Pathologic aspects of AIDS malignancies

Abstract

Since the emergence of the HIV pandemic, a close association between HIV infection and the development of a selected group of cancers has been acknowledged. The introduction of highly active antiretroviral therapy, however, has had a dramatic impact on the incidences of several AIDS-defining malignancies. This suggests the possibility of a direct and indirect role of HIV in HIV-related tumor genesis. The aim of this paper is to review the pathology of AIDS-related malignancies, taking into account the pathogenetic mechanisms and their potential for improving the treatment of these tumors.

Introduction

Kaposi's sarcoma (KS), non-Hodgkin's lymphomas (NHLs) and invasive cervical carcinoma (ICC) are currently considered to be AIDS-defining conditions. In addition, classical Hodgkin's lymphoma (cHL) has been increasingly described in the HIV setting with peculiar clinico-pathologic features. There is also strong evidence of a relationship between HIV-induced immunodeficiency and the development of anal intraepithelial neoplasia (AIN). The introduction of highly active antiretroviral therapy (HAART) has had a dramatic impact on the morbidity and mortality of patients living with HIV (Rabkin, 2001; Tirelli et al., 2002). In addition to a dramatic decline in the incidence of several opportunistic infections, HAART is affecting the incidences of several AIDS-defining malignancies (Gates and Kaplan, 2002). The incidence of KS has dropped precipitously since the introduction of HAART in 1995 (Hengge et al., 2002). The incidence of malignant lymphomas has also decreased following the widespread use of HAART (Rabkin, 2001). In contrast, the incidence of ICC has not significantly changed in the HAART era (Rabkin, 2001). The impact of HAART on the epidemiology of other HIV-associated malignancies, including cHL and anal carcinoma, remains unclear (Gates and Kaplan, 2002). However, in general, data regarding the impact of HAART on the natural history and treatment outcomes of HIV associated malignancies are still ill defined. The cost of antiretroviral therapies also poses a limit to the development of successful global intervention. In all, 90% of the 40 million AIDS patients in the world cannot afford HAART, and AIDS-related malignancies remain a very common problem in developing countries. On these grounds, the field of AIDS research is evaluating alternative therapeutic approaches for the treatment and prevention of AIDS and related diseases (Dal Maso et al., 2001). Nevertheless, antiretroviral therapy remains an important component in the treatment strategy for several HIV-related malignancies and its impact on such malignancies further suggests the possibility of a direct and indirect role of HIV in HIV-related tumor genesis.

This article reviews the recent advances in our knowledge of the pathology of AIDS-related malignancies, taking into account the pathogenetic mechanisms involved and their potential for improving the treatment of these tumors.

Kaposi's sarcoma

Classic KS was first described by Moritz Kaposi in 1872 and was known for an entire century as a rare disorder in older men usually of Eastern European, Mediterranean and/or Jewish origin, in whom it is often an indolent disease that affects the extremities (Kaposi, 1872). In Western Europe and North America, the disease commonly occurs in those born in, or whose families originated from, Italy, Greece and the Middle East. In some equatorial African countries, KS has been known for many decades, predating the emergence of HIV (D'Oliveira and Torres, 1972). This form of the disease is known as ‘endemic KS’ (Olweny, 1984), and is often more aggressive than the classic form. Endemic KS extends to the lymph nodes and is seen in both children and adults. The median age of classic KS patients is 65 years, while the median age for endemic KS is 40 years. In the early 1980 s, the prevalence of KS began to increase dramatically and it soon became the most common malignancy in patients with AIDS (Beral et al., 1990).

KS lesions are composed of a proliferation of spindle cells, usually in a directional streaming pattern, mixed with endothelial cells, fibroblasts and inflammatory cells. Most spindle cells express endothelial markers, such as CD31 and CD34. However, they can also express markers for smooth-muscle cells, macrophages or dendritic cells (Roth et al., 1992). This indicates that spindle cells are either derived from pluripotent precursor cells or represent a heterogenous population of cells. It has recently been shown that the vascular endothelial growth factor receptor-3 (VEGFR-3) (Veikkola et al., 2001), which is the receptor for the lymphangiogenic cytokine vascular endothelial growth factor C (VEGF-C) is ubiquitously expressed by KS spindle cells (Jussila et al., 1998; Dupin et al., 1999). VEGFR-3 is usually only expressed by cells of the lymphatic endothelium and by neoangiogenesis vessels, and not by mature vascular endothelial cells, indicating that KS spindle cells probably belong to the endothelial lineage that differentiates towards lymphatic cells. This supports the hypothesis that KS spindle cells belong to the lymphatic, rather than vascular endothelial lineage.

