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Role of CLIC/GEEC pathway in VCC formation and HIV-1 transmission from macrophages

Award Number: R56AI197882
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: 08/31/2027

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Role of CLIC/GEEC pathway in VCC formation and HIV-1 transmission from macrophages - SUMMARY Myeloid cells capture free HIV-1 particles via interactions between cell surface Siglec-1 and gangliosides on the viral lipid envelope. Following particle capture, the Siglec-1-HIV-1 complexes coalesce on the surface and then are taken into a complex intracellular compartment termed the virus-containing compartment (VCC). The VCC is also a prominent feature in HIV-1-infected myeloid cells, sharing identical late endosome and plasma membrane markers with the VCC that is formed following exogenous particle capture. Thin tubules extend from the PM to the VCC, and HIV-1 particles can be found within these surface-connected tubules. Work in our laboratory recently demonstrated that the tubules represent clathrin-independent carriers (CLICs), part of the CLIC/GEEC pathway. Disruption of CLIC/GEEC endocytosis prevented VCC formation and greatly diminished trans-infection of autologous T cells. The overall objective of this proposal is to define the mechanisms leading to HIV-1 particle internalization and VCC formation in macrophages, and subsequently for transmission of virus to target cells. Our central hypothesis is that the CLIC/GEEC pathway is essential to VCC formation, and dynamin-2 recruitment to CLIC membranes is required for delivery of membrane components and internalized HIV-1 particles to the VCC. Virions within the VCC contribute to cell-cell transmission, so defining the details of VCC formation in macrophages is an important goal. Experiments in Aim 1 will define the role of CD98 heavy chain (CD98hc) and its binding partners in VCC formation. Novel chimeric approaches in iPSC-derived macrophages (iMACs) will be used to identify critical domains and key interactors of CD98hc that contribute to VCC formation. Experiments in Aim 2 will evaluate the CLICs that form in the absence of dynamin-2 and test the hypothesis that the site of HIV-1 assembly on VCC membranes requires CLIC/GEEC endocytosis and dynamin-2. Gene editing approaches will facilitate experiments testing if the GTPase activity of dynamin-2 is required for delivery of HIV-1 particles to the VCC. In Aim 3, the contribution of GRAF1, a CLIC/GEEC regulator that is known to interact directly with dynamin- 2, will be evaluated. The recruitment of GRAF1 to the VCC will be evaluated by super resolution microscopy techniques. GRAF1 depletion in infected MDMs and knockout in iMACs will establish if it is essential for VCC formation and function. Reconstitution with WT or GAP domain mutant GRAF1 will define the role of the Rho GTPase function of GRAF1 in leading to VCC formation. Together these studies will provide important new insights into HIV interactions with myeloid 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 = $703,409 )
2026	2026	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Allergy and Infectious Diseases Research	000	1	8/3/2026	NEW	$703,409
														Subtotal = $703,409

Grand Total All Awards = $703,409

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Role of CLIC/GEEC pathway in VCC formation and HIV-1 transmission from macrophages

Award Number: R56AI197882

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: 08/31/2027

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