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Lentivirus Replication Strategy and Pathogenesis

Award Number: R01AI136581
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: 01/19/2018
PERIOD OF PERFORMANCE END DATE: 03/31/2027

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Lentivirus Replication Strategy and Pathogenesis - Project Summary – Kim Lentiviruses infect both activated/dividing CD4+ T cells and terminally differentiated/nondividing myeloid cells during the course of their pathogenesis. As we previously reported, host SAMHD1 dNTPase restricts viral reverse transcription step specifically in nondividing myeloid cells by depleting cellular dNTPs whereas HIV-2 and some SIVs counteract SAMHD1 by proteosomal degradation through their accessary proteins (e.g. Vpx). In this renewal, we aim to reveal noble mechanistic strategies that lentiviruses employ for their myeloid cell infection and rapid evolution/escape. First, lentiviruses encode an additional polypurine track (PPT) sequence, called central PPT (cPPT), that locates at the center of the viral genome and is used for the additional initiation of the (+) strand DNA synthesis. We previously reported that the concomitant initiation of the (+) strand DNA synthesis from both PPT and cPPT compensates the kinetically delayed HIV-1 reverse transcription in nondividing cells with limited dNTP pools by cutting the size of the (+) strand DNA synthesis from PPT by half. In Aim 1, we will test our hypothesize that the additional cPPT of HIV-1 allows HIV-1 to overcome the SAMHD1-mediated dNTP depletion and complete the (+) strand DNA synthesis even in nondividing myeloid cells without accessary proteins counteracting SAMHD1. Second, we previously reported that the uniquely tight dNTP binding affinity of HIV-1 RT mechanistically contributes to its catalytic capability to execute DNA synthesis even at low dNTP concentrations, which enables HIV-1 to replicate in myeloid cells with very low dNTP pools. Importantly, we also reported that this tight dNTP binding affinity enables HIV-1 RT to efficiently extend mismatch primer post misinsertion, compared to other retroviral RTs, which is responsible for the highly error prone DNA synthesis of HIV-1 RT. Based on these observations, we propose to solve the X-ray structure of HIV-1 RT ternary complex with mismatch primer, which will elucidate the structural nature of the highly error prone HIV-1 replication machinery which is important for viral evolution and escape. Third, while lethal mutagenesis has been observed in other RNA viruses, it remains unclear that the lethal mutagenesis of HIV-1 and lentiviruses can be achieved by pharmacological means. Triphosphate (TP) of Molnupiravir, b-d-N4 hydroxycytidine (NHC) prodrug, is a ribonucleotide substrate and an RNA mutagen for RNA-dependent RNA polymerases of multiple RNA viruses including SARS-CoV-2, which induces viral lethal mutagenesis. Excitingly, our biochemical data demonstrate that host cellular RNA polymerase II also incorporates NHC-TP during RNA synthesis, supporting the likelihood of the NHC-TP incorporation into cellular RNAs by host RNA polymerases. Since lentivirus RNA genomes are synthesized by host DNA-dependent RNA polymerase II, we hypothesize that NHC may be able to induce lethal mutagenesis in lentiviruses. Overall, this renewal application focuses on elucidating the unique mechanistic and structural elements of lentivirus replication machinery, ultimately aiming at developing novel antiviral concepts and tools.


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 = $436,338 )
2026	2026	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Allergy and Infectious Diseases Research	000	9	4/17/2026	NON-COMPETING CONTINUATION	$436,338
														Subtotal = $436,338

Issue Date FY: 2025 ( Subtotal = $445,033 )
2025	2025	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Allergy and Infectious Diseases Research	000	8	4/2/2025	NON-COMPETING CONTINUATION	$445,033
														Subtotal = $445,033

Issue Date FY: 2024 ( Subtotal = $453,473 )
2024	2024	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Allergy and Infectious Diseases Research	000	7	3/29/2024	NON-COMPETING CONTINUATION	$453,473
2024	2023	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Allergy and Infectious Diseases Research	002	6	9/27/2024	COMPETING CONTINUATION	$148,573
2024	2022	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Allergy and Infectious Diseases Research	001	5	9/27/2024	NON-COMPETING CONTINUATION	-$148,573
														Subtotal = $453,473

Issue Date FY: 2023 ( Subtotal = $461,675 )
2023	2023	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Allergy and Infectious Diseases Research	001	6	4/17/2023	COMPETING CONTINUATION	$461,675
2023	2022	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Allergy and Infectious Diseases Research	000	5	4/16/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $461,675

Issue Date FY: 2022 ( Subtotal = $385,498 )
2022	2022	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Allergy and Infectious Diseases Research	000	5	12/21/2021	NON-COMPETING CONTINUATION	$385,498
														Subtotal = $385,498

Issue Date FY: 2021 ( Subtotal = $385,907 )
2021	2021	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Allergy and Infectious Diseases Research	000	4	12/17/2020	NON-COMPETING CONTINUATION	$385,907
														Subtotal = $385,907

Issue Date FY: 2020 ( Subtotal = $386,279 )
2020	2020	EMORY UNIVERSITY	1599 CLIFTON RD.	ATLANTA	GA	30322	DEKALB	USA	Allergy and Infectious Diseases Research	000	3	1/1/2020	NON-COMPETING CONTINUATION	$386,279
														Subtotal = $386,279

Issue Date FY: 2019 ( Subtotal = $386,618 )
2019	2019	EMORY UNIVERSITY	1599 CLIFTON RD.	ATLANTA	GA	30322	DEKALB	USA	Allergy and Infectious Diseases Research	000	2	11/30/2018	NON-COMPETING CONTINUATION	$386,618
														Subtotal = $386,618

Issue Date FY: 2018 ( Subtotal = $386,925 )
2018	2018	EMORY UNIVERSITY	1599 CLIFTON RD.	ATLANTA	GA	30322	DEKALB	USA	Allergy and Infectious Diseases Research	000	1	1/19/2018	NEW	$386,925
														Subtotal = $386,925

Grand Total All Awards = $3,727,746

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Lentivirus Replication Strategy and Pathogenesis

Award Number: R01AI136581

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: 01/19/2018

PERIOD OF PERFORMANCE END DATE: 03/31/2027

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