Modulation of galectin-9 to target HIV persistence

Active Project Grant Awarded Last action

Award ID
R01AI184421
Recipient
Awarding agency
Obligated
$2,430,481

Award facts

Assistance listing
93.855 Allergy and Infectious Diseases Research
Completion date 45% complete
Place of performance
San Francisco, CA 94105, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
While the advent of antiretroviral therapy (art) has dramatically reduced the morbidity and mortality associated with HIV infection, viral eradication is not achievable due to the persistence of latently-infected cells during treatment. Accumulating data suggest that HIV-infected individuals often experience persistent immune dysregulation, chronic inflammation, and accelerated aging even in the setting of art-mediated viral suppression. These realities have created a pronounced interest in developing strategies to eradicate or functionally cure HIV infection. Recent work from our group and others has demonstrated a highly important and pleiotropic role of human galectin-9 (GAL-9), an immunoregulatory β-galactoside-binding lectin, in HIV persistence. We have demonstrated that administration of GAL-9 potently reactivates latent HIV in CD4+ t cells, by signaling through specific glycans on the target cell surface. We have additionally revealed that GAL-9 expression in tissues (e.g. CNS) spatially overlaps with HIV infection, and high levels of endogenous, circulating GAL-9 in plasma are strongly associated with long-term maintenance of intact HIV proviral DNA in the CD4+ t cell compartment during art. Moreover, our recent studies in HIV-infected humanized mice have revealed that exogenously administered GAL-9 significantly increases tissue-associated HIV DNA and RNA levels. In this study, we will comprehensively determine if therapeutic inhibition of GAL-9 signaling at the time of art initiation can accelerate clearance of the latent HIV reservoir, resolve HIV-associated inflammation, and prevent viral rebound following art cessation. These goals are well aligned with the stated objective of PAR-23-297. In aim 1 of our study, we will use established EX vivo latency models to elucidate the molecular and immunologic mechanisms underlying GAL-9-mediated expansion of the HIV reservoir. In aim 2, we will determine how manipulation (supplementation or blockade) of GAL-9 signaling impacts the HIV reservoir and viral rebound kinetics post-art cessation in vivo. Our multidisciplinary investigative team at vitalant research institute / ucsf, weill cornell medicine, and yale university brings a diverse systems biology approach to investigate the impact of GAL-9 on HIV persistence, including tools developed by our group to manipulate GAL-9 signaling in vitro and in vivo (recombinant, stable form exogenous GAL-9, and a panel of anti-GAL-9 monoclonal antibodies that interfere with its virologic effects). Our translational design will leverage carefully designed EX vivo models of HIV persistence, clinical samples from people living with HIV (plwh) on suppressive art, and two complementary murine models of HIV latency. Our findings will guide the development of novel HIV cure strategies that leverage the immunomodulatory activities of host galectins.

Transactions

Action Obligated Date
Amendment $827,545
Amendment $827,545
Original award $775,391

Subawards

Subrecipient Amount Awarded
The Regents Of The University Of Colorado Hemorrhage remains the leading cause of trauma-related death. While platelet transfusions are a hallmark of hemostatic resuscitation approaches, storage… $17,839
The Regents Of The University Of Colorado Dr. Roede and his team will perform experiments to assess biochemical and mitochondrial phenotype and function of alternatively stored platelet products. They… $72,510
Weill Medical College Of Cornell University Dr. Ndhlovu will serve as a co-principal investigator on this proposal and will have several responsibilities over the five year period of the award. Below is… $271,200
Yale Univ The aim of the application is to study the role of the human protein Galectin-9 in HIV persistence and establishment of the long-term reservoir. The Kumar… $251,250
Weill Medical College Of Cornell University Dr. Ndhlovu will serve as a co-principal investigator on this proposal and will have several responsibilities over the five year period of the award. Below is… $242,846
Yale Univ The aim of the application is to study the role of the human protein Galectin-9 in HIV persistence and establishment of the long-term reservoir. The Kumar… $224,981

Quick answers

Who received award R01AI184421?

R01AI184421 was awarded to Vitalant by National Institute of Allergy and Infectious Diseases (National Institutes of Health) on August 1, 2024.

How much is award R01AI184421 worth?

$2,430,481 has been obligated on R01AI184421.

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