Human herpesvirus type 8 (HHV-8) is a gamma family herpesvirus discovered in 1994 by Chang and Moore. The virus has been strongly implicated by serologic antibody studies and PCR detection as the etiologic agent of Kaposi's sarcoma (KS) as well as multicentric Castleman's disease and body cavity lymphomas. Based on the well-documented role of T cell immune responses in herpesvirus infections, we hypothesize that T cell immunity is induced by HHV-8 infection. We postulate further that cytotoxic T lymphocyte (CTL) activity specific for the virus is central to control of HHV-8 infection, and failure of this surveillance mechanism results in development of HHV-8 related disease. Knowledge regarding CTL responses to HHV-8 may be important in development of adequate treatment and prevention methods for this agent. Therefore, we propose the following specific aims for this project: (1) Characterize the longitudinal T cell immmunologic responses (by lytic activity, gamma interferon producing cells and tetramer staining) to regulatory, structural and latent proteins of HHV-8 during primary infection of normal adults subjects, including T cell phenotype, HLA restriction and peptide epitope mapping; (2) Define the role of the anti-HHV-8CTL response in the development of KS in HIV-1 infected subjects; (3) Determine the CTL response in situ to viral proteins related to lytic, latent and transforming properties of HHV-8, and determine if KS tumor cells are capable of suppressing CTL activity; and (4) Determine if the transforming protein K1 elicits HHV-8 clade- specific CTL responses. Application of these methodologies in our laboratories for assessing cellular immunity and HHV-8 expression, combined with access to a longitudinal cohort of HHV-8 seroconvertors in the Multicenter AIDS Cohort Study, offers a unique opportunity to advance our understanding of anti-HHV-8 CTL responses in primary infection and development of KS. Such information is also important for understanding the immune correlates of protection against HHV-8 infection as the basis for development of therapeutic regimens and prophylatic vaccines

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA082053-02
Application #
6173555
Study Section
Special Emphasis Panel (ZRG1-AARR-4 (01))
Program Officer
Read-Connole, Elizabeth Lee
Project Start
1999-07-01
Project End
2002-06-30
Budget Start
2000-07-01
Budget End
2001-06-30
Support Year
2
Fiscal Year
2000
Total Cost
$347,470
Indirect Cost
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Public Health
DUNS #
053785812
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Lepone, Lauren M; Rappocciolo, Giovanna; Piazza, Paolo A et al. (2017) Regulatory T Cell Effect on CD8+ T Cell Responses to Human Herpesvirus 8 Infection and Development of Kaposi's Sarcoma. AIDS Res Hum Retroviruses 33:668-674
Hensler, Heather R; Tomaszewski, Monica J; Rappocciolo, Giovanna et al. (2014) Human herpesvirus 8 glycoprotein B binds the entry receptor DC-SIGN. Virus Res 190:97-103
Knowlton, Emilee R; Rappocciolo, Giovanna; Piazza, Paolo et al. (2014) Human herpesvirus 8 induces polyfunctional B lymphocytes that drive Kaposi's sarcoma. MBio 5:e01277-14
Nadgir, Sagar V; Hensler, Heather R; Knowlton, Emilee R et al. (2013) Fifty percent tissue culture infective dose assay for determining the titer of infectious human herpesvirus 8. J Clin Microbiol 51:1931-4
Knowlton, Emilee R; Lepone, Lauren M; Li, Jun et al. (2012) Professional antigen presenting cells in human herpesvirus 8 infection. Front Immunol 3:427
Lepone, Lauren; Rappocciolo, Giovanna; Knowlton, Emilee et al. (2010) Monofunctional and polyfunctional CD8+ T cell responses to human herpesvirus 8 lytic and latency proteins. Clin Vaccine Immunol 17:1507-16
Colleton, Bonnie A; Huang, Xiao-Li; Melhem, Nada M et al. (2009) Primary human immunodeficiency virus type 1-specific CD8+ T-cell responses induced by myeloid dendritic cells. J Virol 83:6288-99
Hensler, Heather R; Rappocciolo, Giovanna; Rinaldo, Charles R et al. (2009) Cytokine production by human herpesvirus 8-infected dendritic cells. J Gen Virol 90:79-83
Rinaldo, C R (2009) Dendritic cell-based human immunodeficiency virus vaccine. J Intern Med 265:138-58
Rappocciolo, Giovanna; Hensler, Heather R; Jais, Mariel et al. (2008) Human herpesvirus 8 infects and replicates in primary cultures of activated B lymphocytes through DC-SIGN. J Virol 82:4793-806

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