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Does Antibody-Dependent Intracellular Neutralization Limit HSV-1 Reactivation?

Award Number: R21AI173941
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: 11/10/2022
PERIOD OF PERFORMANCE END DATE: 10/31/2025

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Does Antibody-Dependent Intracellular Neutralization Limit HSV-1 Reactivation? - Antibodies that do not promote the destruction of pathogens in situ or prevent their internalization into target cells through opsonization are nevertheless key factors in immunity against intracellular pathogens. An important mechanism by which such “non-neutralizing” antibodies (nNAbs) curtail certain infections has been illuminated by the recent discovery of antibody-dependent intracellular neutralization (ADIN). In ADIN, cytosolic nNAbs bound to pathogens are recognized by the intracellular high-affinity Fc receptor Trim21 and the complex is degraded by the proteasome. ADIN has been found capable of eradicating an enveloped virus. Given that enveloped viruses shed bound antibodies upon cell membrane fusion, the means by which nNAbs access the cytosol is puzzling. That nNAbs access the cytosol in vivo but not in vitro suggests that culture models lack a critical cell or factor for nNAb entry. Herpes simplex viruses (HSV)-1 and -2 initially replicate in a lytic manner at mucosal surfaces but then establish life- long residence within ganglion neurons of the peripheral nervous system. In neuronal nuclei the viral genome enters latency, a state of quiescence in which replication is repressed and lytic proteins are produced at near-undetectable levels. As mature neurons are non-renewable and unchecked viral replication can lead to central nervous system damage, the control of latency is critical to the host. Ganglia are monitored by CD8+ T-cells, which deliver granzyme B at the immunological synapse with infected neurons via perforin pores. Cytosolic granzyme B digests ICP4, an essential transcriptional regulator. The model is therefore that without ICP4 to upregulate transcript production, latency is perpetuated. Our data show that ICP4 antibodies exist in seropositive human trigeminal ganglia, suggestive of a check on ICP4 expression by granzyme B and possibly by antibodies to ICP4 that mediate its ADIN. We hypothesize that antibody-dependent intracellular neutralization of ICP4 limits HSV-1 reactivation. We will address this in experiments of two Specific Aims: 1) assess whether antibodies gain access to the neuronal cytosol through the close interaction between CD8+-T-cells and latently-infected neurons; and 2) determine whether non-neutralizing antibodies direct ADIN of ICP4 produced during latent neuronal infection, stifling viral reactivation. We will use convergent approaches to benefit from both an in vivo → ex vivo mouse model of human HSV-1 latency, and an in vitro model of latent HSV-1 infection in human induced pluripotent stem cell-derived neurons. If successful, Aim 1 will define a heretofore undescribed route of nNAb entry into cells in the context of HSV-1 latency. Aim 2 will elucidate the molecular basis of the complex balance between viral latency and host immunity. If successful, this R21 study will shift the focus of HSV vaccine target design to accommodate a role for ADIN in anti-viral immunity, and indicate potential therapeutic targets including inhibitors of reactivation, or agonists of ADIN. Advances from our studies could also inform far-reaching approaches to antagonize human pathogens with a latency state including HIV, HCMV, MeV, and EBV.


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 = -$1 )
2026	2024	TRUSTEES OF DARTMOUTH COLLEGE	7 LEBANON ST	HANOVER	NH	03755	GRAFTON	USA	Allergy and Infectious Diseases Research	000	2	4/21/2026	NON-COMPETING CONTINUATION	-$1
														Subtotal = -$1

Issue Date FY: 2024 ( Subtotal = $246,000 )
2024	2024	TRUSTEES OF DARTMOUTH COLLEGE	7 LEBANON ST	HANOVER	NH	03755	GRAFTON	USA	Allergy and Infectious Diseases Research	000	2	10/26/2023	NON-COMPETING CONTINUATION	$221,400
2024	2024	TRUSTEES OF DARTMOUTH COLLEGE	7 LEBANON ST	HANOVER	NH	03755	GRAFTON	USA	Allergy and Infectious Diseases Research	001	2	5/9/2024	NON-COMPETING CONTINUATION	$24,600
														Subtotal = $246,000

Issue Date FY: 2023 ( Subtotal = $205,000 )
2023	2023	TRUSTEES OF DARTMOUTH COLLEGE	7 LEBANON ST	HANOVER	NH	03755	GRAFTON	USA	Allergy and Infectious Diseases Research	000	1	11/10/2022	NEW	$205,000
														Subtotal = $205,000

Grand Total All Awards = $450,999

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Does Antibody-Dependent Intracellular Neutralization Limit HSV-1 Reactivation?

Award Number: R21AI173941

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: 11/10/2022

PERIOD OF PERFORMANCE END DATE: 10/31/2025

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