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Molecular determinants and vulnerabilities of HIV-1 spread by cell-to-cell transmission

Award Number: R01AI195206
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: 02/20/2026
PERIOD OF PERFORMANCE END DATE: 01/31/2031

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Molecular determinants and vulnerabilities of HIV-1 spread by cell-to-cell transmission - Abstract. HIV-1 replicates in host cells to produce new virions by two alternative routes. As free virus, HIV-1 buds from infected cells and circulates in the host until encountering a new permissive target cell. In addition, HIV-1 can efficiently spread by direct transmission from infected to uninfected CD4+ T cells at confined local sites formed between the two cells and designated virological synapses (VSs).2,11,13 Within VSs, budding virions are concentrated in close proximity to the membrane of an uninfected cell and their envelope glycoproteins (Envs) can interact with the CD4 and CCR5/CXCR4 receptors to mediate efficient HIV-1 entry.1 In vitro studies indicate that HIV-1 cell-cell transmission (C-CT) is significantly more efficient than free virus infection. Increasing evidence suggests that in vivo C-CT contributes to viral spread and immune evasion. C-CT between cells can contribute to multiple aspects of HIV-1 pathogenesis, replication in tissues, and transmission. Specifically, close interactions between CD4+ T cells could potentially contribute to massive replication in lymph nodes during clinical latency of HIV-1 in people living with HIV-1,6 play a role in HIV-1 reactivation from latency upon anti-retroviral therapy discountinuation,7 and accelerate growth of viral foci during initial virus transmission in non-human primate models of HIV-1 prevention.8 Moreover, in vitro and in vivo studies provided evidence for different levels of resistance of C-CT to small molecule drugs and broadly neutralizing antibodies. Despite potential contribution of C-CT to HIV-1 pathogenesis as well as immune and therapeutics evasion, the mechanisms of HIV-1 C-CT is still not fully understood because of significant obstacles to investigate C-CT that limit our ability to thoroughly study HIV-1 C-CT, especially in primary CD4+ T cells. Here we propose to fill this gap in knowledge by comprehensively dissecting the molecular determinants of HIV- 1 C-CT at a population level of hundreds of different viral strains using highly sensitive tools combined with high- resolution imaging methods that we have recently developed. We will also study the contribution of C-CT to HIV- 1 replication in vivo. Our central hypothesis is that efficient HIV-1 C-CT depends on specific Env determinants and cellular host factors and is vulnerable to targeting host proteins and to cell cytotoxicity. In Aim 1 we will define Env determinants that contribute to HIV-1 C-CT using viral, structural and evolutionary biology approaches. We will also evaluate C-CT during HIV-1 replication in humanized mice, in tissues from patients, and C-CT efficiency of Env that evolved in vivo in patients. In Aim 2 we will study the vulnerabilities of HIV-1 C-CT. Our preliminary results show that type I interferons (IFNs) α and β efficiently inhibit C-CT and we will identify the related gene(s) and underlying mechanism in the context of T cell lines and primary CD4+ T cells. In parallel, we will study the vulnerability of HIV-1 C-CT to cellular cytotoxicity mediated by chimeric antigen receptors and a synthetic T-cell-IgG receptor (TIR) that recognize HIV-1 Envs. Our study will define the C-CT landscape mediated different Envs and provide insights into vulnerabilities of HIV-1 spread by C-CT.


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 = $713,107 )
2026	2026	REGENTS OF THE UNIVERSITY OF MINNESOTA	2221 UNIVERSITY AVE SE STE 100	MINNEAPOLIS	MN	55414	HENNEPIN	USA	Allergy and Infectious Diseases Research	000	1	2/19/2026	NEW	$713,107
														Subtotal = $713,107

Grand Total All Awards = $713,107

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Molecular determinants and vulnerabilities of HIV-1 spread by cell-to-cell transmission

Award Number: R01AI195206

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: 02/20/2026

PERIOD OF PERFORMANCE END DATE: 01/31/2031

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