Yoshiyasu Aoki

A Pilot Study of Cidofovir in Patients with Kaposi Sarcoma

A clinical trial was conducted to test the activity of cidofovir (CDV), a drug with in vitro activity against Kaposi sarcoma (KS)-associated herpesvirus (KSHV), in KS. Five patients with human immunodeficiency virus-associated KS (4 receiving antiretroviral therapy) and 2 patients with classical KS were administered CDV (5 mg/kg/dose) weekly for 2 weeks and then every other week. All 7 patients had progression of their KS at a median of 8.1 weeks (range, 5-27 weeks). Skin biopsy specimens of KS lesions showed no change in expression of latent or early lytic genes, but, in the 1 assessable patient, there was decreased expression of a late lytic gene. There was no decrease in the virus load of KSHV in peripheral blood mononuclear cells. This study does not provide proof of principle for the treatment of KS with CDV. However, it remains possible that antiherpesvirus therapy can be developed for herpes-induced tumors.

Immunoblastic lymphoma in persons with AIDS-associated Kaposi's sarcoma: a role for Kaposi's sarcoma-associated herpesvirus.

Kaposis sarcoma–associated herpesvirus, the viral agent of Kaposis sarcoma, is associated with two lymphoproliferative disorders: primary effusion lymphoma and multicentric Castlemans disease. To identify other lymphoproliferative conditions linked with Kaposis sarcoma–associated herpesvirus, we studied non-Hodgkins lymphomas arising in individuals with AIDS-associated Kaposis sarcoma. Formalin-fixed tissues from 24 such lymphomas were examined. As expected, two primary effusion lymphomas were Kaposis sarcoma–associated herpesvirus–positive, with immunohistochemistry demonstrating the Kaposis sarcoma–associated herpesvirus latency-associated nuclear antigen in the nuclei of all neoplastic cells. Additionally, three of seven evaluable cases of the immunoblastic variant of diffuse large B-cell lymphoma (immunoblastic lymphoma) showed similar latency-associated nuclear antigen staining. These Kaposis sarcoma–associated herpesvirus–positive immunoblastic lymphomas resembled primary effusion lymphoma histologically but were not known to involve body cavities (sites included lymph nodes, soft tissues of the neck, and spleen). Notably, 5–20% of the neoplastic cells in the Kaposis sarcoma–associated herpesvirus–positive immunoblastic lymphomas also showed cytoplasmic staining for viral interleukin-6, a biologically active cytokine homologue found in primary effusion lymphoma. We conclude that Kaposis sarcoma–associated herpesvirus is present in some immunoblastic lymphomas in persons with AIDS-associated Kaposis sarcoma.

Vascular Endothelial Growth Factor/Vascular Permeability Factor in the Pathogenesis of Primary Effusion Lymphomas

Primary effusion lymphomas (PEL), rare lymphomas associated with Kaposis sarcoma-associated herpesvirus (KSHV or HHV-8) infection, present as malignant lymphomatous effusions in body cavities. We have recently found that PEL effusions contain high levels of vascular endothelial growth factor/vascular permeability factor (VEGF/VPF). VEGF/VPF, an important regulator of tumor-angiogenesis in vivo, exerts its effects acting through the receptors KDR/Flk-1 and Flt-1 on the endothelial cell membrane. In vitro, the PEL cell lines BC-1, BCP-1 and BCBL-1 produce high levels of VEGF. RT-PCR analysis of RNA from the PEL cell lines amplified the three VEGF/VPF secreted isoforms, VEGF/VPF121, VEGF/VPF145 and VEGF/VPF165. Two of the PEL cell lines express the VEGF/VPF receptor Flt-1, but VEGF did not stimulate proliferation in these cells. SCID/beige mice inoculated intraperitoneally with BCBL-1 cells developed effusion lymphoma of human cell origin with prominent bloody ascites. In contrast, none of the mice treated with a neutralizing anti-human VEGF/VPF antibody developed ascites and effusion lymphoma. Although the precise mechanisms by which VEGF/VPF can promote vascular permeability are not fully understood, VEGF/VPF stimulation of vascular leakage may be critical to the pathogenesis of PEL.

