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Identifying Roadblocks to Antigen Expression and Enhancing Killing of HIV-Infected Cells That Are Refractory to Clearance

Award Number: R01AI176596
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: 03/02/2023
PERIOD OF PERFORMANCE END DATE: 02/29/2028

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Identifying Roadblocks to Antigen Expression and Enhancing Killing of HIV-Infected Cells That Are Refractory to Clearance - PROJECT ABSTRACT The HIV-1 reservoir is thought to contain cells that vary in their susceptibility to clearance by the host immune system. Identifying mechanisms that allow infected cells to avoid clearance could inform the development of cure strategies that are able to more effectively eliminate HIV-infected cells in the long-lived reservoir. Persistence during long periods of untreated infection, when immune surveillance for HIV-infected cells is highest and the immune environment is highly inflammatory, may select for infected cells with an enhanced ability to evade detection and clearance by the host immune system. This study will focus on two groups of reservoir cells that carry intact proviral genomes and likely differ in susceptibly to clearance. The first are early reservoir cells that were infected (or are a clone of a cell infected) early in untreated infection. The second are late reservoir cells that were infected (or are a clone of a cell infected) near the time of ART initiation. These late reservoir cells have persisted in the reservoir for less time and have primarily persisted during antiretroviral therapy when HIV- specific immune responses are blunted and HIV-infected cells typically have very long half-lives. In contrast, early reservoir cells persisted for long periods of untreated infection when most HIV-infected cells have a short half-life. We hypothesize that early proviruses will have epigenetic features that make them resistant to T cell stimulation and less susceptible to clearance. In this study we will identify intact early and late proviruses in CD4+ T cells isolated from the blood of 15 participants on suppressive ART (Aim 1a). We will then examine phenotypes predicted to impact reservoir clearance. Specifically, we will examine whether early and late proviruses differ in their sensitivity to T cell stimulation (Aim 1b) and/or have different genetic (proviral sequence and integration site) or epigenetic features (Aim 1c). To test the hypothesis that early proviruses are more difficult to clear, we will measure the susceptibility of early and late proviruses to killing by autologous CD8 T cells (Aim 2a) and assess whether disruption of epigenetic regulators alters their susceptibility to killing by autologous CD8 T cells (Aim 2b). Our focus on early and late viruses allows us to explore potential mechanisms associated with clearance in populations that likely differ in their susceptibility to clearance, however, the proposal work will also reveal if features other than proviral age are predictive of susceptibility to clearance. We will then explore strategies to improve antigen presentation in infected cells (Aim 3a) and assess whether improved antigen presentation can enhance killing by autologous CD8 T cells in populations typically refractory to clearance (Aim 3b). The overarching goal of this project is to define a population of cells with an enhanced ability to evade clearance, identify host and proviral features associated with clearance evasion and test whether better antigen presentation can make HIV-infected cells more susceptible to clearance. Successful completion of these aims will connect proviral genetics and epigenetics to virus reactivation and killing to inform the development of improved clearance strategies.


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: 2025 ( Subtotal = $1,132,909 )
2025	2025	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Allergy and Infectious Diseases Research	000	3	2/18/2025	NON-COMPETING CONTINUATION	$1,132,909
														Subtotal = $1,132,909

Issue Date FY: 2024 ( Subtotal = $1,167,948 )
2024	2024	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Allergy and Infectious Diseases Research	001	2	5/23/2024	NON-COMPETING CONTINUATION	$116,793
2024	2024	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Allergy and Infectious Diseases Research	000	2	2/26/2024	NON-COMPETING CONTINUATION	$1,051,155
														Subtotal = $1,167,948

Issue Date FY: 2023 ( Subtotal = $1,167,948 )
2023	2023	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Allergy and Infectious Diseases Research	000	1	3/2/2023	NEW	$1,167,948
														Subtotal = $1,167,948

Grand Total All Awards = $3,468,805

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Identifying Roadblocks to Antigen Expression and Enhancing Killing of HIV-Infected Cells That Are Refractory to Clearance

Award Number: R01AI176596

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: 03/02/2023

PERIOD OF PERFORMANCE END DATE: 02/29/2028

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