The pathogenesis of KS has been better understood since the identification of the novel KS-associated herpesvirus (KSHV), which can be found in all forms of KS (Cesarman and Knowles, 1997). This virus, also called human herpesvirus 8 (HHV-8), carries at least 11 open reading frames (ORFs) that encode homologs to cellular proteins involved in signal transduction, cell cycle regulation, inhibition of apoptosis and/or immune modulation (Cannon and Cesarman, 2000). It therefore has the genetic machinery of an oncogenic virus. Overall, HHV8 seroprevalence correlates with the incidence of KS. However, only a small proportion of HHV8 infected people ever develop KS, and these do so only after a long latency period (Schulz et al., 2002). It is now believed that HHV-8 is necessary, but not sufficient, to cause KS and that other factors, such as immunosuppression play a major role. However, viral oncogenesis and cytokine-induced growth also contribute to the development of KS. Several virally encoded genes, such as bcl-2, interleukin-6, cyclin-D, G protein-coupled receptor and interferon regulatory factor, have key functions in cellular proliferation and survival (Schulz, 2001). In particular viral-Cyclin-D (v-Cyclin-D) forms a complex with CDK6 that phosphorylates RB and inactivates it. The v-cyclin-D/CDK6 complex also phosphorylates and inactivates P27, relieving its inhibition of CYCLIN-E/CDK2 and CYCLIN-A/CDK2 activities (Godden-Kent et al., 1997). The v-cyclin-D/CDK6 complex is partly resistant to inhibition by both families (INK4 and CIP/KIP) of cyclin-dependent kinase inhibitors (Ellis et al., 1999), so this complex might cause unrestrained proliferation when expressed in host cells. v-Cyclin-D/CDK6 also interacts with and phosphorylates proteins of the origin recognition complex (such as ORC1 and CDC6) (Laman et al., 2001), which are involved in DNA replication, sharing this ability with cellular CYCLIN-A/CDK2 complexes. The v-cyclin-D therefore executes the functions of three separate CYCLIN-CDK complexes, encompassing exit from G0 (CYCLIN-D-CDK6) through G1 (CYCLIN-E/CDK2) and entry into S phase (CYCLIN-A/CDK2). Growth promotion of KS is further stimulated by various proinflammatory cytokines and growth factors such as tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), basic fibroblast growth factor (bFGF) and VEGF, resulting in hyperplastic polyclonal lesions with predominantly spindle cells, derived from lymphoid endothelium. Spindle cells, along with inflammatory cells that infiltrate KS lesions, express high levels of IL-6, bFGF, VEGF, TNF-α, oncostatin -M and interferon-γ (IFN-γ) (Salahuddin et al., 1988; Ensoli et al., 1989; Fiorelli et al., 1998; Miles et al., 1990). In vitro, exogenous IL-6 enhances the proliferation of KS cells and IFN-γ induces primary endothelial cells to acquire features that are similar to KS spindle cells. bFGF induces cell proliferation in an autocrine fashion, and synergizes with VEGF to promote the growth of primary KS cells derived from human tumors and the development of angioproliferative KS-like lesions in mice (Ensoli et al., 1994).

The more aggressive nature of HIV-associated KS and the particular distribution of the lesion (such as nose, mouth and genitalia) have led to speculation that HIV-1-encoded proteins themselves might enhance KS growth. Tat protein of HIV-1 virus, for example, induces various cytokines that may synergically interact with the products of HHV8 (Albini et al., 1995; Prakash et al., 2000). Tat also induces growth of KS spindle cells in vitro and has angiogenic properties both in vivo and in transgenic mice (Vogel et al., 1988). It has not been determined, however, whether active circulating Tat actually reaches sufficiently high levels to promote KS cell growth in vivo.

