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How m6A RNA Modifications Regulate HIV-1 Replication in Primary CD4+ T Cells

Award Number: R01AI203406
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: 09/01/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2030

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How m6A RNA Modifications Regulate HIV-1 Replication in Primary CD4+ T Cells - Project Summary/Abstract N6-methyladenosine (m6A) is the most prevalent cellular mRNA modification and plays a critical role in regulating RNA stability, localization, and gene expression. Our recent findings highlight the importance of m6A RNA modification in HIV-1-infected primary CD4+ T cells and suggest its functional significance as a regulatory mechanism in HIV-1 infection. m6A modification is added by the cellular protein complex methyltransferase-like 3 (METTL3) and METTL14 that interact in cells. We found that HIV-1 infection of Jurkat CD4+ T cells and primary CD4+ T cells promoted the interaction between METTL3 and METTL14, but the mechanism is unknown. We also observed that HIV-1 infection of Jurkat cells led to phosphorylation of METTL3 at four unique residues. We recently identified several differentially m6A-modified cellular mRNAs during HIV-1 infection in primary CD4+ T cells, including perilipin 3 (PLIN3). It has been shown that PLIN3 interacts with HIV-1 Gag and is essential for HIV-1 production and HIV-1 envelop protein (Env) incorporation into virions from primary macrophages. We recently reported the importance of PLIN3 in regulating HIV-1 infection of primary CD4+ T cells. We found that HIV-1 infection of primary CD4+ T cells significantly increased PLIN3 mRNA level and nuclear accumulation but reduced PLIN3 protein level. However, it remains unclear how HIV-1 infection modulates PLIN3 mRNA and protein expression in primary CD4+ T cells. Furthermore, we observed that knocking down PLIN3 in primary CD4+ T cells reduced HIV-1 production but enhanced virion infectivity. Our findings indicate that PLIN3 regulates HIV-1 replication and infectivity in primary CD4+ T cells, but the mechanisms remain to be elucidated. To fill these critical knowledge gaps in the field, we will test our novel hypotheses through three specific aims. We hypothesize that (1) HIV-1 infection enhances METTL3 and METTL14 interaction by inducing phosphorylation of METTL3 in primary CD4+ T cells, and (2) PLIN3 modulates HIV-1 production and infectivity in primary CD4+ T cells by affecting Gag and Env interactions and/or Env incorporation into virions. Aim 1. Investigate how HIV-1 infection enhances METTL3 and METTL14 interaction in primary CD4+ T cells; Aim 2. Elucidate how HIV-1 infection alters PLIN3 mRNA and protein expression in primary CD4+ T cells; Aim 3. Determine how PLIN3 modulates HIV-1 production and virion infectivity in primary CD4+ T cells. Overall Impact: Our proposed studies will fill three important knowledge gaps and reveal novel mechanisms by which HIV-1 exploits m6A modifications of cellular RNA to regulate viral replication in primary CD4+ T cells.


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 = $2,505,340 )
2026	2026	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Allergy and Infectious Diseases Research	000	1	8/18/2026	NEW	$2,505,340
														Subtotal = $2,505,340

Grand Total All Awards = $2,505,340

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How m6A RNA Modifications Regulate HIV-1 Replication in Primary CD4+ T Cells

Award Number: R01AI203406

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: 09/01/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2030

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