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HIV Evolution Defines Virus-Host/Drug Interactions In Viremic and Aviremic People

Award Number: R01AI140970
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: 06/25/2018
PERIOD OF PERFORMANCE END DATE: 03/31/2031

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HIV Evolution Defines Virus-Host/Drug Interactions In Viremic and Aviremic People - Project Summary Human immunodeficiency virus type 1 (HIV-1) displays extensive genetic diversity due to several factors including its error-prone viral reverse transcriptase, rapid replication cycle, large intra-host viral population size, selection pressure from the host immune system, and viral recombination when two or more viruses co-infect the same cell. The success of antiviral therapy (ART) against HIV-1 for the past 3 decades not only greatly reduced HIV-1 mortality but also changed the landscape of HIV-1 evolution. People with HIV-1 (PWH) under successful ART have their HIV-1 replication halted, and thus the reservoir viruses do not further evolve. However, interhost viral evolution continues in the absence of suppressive ART, generating new circulating recombinant forms (CRF) and strains with drug resistance mutations (DRMs) against newer antivirals (ARVs) as they replace older regimens. In the previous funding cycle, we studied how the intra-host viral population evolves over time after infection, how low- and high-frequency mutations impact treatment outcomes of non-nucleoside reverse transcriptase inhibitors (NNRTIs)-based regimen, and the evolution of proviral DNA of participants on suppressive ART. We developed two major products from the previous study cycle. The first is an all-in-one phylodynamics assay that measures quantitative recency of infection and detects DRMs at high and low frequency. Another product is that we found that specific DRMs such as K103N, but not all the DRMs at low- frequency, had a direct impact on subsequent ART treatment failure. The work proposed in this application will utilize the knowledge and platform (particularly combining the quantitative recency assay with HIV DRM testing) we developed during the previous funding cycle to answer several important questions related to HIV- 1 drug resistance in the setting of clinical management. Aim 1 of the project is to further improve the quantitative recency model using more advanced machine learning approaches. We will sequence HIV-1 specimens from individuals with known dates of infection from several repositories and use advanced machine learning approaches including deep neural networks (DNNs) and large language models (LLMs) to build a second- generation model to estimate recency. In Aim 2, we will survey DRMs including those against Integrase Strand Transfer Inhibitors (INSTIs) and Capsid Inhibitors (CAIs) with the quantitative recency assay in two settings: 1) newly diagnosed individuals in North Carolina, and 2) in Malawi (as an example of a typical sub-Sahara Africa country). Our hypothesis is that combining quantitative recency assay with DRM testing is a novel approach to monitor new emerging transmitted DRMs. In Aim 3, we will estimate the effect of INSTI DRM at high and low intra-host frequencies on HIV-1 virologic outcomes among PWH with first virologic failure on an initial INSTI- containing ART regimen. The proposed work will demonstrate the utility of UMI-enhanced next gen sequencing to provide key information about HIV-1 in both the public health and clinical management setting.


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 = $769,654 )
2026	2026	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Allergy and Infectious Diseases Research	001	6	4/8/2026	COMPETING CONTINUATION	$0
2026	2026	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Allergy and Infectious Diseases Research	000	6	4/3/2026	COMPETING CONTINUATION	$769,654
														Subtotal = $769,654

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2022	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Allergy and Infectious Diseases Research	000	5	9/3/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Allergy and Infectious Diseases Research	000	5	5/7/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $647,912 )
2022	2022	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Allergy and Infectious Diseases Research	000	5	5/20/2022	NON-COMPETING CONTINUATION	$647,912
														Subtotal = $647,912

Issue Date FY: 2021 ( Subtotal = $658,797 )
2021	2021	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Allergy and Infectious Diseases Research	000	4	5/26/2021	NON-COMPETING CONTINUATION	$658,797
														Subtotal = $658,797

Issue Date FY: 2020 ( Subtotal = $658,797 )
2020	2020	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	6/3/2020	NON-COMPETING CONTINUATION	$658,797
														Subtotal = $658,797

Issue Date FY: 2019 ( Subtotal = $658,797 )
2019	2019	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	6/14/2019	NON-COMPETING CONTINUATION	$658,797
														Subtotal = $658,797

Issue Date FY: 2018 ( Subtotal = $672,672 )
2018	2018	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	6/25/2018	NEW	$672,672
														Subtotal = $672,672

Grand Total All Awards = $4,066,629

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HIV Evolution Defines Virus-Host/Drug Interactions In Viremic and Aviremic People

Award Number: R01AI140970

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: 06/25/2018

PERIOD OF PERFORMANCE END DATE: 03/31/2031

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