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Enforced HIV-1 silencing at the time of ART initiation to control viremia, reservoir persistence, and viral rebound

Award Number: R01AI195437
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2031

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Enforced HIV-1 silencing at the time of ART initiation to control viremia, reservoir persistence, and viral rebound - PROJECT SUMMARY Antiretroviral therapy (ART) suppresses HIV-1 replication to undetectable levels. However, interruption of ART almost inevitably results in resurgence of viral replication. That is because ART does not prevent the establish- ment of long-lived viral reservoirs that rekindle viral replication after treatment interruption. Further, ART does not prevent spontaneous reversal of latency and residual viral expression, which contribute to persistent inflam- mation. These limitations may be compensated by new interventions targeting the establishment and mainte- nance of latency. Their implementation around the time of ART initiation/restart may accelerate the decay of viremia before ART, reduce viral expression during ART, and block, delay, or mitigate viral rebound after ART. The aim of this proposal is to develop a new intervention delivered before initiation/restart of antiretroviral therapy (ART) that (1) silences HIV-1 and accelerates decay of viremia; (2) reduces residual HIV-1 expression during ART; and (3) blocks or delays viral rebound improving post-treatment control. Our central hypothesis is that these goals can be achieved via ectopic expression of an HIV-1-encoded antisense transcript (AST), which we have shown to silence HIV-1 expression via heterochromatization of the HIV-1 5’ long terminal repeat (LTR), promoting the establishment and maintenance of viral latency. The application is centered around three specific aims. In Specific Aim 1, we propose to investigate the molec- ular mechanisms through which AST silences HIV-1 transcription. Specifically, we will test the hypothesis that AST promotes the formation of biomolecular condensates at the 5’ LTR. Specific Aim 2 will utilize a CD4-specific engineered lentiviral (eLV) AST delivery platform to test its efficacy using in-vitro and ex-vivo culture systems, including a novel lymph node on-a-chip organoid model. Finally, Specific Aim 3 will test the efficacy of the new AST-based intervention in a preclinical humanized mouse model. We will investigate whether ectopic expression of AST accelerates the decline of viremia at ART initiation, reduce viral expression during ART, and increase control of viral replication after interruption of ART. The innovative aspects of the proposal include: (1) a new strategy to block residual viral expression during ART and to achieve post-treatment control; (2) an HIV-specific biological molecule to induce viral silencing via bio- molecular consensates; (3) a CD4-specific lentiviral delivery platform; (4) a novel lymph node organoid system; and (5) the triple knockout humanized mouse model that exhibits significantly delayed graft versus host disease. These studies will be led by a team of investigators with complementary sets of expertise that will ensure the success of this application. Dr. Romerio’s work has focused on HIV-1 regulation by AST; Dr. Cai specializes on the role of biomolecular condensates in chromatin organization; Dr. Ferrari has pioneered the development of organoid models; Dr. Simonetti focuses on monitoring viral dynamics and reservoir persistence; and Dr. Heredia is an expert of humanized mouse models.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $781,073 )
2026	2026	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	000	1	8/31/2026	NEW	$781,073
														Subtotal = $781,073

Grand Total All Awards = $781,073

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Enforced HIV-1 silencing at the time of ART initiation to control viremia, reservoir persistence, and viral rebound

Award Number: R01AI195437

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/01/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2031

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