Human herpesvirus 8 (HHV-8) is the etiologic agent of KS, the most common cancer associated with HIV infection and AIDS. We hypothesize that T cell immunity is critical to control of HHV-8 infection and prevention of KS, and that this is linked to interactions with HHV-8 infected, professional antigen presenting cells (APC), particularly blood and tissue dendritic cells (DC) and B cells. We and others have shown that anti-HHV-8 T cell immunity is present in HIV infected and non-HIV infected persons who are seropositive for HHV-8. We have also shown that DC and B cells can be infected with HHV-8, but only activated B cells support complete virus replication, and that infection of all three cell types requires DC-SIGN. However, we know little regarding anti- HHV-8 T cell-APC interactions in controlling viral infection and disease. For the next 5 years of this grant, we propose to define several immunologic interactions of DC with anti-HHV-8 CD8 T cells.
In Aim 1, we will define primary and secondary T cell responses to HHV-8 lytic and latency proteins. We will address the role of the major types of myeloid DC - monocyte-derived DC, Langerhans cells and dermal DC, and B cells - in priming na?ve CD8 T cells and activation of memory T cells using HHV-8 peptide libraries, whole virus and HHV-8 infected apoptotic B cells.
In Aim 2, we will compare primary and secondary T cell responses in our unique cohort of HIV negative and positive persons who seroconverted to HHV-8 in the Multicenter AIDS Cohort Study (MACS). We will assess na?ve CD8 T cells obtained prior to seroconversion to HHV-8 with memory T cells obtained longitudinally after HHV-8 seroconversion for responses to HHV-8 peptide epitopes defined in Aim 1, including MACS participants who developed KS.
In Aim 3, we will identify cytokines/chemokines induced by viral infection and determine their role in inhibiting expression of DC-SIGN and other C-type lectin receptors. We will construct HHV-8 recombinants deficient for expression of K3 and/or K5 in order to determine the effect of these proteins on expression of DC-SIGN and MHC class I, and on stimulation of anti-HHV-8 CTL. This research will provide important information for development of adequate treatment and prevention strategies for HHV-8 infection and related cancers.

Public Health Relevance

Human herpesvirus 8 (HHV-8), or Kaposi's sarcoma (KS) associated herpesvirus, is the etiologic agent of KS, the most common cancer associated with HIV infection and AIDS. We propose to study the role of antigen presentation and T cell immunity in control of HHV-8 infection and prevention of KS. This study will provide important information on CD8 T cell immunity during HHV-8 infection for development of adequate treatment and prevention strategies for HHV-8 related cancers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA082053-12
Application #
8298679
Study Section
AIDS-associated Opportunistic Infections and Cancer Study Section (AOIC)
Program Officer
Read-Connole, Elizabeth Lee
Project Start
1999-07-01
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
12
Fiscal Year
2012
Total Cost
$360,609
Indirect Cost
$118,109
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Public Health
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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
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
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
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
Rinaldo, C R (2009) Dendritic cell-based human immunodeficiency virus vaccine. J Intern Med 265:138-58
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
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
Rappocciolo, Giovanna; Jenkins, Frank J; Hensler, Heather R et al. (2006) DC-SIGN is a receptor for human herpesvirus 8 on dendritic cells and macrophages. J Immunol 176:1741-9
Rappocciolo, Giovanna; Piazza, Paolo; Fuller, Craig L et al. (2006) DC-SIGN on B lymphocytes is required for transmission of HIV-1 to T lymphocytes. PLoS Pathog 2:e70

Showing the most recent 10 out of 15 publications