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Elucidating the Structural Bases of HIV-1-Induced CD4 Degradation

Award Number: R01AI176897
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: 07/01/2023
PERIOD OF PERFORMANCE END DATE: 06/30/2028

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Elucidating the Structural Bases of HIV-1-Induced CD4 Degradation - PROJECT SUMMARY: Currently available antiretroviral therapy is effective in treating HIV infection but cannot eliminate it. Once treat- ment is stopped, viral rebound typically occurs within weeks. Infected individuals must take antiretroviral drugs throughout their lives and, as a consequence, may experience drug resistance and side effects. Novel antiretro- virals that can better treat or even eliminate HIV infection are highly desired. One promising and yet underap- preciated approach is to develop therapeutics that disrupt HIV-induced downregulation of the CD4 receptor and thereby unleash CD4’s remarkable inhibitory power to combat the infection. CD4 is the entry receptor for HIV and plays a vital role in the initial stage of the infection, but its presence later in the virus’ replication cycle strongly inhibits viral replication and sensitizes infected cells to immune-clearance. The potency of CD4 as an inhibitor of the virus is reflected by the stringent, highly concerted mechanisms HIV uses to antagonize CD4. Two viral proteins, Nef and Vpu, are involved in downregulating CD4 from the cell surface and from the endoplasmic reticulum, respectively, leading to degradation of CD4 in either the lysosome (Nef-mediated pathway) or the proteasome (Vpu-mediated pathway). The level of effort here by HIV is arguably unmatched—no other host factors including the well-known restriction factors are antagonized in such a multifaceted manner. This suggests that restoring CD4 levels in infected cells may be significantly damaging to the virus and significantly beneficial to the host. Designing or developing therapeutics to restore CD4 levels, however, is greatly hindered by the lack of high-resolution structural information on the pertinent molecular assemblies, e.g., how Nef and Vpu each recruit CD4 into hijacked host trafficking and degradation machineries. In this project, we will solve such high- resolution structures to gain the knowledge necessary for this drug discovery approach. Our specific aims are: 1) Elucidate how the viral Nef protein hijacks the clathrin adaptor protein AP1 to enable the retention of CD4 in endosomes, thus facilitating the delivery of CD4 to lysosomes for degradation. 2) Reveal how Nef hijacks the host trafficking protein ALIX to channel CD4 into multivesicular bodies and lysosomes for degradation; investigate whether and, if so how, the ALIX-like protein PTPN23 participates in Nef-mediated degradation of CD4 and/or other host factors. 3) Elucidate how the viral Vpu protein targets newly synthesized CD4 in the ER to mediate its polyubiquiti- nation via the β-TrCP/cullin1 complex, thereby redirecting CD4 to the proteasome for degradation. Successful completion of this work should reveal opportunities for the design and/or development of novel ther- apeutics capable of disrupting HIV-induced CD4 degradation, thus restoring CD4 in infected cells to inhibit HIV replication or even eliminate the infection.


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 = $8,528 )
2025	2025	FLORIDA STATE UNIVERSITY	874 TRADITIONS WAY	TALLAHASSEE	FL	32306	LEON	USA	Allergy and Infectious Diseases Research	001	3	3/6/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$467,559
2025	2025	FLORIDA STATE UNIVERSITY	874 TRADITIONS WAY	TALLAHASSEE	FL	32306	LEON	USA	Allergy and Infectious Diseases Research	004	3	5/6/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$10,632
2025	2024	UNIVERSITY OF MASSACHUSETTS DARTMOUTH	285 OLD WESTPORT RD	NORTH DARTMOUTH	MA	02747	BRISTOL	USA	Allergy and Infectious Diseases Research	003	2	5/6/2025	NON-COMPETING CONTINUATION	-$1
2025	2024	UNIVERSITY OF MASSACHUSETTS DARTMOUTH	285 OLD WESTPORT RD	NORTH DARTMOUTH	MA	02747	BRISTOL	USA	Allergy and Infectious Diseases Research	000	2	3/6/2025	NON-COMPETING CONTINUATION	-$459,031
2025	2023	UNIVERSITY OF MASSACHUSETTS DARTMOUTH	285 OLD WESTPORT RD	NORTH DARTMOUTH	MA	02747	BRISTOL	USA	Allergy and Infectious Diseases Research	002	1	5/6/2025	NEW	-$10,631
														Subtotal = $8,528

Issue Date FY: 2024 ( Subtotal = $459,032 )
2024	2024	UNIVERSITY OF MASSACHUSETTS DARTMOUTH	285 OLD WESTPORT RD	NORTH DARTMOUTH	MA	02747	BRISTOL	USA	Allergy and Infectious Diseases Research	001	2	8/13/2024	NON-COMPETING CONTINUATION	$0
2024	2024	UNIVERSITY OF MASSACHUSETTS DARTMOUTH	285 OLD WESTPORT RD	NORTH DARTMOUTH	MA	02747	BRISTOL	USA	Allergy and Infectious Diseases Research	000	2	6/12/2024	NON-COMPETING CONTINUATION	$459,032
														Subtotal = $459,032

Issue Date FY: 2023 ( Subtotal = $531,301 )
2023	2023	UNIVERSITY OF MASSACHUSETTS DARTMOUTH	285 OLD WESTPORT RD	NORTH DARTMOUTH	MA	02747	BRISTOL	USA	Allergy and Infectious Diseases Research	000	1	6/28/2023	NEW	$531,301
														Subtotal = $531,301

Grand Total All Awards = $998,861

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Elucidating the Structural Bases of HIV-1-Induced CD4 Degradation

Award Number: R01AI176897

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: 07/01/2023

PERIOD OF PERFORMANCE END DATE: 06/30/2028

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