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Mechanisms of type I IFN signaling and HIV risk in the female genital tract

Award Number: R01AI162001
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: 04/22/2021
PERIOD OF PERFORMANCE END DATE: 03/31/2026

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Mechanisms of type I IFN signaling and HIV risk in the female genital tract - ABSTRACT Previously, we carried out large-scale analysis of mucosal cytokines and HIV acquisition in high-risk women from KwaZulu-Natal, South Africa, enrolled as part of the CAPRISA 004 TFV 1% gel study (n = 774). Using a prospective cohort design, we validated our previous finding that inflammatory cytokines increase the risk of HIV acquisition. Of the cytokines associated with increased risk, one of the strongest associations was observed for the key type I IFN, IFN2 (p = 10E-6). Women in upper quartile for IFN2 were at 4-fold greater risk of acquiring HIV, compared to women in the lowest quartile (HR 3.9, 95% CI 1.7-9.1). On the surface this seems counter- intuitive, as type I IFN have strong anti-HIV effects both in vitro and when given in vivo as a therapeutic or prophylactic in non-human primate model. To reconcile these observations, we hypothesize that chronic type I IFN upregulation in the female reproductive tract (FRT) leads to dysregulation of IFN signaling, resulting in downregulation of antiviral genes, increase in generalized inflammation and increase in susceptibility of target cells at the site of infection. This hypothesis would provide an explanation as to why a classical anti- viral program that should be protective actually leads to higher rates of HIV acquisition. Utilizing samples from the ongoing CAPRISA 018 tenofovir alafenamide (TAF) sub-dermal implant trial, we will determine whether prolonged IFN2 upregulation in the FRT leads to decreased IFN responsiveness and IFN-stimulated gene (ISG) expression in genital immune cells. Next, we will formally test if the chronic increase in IFN2 expression and ISG downregulation correspond to breakthrough HIV infections in young women enrolled in CAPRISA 018. Finally, we will use an in vitro PBMC model to determine the mechanism by which prolonged IFN upregulation leads to ISG downregulation and subsequent increase in HIV risk.


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 = $98,964 )
2025	2025	CENTRE FOR THE AIDS PROGRAM OF RESEARCH IN SOUTH AFRICA	719 UMBILO ROAD	DURBAN				ZAF	Allergy and Infectious Diseases Research	000	5	7/25/2025	NON-COMPETING CONTINUATION	$98,964
														Subtotal = $98,964

Issue Date FY: 2024 ( Subtotal = $122,682 )
2024	2024	CENTRE FOR THE AIDS PROGRAM OF RESEARCH IN SOUTH AFRICA	719 UMBILO ROAD	DURBAN				ZAF	Allergy and Infectious Diseases Research	000	4	3/18/2024	NON-COMPETING CONTINUATION	$122,682
														Subtotal = $122,682

Issue Date FY: 2023 ( Subtotal = $124,785 )
2023	2023	CENTRE FOR THE AIDS PROGRAM OF RESEARCH IN SOUTH AFRICA	719 UMBILO ROAD	DURBAN				ZAF	Allergy and Infectious Diseases Research	000	3	3/2/2023	NON-COMPETING CONTINUATION	$124,785
														Subtotal = $124,785

Issue Date FY: 2022 ( Subtotal = $130,287 )
2022	2022	CENTRE FOR THE AIDS PROGRAM OF RESEARCH IN SOUTH AFRICA	719 UMBILO ROAD	DURBAN				ZAF	Allergy and Infectious Diseases Research	000	2	3/4/2022	NON-COMPETING CONTINUATION	$130,287
														Subtotal = $130,287

Issue Date FY: 2021 ( Subtotal = $128,760 )
2021	2021	CENTRE FOR THE AIDS PROGRAM OF RESEARCH IN SOUTH AFRICA	719 UMBILO ROAD	DURBAN				ZAF	Allergy and Infectious Diseases Research	000	1	4/22/2021	NEW	$128,760
														Subtotal = $128,760

Grand Total All Awards = $605,478

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Mechanisms of type I IFN signaling and HIV risk in the female genital tract

Award Number: R01AI162001

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: 04/22/2021

PERIOD OF PERFORMANCE END DATE: 03/31/2026

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