AIDS-related lymphoma

The clinico-pathological range of AIDS-related NHLs includes Burkitt's lymphoma (BL), diffuse large B cell lymphoma (DLBCL – often involving the central nervous system), primary effusion lymphoma (PEL) and plasmablastic lymphoma of the oral cavity. The incidence of cHL also increases in the setting of HIV. cHL in HIV-infected persons is characterized by the predominance of unfavorable histological subtypes, mixed cellularity being the most frequently diagnosed subtype. The pathological heterogeneity of AIDS-related lymphomas reflects several pathogenetic mechanisms: chronic antigen stimulation, genetic abnormalities, cytokine deregulation and the role of herpesviruses EBV and HHV8. HIV-related lymphomas are consistently monoclonal and are characterized by a number of common genetic oncogene abnormalities involving the MYC and BCL-6 oncogenes, as well as tumor suppressor genes (Cinti et al., 2000). In AIDS-related BL, the molecular lesions involve activation of C-MYC and inactivation of P53 and P130 (Preudhomme et al., 1995; Lazzi et al., 2002), while most DLBCLs in patients with AIDS carry somatic mutations of immunoglobulin and BCL-6 genes. However, the somatic hypermutation mechanism functions aberrantly in a significant proportion of AIDS-related NHLs, causing the mutation of many genes, and possibly favoring chromosomal translocation, which may be a powerful contributor to malignant transformation (Gaidano et al., 2003). Epstein–Barr virus is identified in the neoplastic cells of approximately 50% of HIV-related lymphomas, but the detection of EBV varies considerably according to the site of presentation and histological types (Ambinder, 2001). EBV infection occurs in almost all of the cases of primary central nervous system lymphoma (PCNSL) and PEL, 80% of DLBCL with immunoblastic features and 30–90% of BL. Nearly all cases of cHL in the setting of HIV infection are associated with EBV. HHV8 is specifically associated with PEL, which often occurs in the late stages of the disease in the setting of profound immunosuppression. EBV-associated B-cell lymphomas represent the various stages of B-cell differentiation and are caused by different programs of EBV latent gene expression (Thorley-Lawson, 2001). HIV associated DLBCLs frequently express latency type 3 antigens including EBNA-1, EBNA-2, EBNA-LP, EBNA-3A and EBNA-3C and the latent membrane protein (LMP-1). In contrast, EBV in HIV-associated BL has latency type 1 profile, expressing only EBNA-1 (Carbone, 2003). When EBV infects resting human B lymphocytes, it drives the cells into the cell cycle and maintains cell division. The lympho-blastoid cell lines (LCLs) that arise from this type of EBV infection are relatively resistant to apoptosis caused by deprivation of serum growth factors. Cells of this LCL type are produced in vivo upon primary infection of humans but are then eliminated by the immune response (Klein, 1994). In the absence of normal immune surveillance, cells of the LCL type can develop into lymphomas (Babcock and Thorley-Lawson, 2000). Genetic analysis of EBV has demonstrated that several viral genes are required for initiation and maintenance of growth. These include the genes that encode the nuclear proteins EBNA-1, EBNA-2, EBNA-LP, EBNA-3A, and EBNA-3C and LMP (Ambinder, 2001). Some of the biochemical functions of these proteins are now becoming clear. EBNA-2 causes transcription activation through several interactions (including the Notch pathway). EBNA-3C causes cells to progress through cell cycle check points in both G1 and G2/M by an unknown mechanism, and the partly related EBNA-3A protein has effects on gene regulation. The LMP protein activates signaling through several transduction pathways, including activation of TNF-κB (Ambinder, 2001).

The association of HHV8 with B cells, as well as the B-cell primary effusion lymphomas and a subtype multicentric Castelman's disease (MCD), indicate a possible similarity with the mechanism by which EBV exploits B cells (Cesarman et al., 1995; Soulier et al., 1995). HHV8-infected B cells in AIDS MCD consist entry express immunoglobulin μ(IgM) and Ig light chain, indicating that this B-cell type could be a natural target or reservoir for HHV8 (Du et al., 2001). However, nearly 50% of AIDS-related systemic lymphomas are negative for EBV and/or HHV8. This implicates other factors in the etiology of these malignancies associated with HIV infection, including polyclonal B-cell expansion and impaired T-cell immunosurveillance.

In HIV-infected individuals, chronic antigen stimulation leads to oligoclonal B-cell expansion. The consistent failure to unequivocally detect HIV sequences within the tumor clone suggests that HIV is not directly implicated in the transformation of B cells in vivo. Rather, the role of HIV in lymphomagenesis appears to be predominantly indirect and related to the disrupting effects of the virus on hosts' immune regulation. Immunological alterations induced by HIV include reduced immunosurveillance, chronic antigen stimulation and cytokine deregulation, which have all been show to play a role in lymphomagenesis of HIV-infected persons. These alterations induced by HIV result in B-cell oligoclonal expansion and proliferation, which commonly occur in the early phases of HIV infection. In clinical and pathological terms, the phase of oligoclonal B-cell expansion and proliferation corresponds to persistent generalized lymphadenopathy. In subsequent phases, the neoplastic transformation of a B-cell clone is due to the accumulation of genetic lesions, which eventually transform the clone into a true NHL. This model of lymphomagenesis, initially developed for NHL associated with HIV, may also be applicable to other examples of virus-associated lymphomagenesis. New molecular and virological evidence of biological features of AIDS-related NHLs may lead to new targets for pathogenetically and biologically oriented therapies.