State-of-the-Art Review Kaposi' s Sarcoma-Associated Herpesvirus-Encoded Interleukin-6

Since the discovery of the virus in 1994, the rapid pace with which Karposis sarcoma-associated herpesvirus (KSHV) research has progressed has quickly led to a broad understanding of the structure of the virus and its biology and pathology in humans. Molecular piracy of potentially useful cellular genes has emerged as a characteristic feature of this virus. The viral homolog of human IL-6, vIL-6 is an example in kind. Studies in vitro and in vivo have shown that vIL-6 can stimulate the growth of KSHV-infected primary infusion lymphoma (PEL) cells, can promote hematopoiesis, and act as an angiogenic factor through the induction of vascular endothelial growth factor (VEGF). It is not difficult to envision how vIL-6, through these properties and perhaps others yet to be identified, can contribute to KSHV survival and spread in the human population.

Neoplastic Conditions in the Context of HIV-1 Infection

HIV-1 infection predisposes to the development of specific types of cancer. Most cancers seen in the AIDS setting are related to oncogenic virus infections, such as Epstein-Barr virus (EBV), Kaposis sarcoma (KS)-associated herpesvirus (KSHV) and human papillomavirus (HPV). It is generally assumed that HIV-1 infection play a passive role in cancer development by impairing the host immune surveillance and increasing the risk of oncogenic virus infection. Recent insights, however, indicate that HIV-1 infection more actively promotes cancer growth. Experimental evidence has shown that HIV-1-encoded proteins can directly induce tumor angiogenesis and enhance KSHV transmission to target cells. Clinical evidence suggests that the oncogenicity of HPV is altered by the presence of HIV-1 infection irrespective of host immune status. The introduction of highly active antiretroviral therapy (HAART) has dramatically decreased the incidence of KS whereas the impact of HAART is variable in EBV-related lymphoma and HPV-related cervical cancer, suggesting that additional factors are involved in the pathogenesis of these cancers. Understanding the direct and indirect roles of HIV-1 in the pathogenesis of neoplastic conditions could provide the rationale for prevention and development of new treatments for AIDS-associated malignancies.

Serum inactivation contributes to the failure of stromal‐derived factor‐1 to block HIV‐I infection in vivo

The chemokine stromal‐derived factor‐1 (SDF‐1) can block human immunodeficiency virus type 1 (HIV‐1) infection in vitro by binding to the CXC chemokine receptor, CXCR‐4, which serves as a coreceptor for T cell tropic HIV‐1. In spite of being constitutively expressed in vivo, SDF‐1 does not appear to block HIV‐1 infection and spread in vivo. We report that SDF‐1 is consistently measured in normal serum (15.4±3.0 ng/ml; mean±sd) and in serum from AIDS patients (16.6±3.7 ng/ml). However, we find that circulating SDF‐1 is modified to an inactive form. When exposed to serum, recombinant SDF‐1 is specifically and rapidly altered to yield an apparently smaller chemokine that does not bind to SDF‐1 receptor‐expressing cells, does not have chemoattractive or pre‐B cell stimulatory activity, and does not block HIV‐1 infection. Thus, serum modification and inactivation contribute to the failure of SDF‐1 to block HIV‐1 infection and spread in man. The inactivation of circulating SDF‐1 may be critical in permitting local gradients to develop and direct cell trafficking.

Pathogenesis and Manifestations of Human Herpesvirus-8 -Associated Disorders

Human herpesvirus-8 (HHV-8), a recently discovered oncogenic human virus, is consistently associated with Kaposis sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castlemans disease (MCD). These disorders occur more frequently, but not exclusively, in human immunodeficiency virus (HIV)-infected individuals, and exhibit more aggressive clinical courses when developing in the setting of acquired immunodeficiency syndrome (AIDS). One of the most intriguing aspects of HHV-8-related disorders is the involvement of numerous growth factors in their pathogenesis. This review will focus on several HHV-8 gene products that exhibit proinflammatory and proangiogenic activities or act as transcriptional activators of cellular cytokines that are involved in the pathogenesis of HHV-8-related disorders.

