Human Herpesvirus 8/Kaposi Sarcoma Herpesvirus Cell Association During Evolution of Kaposi Sarcoma

Abstract

Kaposi sarcoma (KS) is associated with a herpesvirus (HHV-8/KSHV), which expresses a latency-associated nuclear antigen (LANA). The histopathology of KS is characterized by angiogenesis, inflammatory cells, and the development of CD34+ tumor spindle cells (SCs). However, the cellular basis for the recruitment and dissemination of HHV-8 during the development of KS lesions is not clear. Twenty-nine KS biopsies with AIDS (AKS, n=22) and without HIV infection (endemic KS or EKS, n=7) were immunostained by a triple antibody method to characterize HHV-8-infected and noninfected (LANA+/-) CD34+ SCs, infiltrating CD3+, CD68+, CD20+, and CD45+ leukocytes as well as proliferating (Ki67+) cells. The CD34+/LANA+ SCs were more frequent in late (nodular) as compared with early (patch/plaque) KS stages. However, in late AKS 36.0% of SCs (median of 11 cases) were CD34+/LANA- compared with 20.7% in early cases (median of 11 cases). Furthermore, both AKS and EKS showed, at all stages, a small (4.1-6.5%) population of LANA+/CD34- cells. Proliferating Ki67+ cells were seen (4.5-11.5%) at all KS stages, and were usually more frequent in early AKS, but no significant difference was observed between nodular AKS and EKS. Most of the proliferating cells in the KS lesions were LANA+/CD34+ but a small fraction was LANA+/CD34-. Lesional CD68+ and CD3+ cells varied between AKS (7.3 and 5.2%, respectively) and EKS (4.9 and 3.1%, respectively) but were not clearly stage related. No LANA+ cells were CD3+, CD20+, or CD45+ and very few (<0.5%) were CD68+. These results indicate that not all CD34+ KS SCs were LANA+, suggesting recruitment of noninfected SCs to the lesions. Cell proliferation in general was much higher in early as compared with the late AKS stages. LANA+ SCs could have a proliferative advantage as suggested by higher frequency of cycling (Ki67+) LANA+ SCs. Few macrophages but no lymphocytes are LANA+.

KSHV Paracrine Effects on Tumorigenesis

“…Second, KSHV-infected spindle cells do not exhibit enhanced proliferation in KS lesions, but on the contrary, show significantly reduced proliferation rates as compared to uninfected cells (Kaaya et al, 2000;Kaaya et al, 1995;Köster et al, 1996). In this context, Pyakurel and colleagues showed that only a small fraction (up to 5%) of all latency-associated nuclear antigen (LANA)-1-positive KS spindle cells proliferate in KS lesions (Pyakurel et al, 2004). Our data confirmed these findings (Lorenz, 2007).…”

KSHV/HHV-8 infection of human hematopoietic progenitor (CD34+) cells: persistence of infection during hematopoiesis in vitro and in vivo

“…Previous investigations have demonstrated KSHV infection in circulating monocyte/macrophages and B lymphocytes of KS patients, suggesting that these cells may participate in the dissemination of viral infection in vivo. [7][8][9] KSHV can establish limited infections in a variety of cells in vitro, including human B cells, endothelial cells, epithelial cells, fibroblast cells, mesenchymal stem cells, dendritic cells, and macrophages. [4][5][6][10][11][12][13][14][15][16] In vivo, KSHV infection has been localized to human B cells, macrophages, keratinocytes, endothelial cells, and epithelial cells.…”

Avaliação da resposta tecidual "in situ" do fenótipo, da expressão de HHV-8/LANA e de citocinas em lesões cutâneas de sarcoma de Kaposi clássico e sarcoma de Kaposi associado à AIDS na era pré e pós-terapia anti-retroviral combinada

“…Como descrito anteriormente, a lesão de SK independentemente da forma clínico-epidemiológica está associada à proliferação de células fusiformes, as quais são na maioria infectadas pelo HHV-8 (Pyakurel et al, 2004 (Stürzl et al, 1992), assim como, marcadores específicos de vasos linfáticos (VEGFR-3 e D2-40) (Weninger et al, 1999 (Hong et al, 2004;Carrol et al, 2004).…”

“…A participação dessas células na patogênese do SK tem sido demonstrada por outros autores (Pyakurel et al, 2004;Hussein, 2007), (Donaghy et al, 2001;Pacanowski et al, 2001), outros demonstraram que essa diminuição de populações celulares de origem distinta não ocorre concomitantemente (Grassi et al, 1999;Soumelis et al, 2001).…”

“…Nas lesões de SK o HHV-8 tem sido demonstrado nas células fusiformes, células endoteliais e células mononucleares (Katano et al, 2000;Pyakurel et al, 2004;Pak et al, 2007;Ramos da Silva et al, 2007).…”