Invasive cervical cancer

Over the last 10 years, the relationship between human papilloma virus (HPV) infection and female cervical intraepithelial neoplasia (CIN) has been established (Boccalon et al., 1996; Wallace and Carlin, 2001; Clarke and Chetty, 2002). Several studies have described an increased prevalence in both cervical HPV infection and CIN among HIV-positive women compared to HIV-negative ones. A high recurrence rate of CIN after standard treatment has been noted in HIV-positive women and the severity of these lesions seems to be inversely correlated to immune function. Taking into account these data, since 1993 the Centers for Disease Control (CDC) have included ICC among the conditions it considers AIDS-defining. Once cervical cancer develops in HIV-positive women, the disease may be aggressive and less responsive to treatment. Cervical cytology appears to be adequate as a screening tool for cervical intraepithelial neoplasia in HIV-positive women, but the high recurrence rate and multifocality of this disease reinforces the need for careful evaluation and follow-up of the entire anogenital tract in these women. Cervical tumors represent one of the most frequent complications of HIV infection in developing countries, representing a part of progression through AIDS. This points to a need for greater interdisciplinary cooperation for a best disease definition and for the development of effective prevention measures.

The relation between HIV and cervical cancer is even more complex than with KS and NHLs. Some authors have commented on the lack of a significant difference regarding the severity of neoplasia in asymptomatic HIV positive women and those with AIDS. Cervical cancer has long been associated with HPV infection. Just as EBV takes advantage of normal B-cell differentiation pathways to promote its own replication, HPV exploits the normal epithelial differentiation pathway. HPV infects the proliferating undifferentiated basal layers of the epithelium and multiplies as an episome in the nuclei of differentiating upper layers of epithelium (such as keratinocytes). Viral DNA integrates into that of host cells. This process disrupts the viral regulatory gene E2, leading to the derepression of the oncogenic E6 and E7 proteins. The E7 ORF of HPV, HPV-E7, encodes the main transforming activity of this virus and regulates various components of the cell cycle. E7 associates with the retinoblastoma tumor-suppressor protein family (including RB, p107 and p130) (Dyson et al., 1989), as well as histone deacetylase and AP1 transcription factors. The E7 proteins of the more oncogenic papillomavirus subtypes (HPV16 and HPV18) bind with greater affinity to the RB-family proteins (Gage et al., 1990). E7 binding to RB releases E2F (which RB normally inhibits), allowing E2F to activate the transcription of genes that are involved in DNA synthesis, such as E2F1, and genes that encode DNA polymerase (POL), thymidine synthethase (TS) and thymidine kinase (TK). HPV-E7 also activates CYCLIN-E/CDK2 complexes, leading to phosphorylation (P) (inactivation) of RB. Finally, E7 interacts with p21 to abrogate p21-mediated inhibition of CYCLIN-E/CDK2 and CYCLIN-A/CDK2 kinase activities. Overall, E7 promotes cell cycle progression, extending the duration of viral replicative competence in the host cell. However, this alone is insufficient to cause cervical cancer and other carcinogens and further genetic changes are required for disease progression. A primary means by which HIV infection may influence the pathogenesis of HPV-associated cervical pathology is by molecular interaction between HIV and HPV genes. Although not yet well defined, an upregulation of HPV E6 and E7 gene expression by HIV proteins (such as Tat) has been postulated by some authors.

Anal carcinoma

There is also strong evidence of a relationship between HIV-induced immunodeficiency, HPV infection and the development of AIN, also known as squamous intraepithelial lesion (SIL) (Tirelli et al., 2002). Patients with HIV infection are more likely to have both HPV infection and AIN than are non-HIV-infected persons with similar demographic characteristics. Moreover, AIN is more common among HIV-infected persons with lowCD4 cell count and a more advanced clinical stage of HIV disease (Tirelli et al., 2002).

