservoir features associated with the partial efficacy of eCLEAR, ii) Validation of underlying
mechanisms, to guide future iterations of clinical interventions at the time of ART initiation.
Investigators at Aarhus University are conducting experiments to understand T cell function
from the United States and Denmark sponsored eCLEAR clinical trial that demonstrated
that some people living with HIV can control HIV without antiretroviral therapy.
Determining how T cells can control HIV replication without antiretroviral therapy may lead
to the development of strategies to enable the 1.2 million Americans currently living with
HIV to control or even cure HIV. It is necessary to perform these studies in Denmark
because the trial samples are currently located in Denmark, and it is well known that
temperature fluctuations due to shipping can have detrimental functions on T cell function.
Istituzione: UNIVERSITY OF PENNSYLVANIA
PI: Michael R Betts, Brad R Jones, Ole Schmeltz Søgaard
Progetto: 5R01AI184285-03
Settori: National Institute of Allergy and Infectious Diseases
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