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Principal Investigator: Javier Gordon Ogembo
Organization: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
Fiscal Year: 2024
Award: $840,321
Funding agency: National Cancer Institute
PROJECT SUMMARY
More than 44,000 new cases of Kaposi sarcoma (KS) are reported globally each year, 84% of which occur in
Africa. This and other Kaposi sarcoma-associated herpesvirus (KSHV)-induced malignancies predominate in
people with acquired or iatrogenic immunodeficiencies. Although KSHV can be detected in other human body
fluids, its frequent detection in saliva in groups both with and without risk of sexually transmitted infections (e.g.,
children) suggests that the oral cavity is the site of primary acquisition. However, the mechanism of KSHV oral
transmission in vivo, particularly the critical viral envelope glycoproteins (gps) required for viral entry,
remains unresolved. Several KSHV–host interactions have been identified, but all prior experiments were
performed in vitro and have not been validated in vivo due to prior lack of an appropriate animal model. Through
collaboration with the Wisconsin National Primate Research Center, our laboratory has access to the common
marmoset (Callithrix jacchus, CJ), a recently developed KSHV non-human primate model that is susceptible to
KSHV oral infection, and under immunosuppression acquires KS-like skin lesions. The objective of this
application is to elucidate the minimum gps required to initiate primary oral infection in vivo, as a prerequisite to
selecting key gps for developing an effective prophylactic vaccine candidate. This application builds on Dr.
Ogembo’s recently completed NCI K01 CA184388-05 research on KSHV entry mechanisms and vaccine
development. Recently, we showed that in vitro, the KSHV glycoprotein gH/gL is essential for viral infection of
epithelial, endothelial, and fibroblasts cells, but not B cells. Notably, we and others have also shown that both
monoclonal and polyclonal Abs to KSHV glycoproteins gB, gH/gL, and gpK8.1, can neutralize KSHV infection of
diverse permissive human cells in vitro. Building on this success, we generated KSHV deletion mutants lacking
the four glycoproteins thought to be critical for viral entry (gB, gH/gL, gpK8.1) and various monoclonal antibodies
specific to these gps. In this project, we will use human ex vivo samples and the CJ KSHV model to test the
hypothesis that gB and gH/gL are critical for KSHV in vivo oral transmission. The premise of our proposal is
built on strong evidence that 1) KSHV can infect CJ, which develop KS-like skin lesions, and 2) Abs against the
KSHV glycoproteins gB and gH/gL can neutralize KSHV infection in vitro and ex vivo. Furthermore, the
permissiveness to KSHV infection of human cells ex vivo and CJ makes these platforms ideal to test the KSHV
gp requirements for infection. Successful completion of the proposed study will elucidate the minimum KSHV
gps required for primary infection in ex vivo and in vivo models, advancing our long-term goal of defining the
initial steps in KSHV infection of humans and the role of antibodies in protecting against the early steps of KSHV
transmission. This will ultimately inform design and development of prophylactic vaccines that can prevent KSHV
infection and its associated cancers.
Terms: <0-11 years old><AIDS/HIV><Ab-mediated immunity><Ab-mediated protection><Africa><Age><Animal Model><Animal Models and Related Studies><Antibodies><Antibody immunity><Antibody protection><Antibody-mediated protection><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><Binding><Body Fluids><Buccal Cavity><Buccal Cavity Head and Neck><Callithrix jacchus><Callithrix jacchus jacchus><Cancers><Cavitas Oris><Cell Body><Cell Communication and Signaling><Cell Signaling><Cell surface><Cells><Child><Child Youth><Children (0-21)><Clinical Treatment Moab><Collaborations><Common Marmoset><Complex><Data><Detection><Development><Disease><Disorder><Endothelial Cells><Endothelium><Epithelial Cells><Epithelium><Fibroblasts><Future><Glycoproteins><Goals><HHV-8><HHV8><HIV/AIDS><Herpes infection><Herpesviridae><Herpesviridae Infections><Herpesviridae disease><Herpesvirus Infections><Herpesviruses><Human><Human Figure><Human Herpesvirus 8><Human body><Iatrogenesis><Immunity><Immunize><Immunocompetent><Immunocompromised><Immunocompromised Host><Immunocompromised Patient><Immunosuppressed Host><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><In Vitro><Infection><Intracellular Communication and Signaling><KSHV><Kaposi Sarcoma><Kaposi Sarcoma-Associated Herpes Virus><Kaposi Sarcoma-Associated Herpesvirus><Kaposi sarcoma associated virus><Kaposi sarcoma herpes virus><Kaposi's Sarcoma><Kaposi's sarcoma (KS)-associated herpesvirus><Laboratories><Lesion><Lymphatic cell><Lymphocyte><Lymphocytic><Malignant Neoplasms><Malignant Tumor><Malignant lymphoid neoplasm><Maternal antibody><Measures><Membrane><Modeling><Modern Man><Molecular Interaction><Monoclonal Antibodies><Mouth><Multiple Hemorrhagic Sarcoma><Oral><Oral cavity><Pattern><Persons><Predisposition><Preventative vaccine><Preventive vaccine><Primary Infection><Primates><Primates Mammals><Prophylactic vaccine><Receptor Cell><Receptor Protein><Recombinants><Reporting><Research><Risk><Role><Saliva><Sampling><Sexually Transmitted Diseases><Sexually Transmitted Disorder><Sexually Transmitted Infection><Signal Transduction><Signal Transduction Systems><Signaling><Site><Susceptibility><T-Cells><T-Lymphocyte><Testing><Tonsil><Transmission><Transplant Recipients><Tropism><Venereal Diseases><Venereal Disorders><Venereal Infections><Viral><Viral Diseases><Viremia><Virion><Virus Diseases><Virus Particle><Virus-HHV8><Wisconsin><Work><ages><antibody-mediated immunity><biological signal transduction><cell type><design><designing><develop a vaccine><develop vaccines><development of a vaccine><developmental><experiment><experimental research><experimental study><experiments><herpes virus><human model><hypoimmunity><iatrogenic><iatrogenically><iatrogenicity><immune competent><immune deficiency><immune suppression><immune suppressive activity><immune suppressive function><immunodeficiency><immunosuppressed><immunosuppressed patient><immunosuppressive activity><immunosuppressive function><immunosuppressive response><in vivo><in vivo Model><infection mouth><kaposi's sarcoma herpesvirus><kaposi's sarcoma-associated human herpesvirus><kids><latent infection><lymph cell><lymphoid cancers><lymphoid malignancy><mAbs><malignancy><membrane structure><model of animal><model of human><monoclonal Abs><mutant><neoplasm/cancer><non-human primate><nonhuman primate><novel><oral infection><oral infectious><permissiveness><polyclonal antibody><polyclonal human antibody><prevent><preventing><prophylactic><receptor><sexually acquired infection><skin lesion><social role><success><thymus derived lymphocyte><tonsillar><tool><transmission process><transplant patient><vaccine candidate><vaccine development><viraemia><viral infection><viral sepsis><virus infection><virus-induced disease><virusemia><youngster>