Discussion

Since the emergence of the HIV pandemic, a close association between HIV infection and the development of a selected group of cancers has been brought to light (Boshoff et al., 2002). Several mechanisms of pathogenesis have been reported (Table 1), yet the reason why neoplasia, in particular NHL are more common in the HIV than in other forms of immunodepression is not completely understood (Gaidano et al., 1998; Knowles, 1999). There are several schools of thought to account for this difference in both clinical and molecular behavior, each implicating different biological aspects. Some favor HIV targeting of specific genes. Others have suggested local immune deregulation involving both alteration in cell profile and alteration of cytokine profiles, whereas others again favor direct viral–viral interactions. HIV infection is associated with a reduction of cell-mediated immunity, and the failure of CD4-helper T cells to recognize clones of abnormal proliferating cells may be one of the reasons behind the development of AIDS-associated malignancies (Dalgleish et al., 2002). The humoral predominant chronic immune activation seen in AIDS may also be important in providing the necessary environment for oncogenic viruses to induce lymphoma, KS and anogenital cancers. The interactions of EBV, HHV8 and HPV with the disrupted immunological and cytokine microenvironment induced by HIV have already been mentioned in the previous paragraphs and represent some aspects of the pathogenetic mechanisms involved in the development of AIDS-related malignancies. Here, we would like to focus on other pathways of tumorigenesis. The pathway of tumor progression is determined by a specific cell cycle checkpoint aberration (Figure 1) and, as previously reported, one mechanism by which cell cycle control may be altered is by interaction with viral oncoproteins. DNA viruses may stimulate G1 progression and S-phase entry for successful replication of their genomes, thus resulting in disruption of the normal cell cycle control regulatory mechanisms. In addition, loss of control at the G1/S checkpoint allows the accumulation of numerous small genetic changes leading to unchecked progression through G2/M. Loss of tumor suppressor genes, referred to as the loss of the heterozygosity (LOH) pathway, and genetic instability at the microsatellite (MSI) loci are among these genetic changes, both involved in tumor progression in AIDS-associated malignancies. LOH has also consistently been detected at specific loci such as 3p14.1Bp22, 4p16, 6p21, 3p25 and 17p13.3 (Mullokandov et al., 1996; Kersemaekers et al., 1998). This has led to speculation as to candidate tumor suppressor genes. Defects in the mismatch repair (MMR) genes, which prevent them from repairing slippage errors that occur during replications are believed to cause MSI. An increased rate of MSI has been described in several HIV-related malignancies including KS, NHLs, AIN and HIV-associated lung cancers (Bedi et al., 1995). HIV-related CIN lesions have also shown a significantly higher frequency of MSI, independently of CD4 counts (Wistuba et al., 1999). There are several possible explanations. It has been suggested that HIV may target the MMR genes or other repair pathways. Alternatively, a viral protein may specifically bind to the DNA or cellular proteins, corrupting the replication process. However, the HIV genome has not been detected in tumor samples and, in those studies where it has been detected in low copy numbers, it has been attributed to HIV in background inflammatory cells. The hypothesis that HIV might use a ‘hit and run’ mechanism, modifying the cell without detection of the viral genome, should also be considered (Clarke and Chetty, 2002).

Table 1 Pathogenetic mechanisms of AIDS malignancies
Figure 1
figure1

Schematic representation of the molecular network for cell cycle regulation

Tat protein of HIV is also a likely candidate to contribute to tumor pathogenesis in HIV-infected patients (Ensoli et al., 1994; Fiorelli et al., 1998; Altavilla et al., 1999; Kundu et al., 1999). Tat protein is an early nonstructural protein necessary for virus replication, which is secreted by infected cells and taken up by uninfected cells (Rubartelli et al., 1998). Extensive evidence indicates that Tat is a cofactor in the development of AIDS-related neoplasms (Noonan et al., 2000) and the protein has also been found to have an oncogenic role in vitro and in vivo (Kim et al., 1992; Corallini et al., 1993, 1996; Kundu et al., 1999). However, the molecular mechanism of Tat-mediated tumorigenesis is not clear at present. There is experimental evidence to suggest a potential role of Tat-mediated chemotaxis and invasion in the pathogenesis of AIDS-related malignancies (Barillari et al., 2002). Deregulation of cellular genes and functions by Tat can also cause abnormalities that may contribute to AIDS pathogenesis and to the development of AIDS-associated disorders (Kundu et al., 1997,1998; Kashanchi et al., 2000). Extracellular Tat is able to regulate many cellular genes which are involved in cell signaling and translation and ultimately controls the host proliferation and differentiation signals (Chang et al., 1995; Li et al., 1995; Zauli et al., 1995; De La Fuente et al., 2002). The molecular mechanism underlying Tat's pleotropic activity may include the generation of functional heterodimers of Tat with cell cycle proteins (Kashanchi et al., 2000). In particular, Tat protein of HIV has also recently been shown to physically interact with the RB2/p130 tumor suppressor gene product (Lazzi et al., 2002) and E2F4 (Ambrosino et al., 2002). The RB2/p130 tumor suppressor gene belongs to the retinoblastoma gene family together with RB and p107 (Stiegler et al., 1998). Many of the sequence similarities among these genes reside in a homologous functional domain known as the pocket region. This particular region mediates the interaction with E2F/DP members and viral oncoproteins. Besides mutations of the gene (Claudio et al., 2000a,2000b; Cinti et al., 2000), interaction with viral oncoproteins is another important mechanism of inactivation of pRb2/p130, as oncoviral disruption of E2F/DP complexes re-induce site-dependent transcription and cell cycle progression (Fattaey et al., 1993; De Luca et al., 1997). Recent data demonstrated that Tat and pRb2/p130 interact through the pocket region of pRb2/p130, resulting in the inhibition of pRb2/p130 oncosuppressive properties and uncontrolled cell proliferation (De Falco et al., 2003). Whether this can occur through an ATP-dependent chaperone model remains to be determined (Figure 2). In addition, the interaction of Tat and RB2/p130 alone may not be sufficient for neoplastic transformation in vivo and other cofactors may be required. This is also consistent with the finding that Tat cannot induce cell growth unless cells are previously activated with inflammatory cytokines (Ensoli et al., 1990; Barillari et al., 1992; Albini et al., 1995; Fiorelli et al., 1998). Further studies are necessary to completely elucidate the molecular mechanism underlying the Tat-pRb2/p130 interaction. Nevertheless, these results open a window on the role of pRb2/p130 in AIDS-related oncogenesis and suggest a re-evaluation of HIV itself as an oncogenic virus. This may result in the implementation of future therapeutic regimens and the design of new therapeutic approaches.

