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Use of a non-human primate model to define the role of T cell immune responses in persistent Kaposi sarcoma-associated herpesvirus infection and Kaposi sarcoma pathogenesis

Award Number: R21AI168750
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT ABSTRACT Kaposi sarcoma-associated herpesvirus (KSHV) is the causative agent of several human malignancies including Kaposi sarcoma (KS). KS is the most common KSHV-associated malignancy, with >44,000 new cases reported worldwide each year. The population most vulnerable to KSHV/KS are immunocompromised individuals such as people infected with HIV. Individuals with HIV/AIDS have a higher risk of developing KS when compared to HIV-negative individuals. The adaptive T cell immune response, especially CD4+ and CD8+ T cells, has been shown to play a crucial role in KSHV infection and subsequent KS pathogenesis. Although correlations between CD4+ and CD8+ T cell levels and KS development have been observed, this relationship has not been experimentally validated due to the lack of a suitable animal model. The recent development of the common marmoset (Callithrix jacchus) as a non-human primate (NHP) model that is susceptible to KSHV infection and capable of developing KS-like lesions under immunosuppression opens new frontiers to experimentally validate the role immune cells play in KS development. Thus, our objective is to define the role of reduced CD4+ and CD8+ T cell levels in persistent KSHV infection and subsequent KS pathogenesis in the marmoset NHP model. Anti-CD4 and anti-CD8 monoclonal antibodies (mAbs) have been used to deplete T cells and induce immunosuppression in both murine and NHP animal models, enabling study of CD4+/CD8+ T cells in controlling replication of several viruses. To avoid any adverse responses to murine mAbs when administered into marmosets, we will chimerize (murine-marmoset) anti-CD4/CD8 mAbs and characterize their biochemical and pharmacokinetic properties in vitro and in mice, then we will determine the effects of antibody-mediated T cell depletion on various immune cell populations (Aim 1). We will then challenge immunosuppressed marmosets with KSHV.219 virus and determine the extent to which antibody-mediated depletion of CD4+ and/or CD8+ T cells enables persistent KSHV infection and KS pathogenesis in immunocompromised marmosets (Aim 2). The successful completion of this project will validate the common marmoset as a tool for understanding the etiology of KS and uncover the critical role that CD4+ and/or CD8+ T cell depletion plays in allowing persistent KSHV infection and subsequent KS pathogenesis in immunocompromised animals.


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: 2024 ( Subtotal = $293,864 )
2024	2024	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	2	1/9/2024	NON-COMPETING CONTINUATION	$293,864
														Subtotal = $293,864

Issue Date FY: 2023 ( Subtotal = $345,516 )
2023	2023	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	1	1/27/2023	NEW	$345,516
2023	2023	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Allergy and Infectious Diseases Research	001	1	9/15/2023	NEW	$0
														Subtotal = $345,516

Grand Total All Awards = $639,380

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Use of a non-human primate model to define the role of T cell immune responses in persistent Kaposi sarcoma-associated herpesvirus infection and Kaposi sarcoma pathogenesis

Award Number: R21AI168750

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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