PROJECT SUMI (IARY (See instructions): The oropharynx is central to Kaposi sarcoma-assocaited herpesvirus (KSHV) infection;it is the primary site of viral replication, and saliva is the major route of KSHV transmission. Uncontrolled KSHV infection is associated with progression to KS. Some immunocompetent KSHV-infected people have frequent, high quantity oral replication, whereas others either rarely or never shed KSHV in saliva. This striking difference in the ability to control oral KSHV infection has clear implications for viral transmission, but may also be important for disease progression, since oral replication is strongly correlated with subsequent KSHV viremia and dissemination within the host. KSHV replication and development of KS occur much more often among people with HIV and other immunodeficiencies, which demonstrates the critical role of the immune system for preventing KSHV-associated disease. It is unknown, however, which immune responses to KSHV are most relevant for controlling infection. Despite the importance of the oral cavity in KSHV infection, mucosal immunity against KSHV has not been well studied. Neither is it understood how HIV infection and antiretroviral therapy (ART) affect oral immune responses to KSHV. The overall goal of this project is to identify correlates of the mucosal immune response associated with control of oral KSHV infection and viremia, and define how they are impaired by HIV infection.
In Aim 1, mucosal immune effector mechanisms mediating control of KSHV infection in the oral cavity and blood will be identified. Cohorts of KSHV infected/ HIV-negative people infection will be followed in Uganda to quantify the levels of KSHV detected in saliva and blood, and correlate them with: (1) neutralizing antibody in saliva;(2) gama delta+ T cell responses;and (3) innate immune mediators in saliva.
In Aim 2, the effect of untreated HIV infection on mucosal immune responses to KSHV will be evaluated by comparing the frequency and strength of the immune effector mechanisms described in HIV-uninfected people in Aim 1 to those in a second cohort of HIV-infected/ART naive subjects. Finally, in Aim 3, it will be determined whether ART is able to normalize mucosal immune responses to KSHV bv following HIV-infected subiects before and after initiation of ART.

Public Health Relevance

KS is the most common cancer in people infected with HIV. Moreover, in some parts of sub-Saharan Africa, such as Uganda, the clinical site for this study, KS is the most common cancer in the general population. Even with optimal therapy, complete resolution is only achieved in approximately half of patients, indicating the need for new strategies to prevent and treat KS.

Agency
National Institute of Health (NIH)
Type
Research Program Projects (P01)
Project #
5P01DE021954-04
Application #
8657382
Study Section
Special Emphasis Panel (ZDE1)
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Seattle Children's Hospital
Department
Type
DUNS #
City
Seattle
State
WA
Country
United States
Zip Code
98121
Bruce, A Gregory; Horst, Jeremy A; Rose, Timothy M (2016) Conservation of the glycoprotein B homologs of the Kaposi׳s sarcoma-associated herpesvirus (KSHV/HHV8) and old world primate rhadinoviruses of chimpanzees and macaques. Virology 494:29-46
DiMaio, Terri A; Wentz, Breanna L; Lagunoff, Michael (2016) Isolation and characterization of circulating lymphatic endothelial colony forming cells. Exp Cell Res 340:159-69
Lagunoff, Michael (2016) Activation of cellular metabolism during latent Kaposi's Sarcoma herpesvirus infection. Curr Opin Virol 19:45-9
Sanchez, Erica L; Lagunoff, Michael (2015) Viral activation of cellular metabolism. Virology 479-480:609-18
Fontaine, Krystal A; Sanchez, Erica L; Camarda, Roman et al. (2015) Dengue virus induces and requires glycolysis for optimal replication. J Virol 89:2358-66
Bruce, A Gregory; Thouless, Margaret E; Haines, Anthony S et al. (2015) Complete genome sequence of Pig-tailed macaque rhadinovirus 2 and its evolutionary relationship with rhesus macaque rhadinovirus and human herpesvirus 8/Kaposi's sarcoma-associated herpesvirus. J Virol 89:3888-909
DiMaio, Terri A; Gutierrez, Kimberley D; Lagunoff, Michael (2014) Kaposi's sarcoma-associated herpesvirus downregulates transforming growth factor β2 to promote enhanced stability of capillary-like tube formation. J Virol 88:14301-9
Fontaine, Krystal A; Camarda, Roman; Lagunoff, Michael (2014) Vaccinia virus requires glutamine but not glucose for efficient replication. J Virol 88:4366-74
Staheli, Jeannette P; Dyen, Michael R; Lewis, Patrick et al. (2014) Discovery and biological characterization of two novel pig-tailed macaque homologs of HHV-6 and HHV-7. Virology 471-473:126-40
Stockinger, Diane E; Fong, Derek L; Vogel, Keith W et al. (2014) Oral squamous cell carcinoma in a pigtailed macaque (Macaca nemestrina). Comp Med 64:234-9

Showing the most recent 10 out of 23 publications