Figure 2
figure2

Tat with a chaperone may elicits a conformational changes in the pRb2-E2F4 complex. The release of free molecules may occur through an energy-dependent mechanisms, that is, ATP hydrolysis

References

  1. Albini A, Barillari G, Benelli R, Gallo RC and Ensoli B . (1995). Proc. Natl. Acad. Sci. USA, 92, 4838–4842.

  2. Altavilla G, Trabanelli C, Merlin M, Caputo A, Lanfred M, Barbanti Brodand G and Corallini A . (1999). Am. J. Pathol., 154, 1231–1244.

  3. Ambinder RF . (2001). Eur. J. Cancer, 37, 1209–1216.

  4. Ambrosino C, Palmieri C, Puca A, Trimboli F, Schiavone M, Olimpico F, Ruocco MR, Di Leva F, Toriello M, Quinto I, Venuta S and Scala G . (2002). J. Biol. Chem., 277, 31448–31458.

  5. Babcock GJ and Thorley-Lawson DA . (2000). Proc. Natl. Acad. Sci. USA, 97, 12250–12255.

  6. Barillari G, Buonaguro L, Fiorelli V, Hoffman J, Michaels F, Gallo RC and Ensoli B . (1992). J. Virol., 66, 7159–7167.

  7. Barillari G and Ensoli B . (2002). Clin. Microbiol. Rev., 15, 310–326.

  8. Bedi GC, Westra WH, Farzadegan H, Pitha PM and Sidransky D . (1995). Nat. Med., 1, 65–68.

  9. Beral V, Peterman TA, Berkelman RL and Jaffe HW . (1990). Lancet, 335, 123–128.

  10. Boccalon M, Tirelli U, Sopracordevole F and Vaccher E . (1996). Eur. J. Cancer, 32A, 2212–2217.

  11. Boshoff C and Weiss R . (2002). Nat. Rev. Cancer, 5, 373–382.

  12. Cannon M and Cesarman E . (2000). Semin. Oncol., 27, 409–419.

  13. Carbone A . (2003). Lancet Oncol., 4, 22–29.

  14. Cesarman E, Chang Y, Moore PS, Said JW and Knowles DM . (1995). N. Engl. J. Med., 332, 1186–1191.

  15. Cesaman E and Knowles DM . (1997). Semin. Diagn. Pathol., 14, 54–66.

  16. Chang HK, Gallo RC and Ensoli B . (1995). J. Biomed. Sci., 2, 189–202.

  17. Cinti C, Leoncini L, Nyongo A, Ferrari F, Lazzi S, Bellan C, Vatti R, Zamparelli A, Cevenini G, Tosi GM, Claudio PP, Maraldi NM, Tosi P and Giordano A . (2000). Am. J. Pathol., 156, 751–760.

  18. Clarke B and Chetty R . (2002). Mol. Pathol., 55, 19–24.

  19. Claudio PP, Caputi M and Giordano A . (2000a). Clin. Cancer Res., 6, 754–764.

  20. Claudio PP, Howard CM, Pacilio C, Cinti C, Romano G, Minimo C, Maraldi NM, Minna JD, Gelbert L, Leoncini L, Tosi GM, Micheli P, Caputi M, Giordano GG and Giordano A . (2000b). Cancer Res., 60, 372–382.

  21. Corallini A, Altavilla G, Pozzi L, Bignozzi F, Negrini M, Rimessi P, Gualandi F and Barbanti-Brodano G . (1993). Cancer Res., 53, 5569–5575.

