R01AI186809
Project Grant
Overview
Grant Description
Targeting the HIV-1 reservoir at CART initiation with CD4-mimetic interventions - Summary
Combination antiretroviral therapy (CART) fails to eliminate HIV-1 persisting in reservoirs or prevent long-term complications in people living with HIV (PLWH); therapy interruption leads to rapid viral rebound.
Therefore, new approaches aimed at eradicating HIV-1 or enabling durable virus control without CART are needed.
This is an R01 application in response to the NOFO PAR-23-297: “Opportunities for HIV cure strategies at the time of ART initiation (R01 clinical trial not allowed).”
This application is built on collaborative research centered around the development and translation of small-molecule CD4-mimetic compounds (CD4MCs) as a cure strategy for HIV-1.
CD4MCs synergize with CD4-induced (CD4I) Env antibodies (Abs) to render virus-infected cells highly vulnerable to antibody-mediated cellular cytotoxicity (ADCC) and clearance by immune effector cells.
These CD4I Abs are present in most PLWH.
This application leverages the recent discovery of a new class of indoline CD4MCs that displays remarkable improvements in antiviral potency and breadth against diverse primary HIV-1 strains.
Treatment of HIV-1-infected humanized mice (Hu-mice) with an indoline CD4MC and two types of CD4I Abs (anti-CORBS/anti-cluster A Abs) at the time of CART initiation resulted in a dramatic reduction in the size of the viral reservoir.
This early CD4MC/Ab regimen enabled sustained virus control after analytical treatment interruption (ATI)!
Furthermore, we identified a new family of Abs in PLWH that recognizes additional CD4I Env epitopes and that cooperate with indoline CD4MCs to significantly enhance ADCC.
In line with these exciting discoveries, this application proposes three independent and interactive aims:
Specific Aim 1 will investigate physiological variables (virologic parameters and timing of treatment) that facilitate effective reservoir elimination by CD4MC/Ab interventions in new-generation Hu-mice that support immune effector cell function.
In addition, multi-dimensional single-cell analytical techniques will identify the phenotypes, physiology, and spatial organization of immune-effector cells and virus-infected cells in tissues harboring HIV-1 reservoirs.
These studies will determine the factors related to CD4MC/Ab intervention that tip the balance in favor of durable viral control after ATI.
Specific Aim 2 will formulate a highly effective CD4MC/Ab cocktail by screening plasma of PLWH to identify additional families of CD4I Abs with enhanced potency in mediating ADCC and evaluate them in Hu-mice.
Specific Aim 3 will systematically explore how the properties of the infecting viral Env influence reservoir establishment and susceptibility to elimination by the new indoline CD4MC/Ab cocktails in Hu-mice.
The outcome of these proof-of-principle studies is expected to inform the development of a CD4MC/Ab-based early intervention cure strategy for HIV-1.
Combination antiretroviral therapy (CART) fails to eliminate HIV-1 persisting in reservoirs or prevent long-term complications in people living with HIV (PLWH); therapy interruption leads to rapid viral rebound.
Therefore, new approaches aimed at eradicating HIV-1 or enabling durable virus control without CART are needed.
This is an R01 application in response to the NOFO PAR-23-297: “Opportunities for HIV cure strategies at the time of ART initiation (R01 clinical trial not allowed).”
This application is built on collaborative research centered around the development and translation of small-molecule CD4-mimetic compounds (CD4MCs) as a cure strategy for HIV-1.
CD4MCs synergize with CD4-induced (CD4I) Env antibodies (Abs) to render virus-infected cells highly vulnerable to antibody-mediated cellular cytotoxicity (ADCC) and clearance by immune effector cells.
These CD4I Abs are present in most PLWH.
This application leverages the recent discovery of a new class of indoline CD4MCs that displays remarkable improvements in antiviral potency and breadth against diverse primary HIV-1 strains.
Treatment of HIV-1-infected humanized mice (Hu-mice) with an indoline CD4MC and two types of CD4I Abs (anti-CORBS/anti-cluster A Abs) at the time of CART initiation resulted in a dramatic reduction in the size of the viral reservoir.
This early CD4MC/Ab regimen enabled sustained virus control after analytical treatment interruption (ATI)!
Furthermore, we identified a new family of Abs in PLWH that recognizes additional CD4I Env epitopes and that cooperate with indoline CD4MCs to significantly enhance ADCC.
In line with these exciting discoveries, this application proposes three independent and interactive aims:
Specific Aim 1 will investigate physiological variables (virologic parameters and timing of treatment) that facilitate effective reservoir elimination by CD4MC/Ab interventions in new-generation Hu-mice that support immune effector cell function.
In addition, multi-dimensional single-cell analytical techniques will identify the phenotypes, physiology, and spatial organization of immune-effector cells and virus-infected cells in tissues harboring HIV-1 reservoirs.
These studies will determine the factors related to CD4MC/Ab intervention that tip the balance in favor of durable viral control after ATI.
Specific Aim 2 will formulate a highly effective CD4MC/Ab cocktail by screening plasma of PLWH to identify additional families of CD4I Abs with enhanced potency in mediating ADCC and evaluate them in Hu-mice.
Specific Aim 3 will systematically explore how the properties of the infecting viral Env influence reservoir establishment and susceptibility to elimination by the new indoline CD4MC/Ab cocktails in Hu-mice.
The outcome of these proof-of-principle studies is expected to inform the development of a CD4MC/Ab-based early intervention cure strategy for HIV-1.
Awardee
Funding Goals
NOT APPLICABLE
Grant Program (CFDA)
Awarding / Funding Agency
Place of Performance
Connecticut
United States
Geographic Scope
State-Wide
Related Opportunity
Analysis Notes
Amendment Since initial award the total obligations have increased 207% from $1,314,572 to $4,032,469.
Yale Univ was awarded
HIV-1 Reservoir Targeting with CD4-Mimetic Interventions: A Cure Strategy
Project Grant R01AI186809
worth $4,032,469
from the National Institute of Allergy and Infectious Diseases in August 2024 with work to be completed primarily in Connecticut United States.
The grant
has a duration of 4 years 10 months and
was awarded through assistance program 93.855 Allergy and Infectious Diseases Research.
The Project Grant was awarded through grant opportunity Opportunities for HIV Cure Strategies at the Time of ART Initiation (R01 Clinical Trial Not Allowed).
Status
(Ongoing)
Last Modified 7/6/26
Period of Performance
8/20/24
Start Date
6/30/29
End Date
Funding Split
$4.0M
Federal Obligation
$0.0
Non-Federal Obligation
$4.0M
Total Obligated
Activity Timeline
Subgrant Awards
Disclosed subgrants for R01AI186809
Transaction History
Modifications to R01AI186809
Additional Detail
Award ID FAIN
R01AI186809
SAI Number
R01AI186809-893912895
Award ID URI
SAI UNAVAILABLE
Awardee Classifications
Private Institution Of Higher Education
Awarding Office
75NM00 NIH National Institute of Allergy and Infectious Diseases
Funding Office
75NM00 NIH National Institute of Allergy and Infectious Diseases
Awardee UEI
FL6GV84CKN57
Awardee CAGE
4B992
Performance District
CT-90
Senators
Richard Blumenthal
Christopher Murphy
Christopher Murphy
Modified: 7/6/26