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Determinants of retroviral replication in non-native hosts for modeling HIV infection

Award Number: R01AI172615
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: 07/01/2024
PERIOD OF PERFORMANCE END DATE: 06/30/2028

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Determinants of retroviral replication in non-native hosts for modeling HIV infection - PROJECT SUMMARY/ABSTRACT HIV-1 does not persistently infect macaques due to restriction by several species-specific host factors necessitating the use of chimeric SIV/HIV-1 viruses (SHIVs) as surrogates to model HIV-1 infection in macaques. Infection of macaques with SHIVs is the most preferred model system for vaccine and prevention studies because SHIVs encode HIV-1 Envelope glycoprotein (Env) – the sole target of HIV-1 neutralizing antibodies. Because the goal of vaccines is to prevent new infection, SHIVs based on circulating, transmitted forms of Env variants are desired as challenge viruses. Existing SHIV/macaque models typically employ SHIVs that encode HIV-1 Env from laboratory-adapted viruses, whose neutralization sensitivities differ from circulating Env variants. This significantly limits the ability of the existing SHIV/macaque models to predict efficacious intervention(s) in humans. Development of SHIVs encoding circulating Env variants has been extremely challenging, mainly because such SHIVs replicate poorly in macaques, if at all. To increase their replication and pathogenicity, SHIVs require extensive adaptation in vivo via serial passage in macaques. The process of serial macaque passage results in accumulation of adaptive mutations in Env that facilitates robust replication. Serial passage is typically performed within the first two weeks of infection, a time during which macaques mount a robust type-I interferon (IFN) response to infection. The host IFN response presents an early barrier against infection because production of IFNs upregulates expression of several IFN-stimulated genes (ISGs), which results in induction of an ‘antiviral state’. Proteins encoded by certain ISGs, referred to as restriction factors, act as potent barriers against cross-species lentiviral transmission. Thus, macaque restriction factors have the potential to block SHIV infection as they can antagonize HIV-1 Env. We recently identified macaque interferon-induced transmembrane proteins (IFITMs) as ISGs that selectively restrict replication of SHIVs encoding circulating HIV-1 Env variants. Our preliminary results suggest that unpassaged SHIV is potently inhibited by IFN in macaque lymphocytes. In contrast, serial passaged SHIVs are resistant to IFN. We found that the loss to two N-linked glycans in Env upon serial passage is sufficient to increase replication and confer resistance to IFN. This research proposal will: 1) characterize the adaptive changes in Env of serial passaged SHIVs that increase replication and IFN resistance; 2) determine the role of N-linked Env glycans in SHIV infection of primary macaque immune cell subsets ex vivo, and mucosal transmission and pathogenicity of SHIVs in vivo; and 3) evaluate the contribution of five macaque IFITM homologs, which are upregulated by IFN, in restriction of unpassaged, IFN-sensitive SHIVs. Upon completion, this study will provide mechanistic insights at the host-viral interface that drive selection, adaptation, and pathogenicity of SHIVs in macaques.


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 = $566,991 )
2025	2025	NORTH CAROLINA STATE UNIVERSITY	2601 WOLF VILLAGE WAY	RALEIGH	NC	27695	WAKE	USA	Allergy and Infectious Diseases Research	003	3	6/12/2025	NON-COMPETING CONTINUATION	$732,233
2025	2024	NORTH CAROLINA STATE UNIVERSITY	2601 WOLF VILLAGE WAY	RALEIGH	NC	27695	WAKE	USA	Allergy and Infectious Diseases Research	002	2	2/18/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$339,256
2025	2023	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Allergy and Infectious Diseases Research	000	1	10/22/2024	NEW	-$165,242
2025	2023	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Allergy and Infectious Diseases Research	001	1	2/18/2025	NEW	-$339,256
														Subtotal = $566,991

Issue Date FY: 2024 ( Subtotal = $746,254 )
2024	2024	NORTH CAROLINA STATE UNIVERSITY	2601 WOLF VILLAGE WAY	RALEIGH	NC	27695	WAKE	USA	Allergy and Infectious Diseases Research	001	2	7/15/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$746,254
2024	2023	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Allergy and Infectious Diseases Research	000	1	7/12/2024	NEW	$0
														Subtotal = $746,254

Issue Date FY: 2023 ( Subtotal = $872,509 )
2023	2023	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Allergy and Infectious Diseases Research	000	1	7/10/2023	NEW	$872,509
														Subtotal = $872,509

Grand Total All Awards = $2,185,754

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Determinants of retroviral replication in non-native hosts for modeling HIV infection

Award Number: R01AI172615

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: 07/01/2024

PERIOD OF PERFORMANCE END DATE: 06/30/2028

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