  22. Dal Maso L, Serraino D and Franceschi S . (2001). Eur. J. Cancer., 37, 1188–1201.

  23. De Falco G, Bellan C, Lazzi S, Claudio PP, La Sala D, Cinti C, Tosi P, Giordano A and Leoncini L . (2003). Oncogene, in press.

  24. Dalgleish AG and O'Byrne KJ . (2002). Adv. Cancer Res., 84, 231–276.

  25. De La Fuente C, Santiago F, Deng L, Eadie C, Ziberman I, Kehn K, Maddukuri A, Baylor S, Wu K, Lee CG, Pumfery A and Kashanchi F . (2002). BMC Biochem., 3, 14.

  26. De Luca A, Machachlan TK, Bagella L, Dean C, Howard CM, Claudio PP, Baldi A, Khalili K and Giordano A . (1997). J. Biol. Chem., 272, 20971–20974.

  27. D'Oliveira JJ and Torres FO . (1972). Cancer, 30, 553–561.

  28. Du MQ, Liu H, Diss TC, Ye H, Hamoudi RA, Dupin, N, Meignin V, Oksenhendler E, Boshoff C and Isaacson PG . (2001). Blood, 97, 2130–2136.

  29. Dupin N, Fisher C, Kellam P, Ariad S, Tulliez M, Franck N, van Marck E, Salmon D, Gorin I, Escande, JP, Weiss RA, Alitalo K and Boshoff C . (1999). Proc. Natl. Acad. Sci. USA, 96, 4546–4551.

  30. Dyson N, Howley PM, Munger K and Harlow E . (1989). Science, 243, 934–937.

  31. Ellis M, Chew YP, Fallis L, Freddersdorf S, Boshoff C, Weiss RA, Lu X and Mittnacht S . (1999). EMBO J., 18, 644–653.

  32. Ensoli B, Barillari G, Salahuddin SZ, Gallo RC and Wong-Staal F . (1990). Nature, 345, 84–86.

  33. Ensoli B, Gendelman R, Markham P, Fiorelli V, Colombini S, Raffeld M, Cafaro A, Chang HK, Brady JN and Gallo RC . (1994). Nature, 371, 674–680.

  34. Ensoli B, Nakamura S, Salahuddin SZ, Biberfeld P, Larsson L, Beaver B, Wong-Staal F and Gallo RC . (1989). Science, 243, 223–226.

  35. Fattaey AR, Harlow E and Helin K . (1993). Mol. Cell Biol., 13, 7267–7772.

  36. Fiorelli V, Gendelman R, Sirianni MC, Chang HK, Colombini S, Markham PD, Monini P, Sonnabend J, Pintus A, Gallo RC and Ensoli B . (1998). Blood, 91, 956–967.

  37. Gage JR, Meyers C and Wettstein FO . (1990). J. Virol., 64, 723–730.

  38. Gaidano G, Carbone A and Dalla Favera R . (1998). Am. J. Pathol., 152, 623–630.

  39. Gaidano G, Pasqualucci L, Capello D, Berra E, Deambrogi C, Rossi D, Larocca LM, Gloghini A, Carbone A and Dalla-Favera R . (2003). Blood, Apr. 24 (EPUB ahead of print).

  40. Gates AE and Kaplan LD . (2002). Oncology (Huntingt), 16, 657–665, discussion 665, 668–670.

  41. Godden-Kent D, Talbot SJ, Boshoff C, Chang Y, Moore P, Weiss RA and Mittnacht S . (1997). J. Virol., 71, 4193–4198.

  42. Hengge UR, Ruzicka T, Tyring SK, Stuschke M, Roggendorf M, Schwartz RA and Seeber S . (2002). Lancet Infect. Dis., 2, 344–352.

  43. Jussila L, Valtola R, Partanen TA, Salven P, Heikkila P, Matikainen MT, Renkonen R, Kaipainen A, Detmar M, Tschachler E, Alitalo R and Alitalo K . (1998). Cancer Res., 58, 1599–1604.

  44. Kaposi M . (1872). Arch. Dermatologie Syphillis, 265–273.

  45. Kashanchi F, Agbottah ET, Pise-Masison CA, Mahieu R, Duvall J, Kumar A and Brady NJ . (2000). J. Virol, 74, 652–660.

  46. Kersemaekers AM, Hermans J, Fleuren GJ and van de Vijver MJ . (1998). Br. J. Cancer, 77, 192–200.

  47. Klein G . (1994). Cell, 77, 791–793.

  48. Kim CM, Vogel J, Jay G and Rhim JS . (1992). Oncogene, 7, 1525–1529.

  49. Knowles DM . (1999). Mod. Pathol., 12, 200–217.

  50. Kundu M, Guermah M, Roeder RG, Amini S and Khalili K . (1997). J. Biol. Chem., 272, 29468–29474.

  51. Kundu RK, Sangiorgi F, Wu LY, Pattengale PK, Hinton DR, Gill PS and Maxson R . (1999). Blood, 94, 275–282.

  52. Kundu M, Sharma S, De Luca A, Giordano A, Rappaport J, Khalili K and Amini S . (1998). J. Biol. Chem., 273, 8130–8136.

