This proposal is aimed at exploring the roles of viral infection with Human Immunodeficiency virus (HIV) and Kaposi's sarcoma-associated herpes virus (KSHV) in the pathogenesis of HIV-associated pulmonary hypertension. We will examine the effect of HIV and KSHV viral infection on activation of the bone morphogenetic protein receptor (BMPR) pathway and abnormal cytokine, vasoconstrictor and vasodilator production in endothelial cells. Primary Pulmonary Hypertension (PPH) is a disease that causes narrowing of the pulmonary vasculature leading to a high pulmonary blood pressure that often results in heart failure. The development of PPH is thought to occur through multiple events involving genetic and cellular environment factors. The primary dysfunction lies in the pulmonary endothelial cells which exhibit enhanced synthesis of vasoconstrictors, reduced synthesis of vasodilator production, and enhanced thrombogenesis. Endothelial cells are the predominant component of the plexiform. It has been estimated that the incidence of pulmonary hypertension among HIV-positive persons is several thousand times greater than among the general population. In both PPH and AIDS-associated PPH, the plexiform lesions contain proliferating endothelial cells. HIV might play either a direct or indirect role in endothelial cell dysfunction seen in PPH. The inability to identify HIV protein or RNA in pulmonary arteries of patients with HIV-associated pulmonary hypertension suggests that HIV does not directly infect the endothelial cells in the lesion. Thus, HIV may play an indirect role in the endothelial cell dysfunction seen in PPH. This could occur through the up regulation of paracrine factors such as proinflammatory cytokines or growth factors, leading to endothelial dysfunction and PPH. KSHV has also been recently linked to the development of PPH. Cool et al. reported that 62% of PPH patients displayed KSHV antigen within and around the plexiform lesions and the lesions themselves resembled Kaposi's sarcoma (KS) cutaneous lesionslt is very well established that KSHV can infect endothelial cells both in vitro and in vivo. Our hypothesis is that KSHV infection of endothelial cells predisposes the endothelial cells to aberrant signaling and proliferation, and this dysfunction is enhanced with HIV co infection.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL083469-04
Application #
7446601
Study Section
Special Emphasis Panel (ZHL1-CSR-B (S1))
Program Officer
Peavy, Hannah H
Project Start
2005-09-29
Project End
2010-06-30
Budget Start
2008-07-01
Budget End
2009-06-30
Support Year
4
Fiscal Year
2008
Total Cost
$344,622
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
West, John A; Damania, Blossom (2010) Kaposi's sarcoma-associated herpesvirus and innate immunity. Future Virol 5:185-196
Wen, Kwun Wah; Damania, Blossom (2010) Kaposi sarcoma-associated herpesvirus (KSHV): molecular biology and oncogenesis. Cancer Lett 289:140-50
Wen, K W; Damania, B (2010) Hsp90 and Hsp40/Erdj3 are required for the expression and anti-apoptotic function of KSHV K1. Oncogene 29:3532-44
O'Hara, Andrea J; Wang, Ling; Dezube, Bruce J et al. (2009) Tumor suppressor microRNAs are underrepresented in primary effusion lymphoma and Kaposi sarcoma. Blood 113:5938-41
O'Hara, Andrea J; Chugh, Pauline; Wang, Ling et al. (2009) Pre-micro RNA signatures delineate stages of endothelial cell transformation in Kaposi sarcoma. PLoS Pathog 5:e1000389
Wang, Ling; Damania, Blossom (2008) Kaposi's sarcoma-associated herpesvirus confers a survival advantage to endothelial cells. Cancer Res 68:4640-8
Tomlinson, Christine C; Damania, Blossom (2008) Critical role for endocytosis in the regulation of signaling by the Kaposi's sarcoma-associated herpesvirus K1 protein. J Virol 82:6514-23
Nun, Tamara K; Kroll, David J; Oberlies, Nicholas H et al. (2007) Development of a fluorescence-based assay to screen antiviral drugs against Kaposi's sarcoma associated herpesvirus. Mol Cancer Ther 6:2360-70
Sin, Sang-Hoon; Roy, Debasmita; Wang, Ling et al. (2007) Rapamycin is efficacious against primary effusion lymphoma (PEL) cell lines in vivo by inhibiting autocrine signaling. Blood 109:2165-73
Dittmer, Dirk P; Damania, Blossom (2007) KSHV-associated disease in the AIDS patient. Cancer Treat Res 133:129-39

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