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Impact of Non - B HIV - 1 Subtype on second line Protease Inhibitor Regimens in Africa (INSPIRE)

Award Number: R01AI147331
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Abstract of research The finding that most patients with virologic failure (HIV-1 RNA >=1,000cp/mL) on second-line PI- containing regimens lack PI-resistance mutations in the protease (PR) gene is one of the main enigmas of antiretroviral drug resistance research. We hypothesized that env and gag sequences from these patients contain compensatory mutations, specifically in the Env, that confer PI resistance. A role of the gp41 CT in PI resistance may be linked to the role of virus maturation, triggered by PR, in activating Env fusion activity. In recent years, increasing numbers of clinical reports have observed failure of DTG-containing therapy in the absence of integrase (IN) mutations, suggesting that mutations outside IN may confer resistance in these patients. Our studies demonstrated the first instance of de novo selection of Env mutations that confer resistance to Dolutegravir (DTG) in vitro (unpublished data). We attribute this phenotype to the ability of the Env mutants to mediate highly efficient cell-to-cell transmission, resulting in an increase in the multiplicity of infection. In addition, up to 20-, 6- and 24-fold reduction in susceptibility to ATV, DRV and LPV, respectively, was observed in absence of PR mutations among HIV-1 CRF_02AG and subtype G infected patients. These findings have broad implications for our understanding of Env and Gag functions and the evolution of HIV-1 drug resistance. Our goal is to identify factors that predict virological failure (VF) on ATV/r or LPV/r as patients with VF on a PI-containing regimens have suboptimal future treatment and may be at an increased risk for developing integrase resistance inhibitor on a third-line regimen. A collaborative team involving investigators led by the Institute of Human Virology Nigeria will exploit robust longitudinal cohorts (Cameroon, Nigeria and Uganda) of patients on 2L regimens, coupled to well- characterized and archived clinical specimens that underpin a rigorous nested case-control study design. To test these interlocking hypotheses, we propose to: (i) use our newly developed HIV-xGen next generation sequencing method to extend understanding of viral evolution and HIV drug resistance across the viral genome and to determine whether there is effect modification by non-B HIV-1 subtypes, (ii) characterize recombinant viruses carrying mutations identified in Aim 1, using established phenotypic assays to determine their effect on drug susceptibility and site-directed mutagenesis, and lastly (iii) determine differences in replicative fitness on drug susceptibility with use of a yeast recombination-based cloning system. Our plans to study these patients and their viruses (subtype A, C, D, G, and CRF02_AG, CRF43_02G, HIV-1 O and HIV-1 N) provides a unique opportunity to determine the phenotypic and clinical significance of genotypic changes in HIV-1 gag, gag-pol and env genes. All in all, this proposal will permit exciting epidemiological, clinical, and public health research opportunities.


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: 2024 ( Subtotal = $313,674 )
2024	2024	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	000	4	2/5/2024	NON-COMPETING CONTINUATION	$282,306
2024	2024	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	001	4	4/16/2024	NON-COMPETING CONTINUATION	$31,368
														Subtotal = $313,674

Issue Date FY: 2023 ( Subtotal = $621,170 )
2023	2023	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	000	3	1/3/2023	NON-COMPETING CONTINUATION	$621,170
2023	2022	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	002	2	4/5/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$81,600
2023	2020	INSTITUTE OF HUMAN VIROLOGY NIG LTDGTE	PLOT 62, EMERITUS UMARU SHEHU AVENUE	ABUJA				NGA	Allergy and Infectious Diseases Research	001	1	4/5/2023	NEW	-$81,600
														Subtotal = $621,170

Issue Date FY: 2022 ( Subtotal = $715,198 )
2022	2022	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	000	2	1/25/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$715,198
2022	2022	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	002	2	5/9/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2022	2020	INSTITUTE OF HUMAN VIROLOGY	PLOT 252 HERBERT MACAULAY WAY CBD	ABUJA				NGA	Allergy and Infectious Diseases Research	001	1	1/26/2022	NEW	$0
														Subtotal = $715,198

Issue Date FY: 2020 ( Subtotal = $581,600 )
2020	2020	INSTITUTE OF HUMAN VIROLOGY	PLOT 252 HERBERT MACAULAY WAY CBD	ABUJA		23409		NGA	Allergy and Infectious Diseases Research	000	1	4/27/2020	NEW	$581,600
														Subtotal = $581,600

Grand Total All Awards = $2,231,642

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Impact of Non - B HIV - 1 Subtype on second line Protease Inhibitor Regimens in Africa (INSPIRE)

Award Number: R01AI147331

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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