  53. Laman H, Coverley D, Krude T, Laskey R and Jones N . (2001). Mol. Cell. Biol., 21, 624–635.

  54. Lazzi S, Bellan C, De Falco G, Cinti C, Ferrari F, Nyongo A, Claudio PP, Tosi GM, Vatti R, Gloghini A, Carbone A, Giordano A, Leoncini L and Tosi P . (2002). Hum. Pathol., 33, 723–731.

  55. Li CJ, Wang C, Friedman DJ and Pardee AB . (1995). Proc. Natl. Acad. Sci. USA, 92, 5461–5464.

  56. Miles SA, Rezai AR, Salazar-Gonzalez JF, Vander Meyden M, Stevens RH, Logan DM, Mitsuyasu RT, Taga T, Hirano T and Kishimoto T et al. (1990). Proc. Natl. Acad. Sci. USA, 87, 4068–4072.

  57. Mullokandov MR, Kholodilov NG, Atkin NB, Burk RD, Johnson AB and Klinger HP . (1996). Cancer Res., 56, 197–205.

  58. Noonan D and Albini A . (2000). Adv. Pharmacol., 48, 229–250.

  59. Olweny CL . (1984). IARC Sci. Publ., 63, 543–548.

  60. Prakash O, Tang ZY, He YE, Ali MS, Coleman R, Gill J, Farr G and Samaniego F . (2000). J. Natl. Cancer Inst., 92, 721–728.

  61. Preudhomme C, Dervite I, Wattel E, Vanrumbeke M, Flactif M, Lai JL, Hecquet B, Coppin MC, Nelken B and Gosselin B . (1995). J. Clin. Oncol., 13, 812–820.

  62. Rabkin CS . (2001). Eur. J. Cancer., 37, 1316–1319.

  63. Roth WK, Brandstetter H and Stuizl M . (1992). AIDS, 6, 895–913.

  64. Rubartelli A, Poggi A, Sitia R and Zocchi MR . (1998). Immunol. Today, 19, 543–545.

  65. Salahuddin SZ, Nakamura S, Biberfeld P, Kaplan MH, Markham PD, Larsson L and Gallo RC . (1988). Science, 242, 430–433.

  66. Schulz TF . (2001). Eur. J. Cancer, 37, 1217–1226.

  67. Schulz TF, Sheldon J and Greensill J . (2002). Virus Res., 82, 115–126.

  68. Soulier J, Grollet L, Oksenhendler E, Cacoub P, Cazals-Hatem D, Babinet P, d'Agay MF, Clauvel JP, Raphael M and Degos L et al. (1995). Blood, 86, 1276–1280.

  69. Stiegler P, Kasten M and Giordano A . (1998). J. Cell Biochem. Suppl., 30–31, 30–36.

  70. Thorley-Lawson DA . (2001). Nat. Rev. Immunol., 1, 75–82.

  71. Tirelli U, Bernardi D, Spina M and Vaccher E . (2002). Crit. Rev. Oncol. Hematol., 41, 299–315.

  72. Veikkola T, Jussila L, Makinen T, Karpanen T, Jeltsch M, Petrova TV, Kubo H, Thurston G, McDonald DM, Achen MG, Stacker SA and Alitalo K . (2001). EMBO J., 20, 1223–1231.

  73. Vogel J, Hinrichs SH, Reynolds RK, Luciw PA and Jay G . (1988). Nature, 335, 606–611.

  74. Wallace SV and Carlin EM . (2001). Int. J. STD AIDS, 12, 283–285.

  75. Wistuba II, Syed S, Behrens C, Duong M, Milchgrub S, Muller CY, Jagirdar J and Gazdar AF . (1999). Gynecol. Oncol., 74, 519–526.

  76. Zauli G, Gibellini D, Caputo A, Bassini A, Negrini M, Monne M, Mazzoni M and Capitani S . (1995). Blood, 86, 3823–3834.

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We acknowledge the help of Emma Thorley in editing the manuscript.

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Correspondence to L Leoncini.

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Bellan, C., Falco, G., Lazzi, S. et al. Pathologic aspects of AIDS malignancies. Oncogene 22, 6639–6645 (2003) doi:10.1038/sj.onc.1206815

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Keywords

  • AIDS
  • HIV
  • neoplasm
  • pathology

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