Targeted Inhibition of Angiogenic Factors in AIDS-related Disorders

Immunosuppression associated with human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS) markedly increases the risk for development of several cancers. Despite its dramatic decrease in frequency after the introduction of highly active antiretroviral therapy (HAART), Kaposis sarcoma (KS) remains the most common neoplastic manifestation of AIDS. KS is a multicentric angioproliferative tumor, characterized microscopically by spindle cells. KS cells produce and respond to angiogenic factors such as basic fibroblast growth factor (bFGF) and vascular endothelial growth factor-A (VEGF-A). In addition to cellular growth factors, the trans-activator HIV protein Tat plays a major role in the pathogenesis of AIDS-related KS by augmenting the angiogenic activities of bFGF and VEGF-A, and activating the VEGF receptor-2. Viral products from the recently described Kaposis sarcoma-associated herpesvirus (KSHV) also exhibit potent angiogenic activities. KSHV is consistently associated with KS and two lymphoproliferative disorders, primary effusion lymphoma (PEL) and the plasma cell variant of multicentric Castlemans disease (MCD). Several viral genes may contribute to the phenotype of PEL and MCD: among them, a viral homologue of interleukin-6 (vIL-6) has attracted much attention due to its potential to stimulate B cell growth and accelerate angiogenesis via VEGF-A induction. In this review, we summarize current knowledge and hypothesis regarding the cellular and viral angiogenic factors involved in the pathogeneses of AIDS-related malignancies, and discuss novel therapeutic strategies based on targeting pro-angiogenic factors.

Further Clonal Expansion of T Cells upon Rechallenge of Superantigen Staphylococcal Enterotoxin A

Superantigens are known to induce clonal anergy and/or deletion in reactive T cells peripherally. This study was undertaken to investigate the T‐cell status early after exposure to staphylococcal enterotoxin A (SEA) in vivo and in vitro. At the peak of clonal expansion following the administration of 5 μg SEA (i.e., 2 days after the injection), C57BL/6 mice were rechallenged with the same dose of SEA in vivo. The secondary stimulation augmented clonal expansion of the T cells bearing Vβ3 and Vβ11 in both CD4+ and CD8+ populations. In vitro restimulation of the spleen cells taken from the SEA‐primed mice also induced further expansion of the Vβ3+ T cells during 2 days of culturing, whereas without restimulation, a marked reduction of Vβ3+ T cells occurred. The spleen cells from the SEA‐primed mice were hyper‐reactive to in vitro restimulation with SEA as measured by 3H‐TdR uptake on day 1 of culturing, but augmented proliferation leveled off thereafter. By day 3, the values of 3H‐TdR uptake were less than 20% of those of the controls in which spleen cells from native mice were stimulated with SEA in vitro. These results suggest that T cells exposed to SEA in vivo are still capable of proliferating upon SEA rechallenge, but subsequently, the proliferation starts to wane.

Viral and Cellular Cytokines as Therapeutic Targets in AIDS-Related Lymphoproliferative Disorders

Since the advent of highly active antiretroviral therapy (HAART) and its widespread use, the incidence of AIDS-defining illnesses has decreased dramatically, leading to a much longer survival of patients. Despite some exciting new leads, non-Hodgkins lymphoma (NHL) remains a fatal malignancy for the vast majority of patients with acquired immunodeficiency syndrome (AIDS). Multiple molecular pathways appear to operate in AIDS lymphomagenesis and some may preferentially be associated with specific malignant histopathologic categories or anatomic sites of origin. AIDS-associated lymphomas share several features, including B-cell lineage derivation, diffuse aggressive histology, and frequent origin from or involvement of extranodal sites. Recently, high-grade primary effusion lymphomas (PEL) have been reported in patients with advanced AIDS. PEL is recognized as a distinct clinicopathologic entity associated with Kaposis sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus-8 (HHV-8). KSHV genes are likely to contribute to the neoplastic phenotype of PEL cells that require cytokines and factors from the host or encoded by the virus for growth in vivo. KSHV is also thought to dramatically affect the incidence, type, and course of multicentric Castlemans disease, another lymphoproliferative disorder over-represented in patients with AIDS. This review summarizes the current knowledge of autocrine growth factor loops and angiogenic factors that are involved in the pathogenesis of KSHV-related lymphoproliferative disorders in AIDS. Deregulated cytokines may represent potential targets of novel therapeutic strategies.