Etiology And Pathogenesis Of Aidslymphoma

Common to all AIDS-related lymphomas is the concept that they arise in the setting of on-going B cell proliferation and stimulation. This B-cell hyperstimulation is partially due to HIV itself (13), and may explain the polyclonal hypergammaglobulinemia characteristic of HIV infection, as well as the reactive lymphadenopathy, consisting of florid follicular (B-cell) hyperplasia. Aside from its direct effects on B lymphocytes,

HIV may also exert its effects indirectly, by inducing an inflammatory cytokine response from monocytes and T cells, leading to secretion of interleukin (IL)-6 and IL-10, both of which have been shown to induce B-cell proliferation (14-18). Antigen-selected B-cell clones may be preferentially stimulated, as shown by the high rate of somatic mutations in the hypervariable regions of the immunoglobulin genes utilized by AIDS-lymphoma (19,20), and by the fact that the repertoire of immunoglobulin genes utilized by AIDS-lymphoma show preferential usage of the V #4 family, which have been implicated in the generation of B-cell autoreactive clones (21,22).

In this setting of polyclonal B-cell proliferation, the progressive accumulation of mutational errors may predispose a given B-cell clone to a growth advantage, eventually leading to the development of monoclonal B-cell lymphoma. The specific genetic alterations leading to malignancy differ between the various pathologic types of AIDS-related lymphoma.

In AIDS-related Burkitt's lymphoma, a reciprocal chromosomal translocation between band 8q24 and one of the immunoglobulin gene loci (14q 32, 2p11, or 22q11) leads to transcriptional deregulation of the c-myc protooncogene on chromosome 8 (23,24). c-myc is a transcription factor that is involved in the entry of cells into the cell cycle (G0/Gi). The deregulation of c-myc permits the transactivation of downstream immunoglobulin genes, with resultant monoclonal B-cell expansion. While Epstein-Barr virus (EBV) is present in approx 30% of AIDS-related Burkitt's lymphomas (25), EBV transforming latent antigens are not expressed, suggesting that this virus is not intricately involved in the molecular pathogenesis of AIDS-related Burkitt's lymphoma. However, additional mutational errors, such as inactivating mutations and/or deletions of the p53 tumor suppressor gene are present in approx 60% of AIDS-related Burkitt's lymphoma (26), providing another mechanism for malignant outgrowth of clonal B lymphocytes. Mutations of ras genes has also been noted in occasional cases (26).

The most common molecular aberrations described in AIDS-related diffuse large B-cell lymphoma and B-immunoblastic lymphoma include EBV infection and dysregula-tion of bcl-6. EBV infection is present in approx 70-80% of such cases (27,28), with frequent expression of the EBV-encoded latent antigen LMP-1 (28). Recent work by Liebowitz (29) has demonstrated the transforming ability of LMP-1, as it binds to TRAF molecules (TNF receptor associated factors), thereby activating NFkB, with further signaling serving to drive cell division. While EBV is not the only pathogenic factor in the development of AIDS-diffuse large-cell lymphoma, Kersten and colleagues have demonstrated that decreases of EBV-specific cytotoxic T-cell responses, with subsequent increased EBV viral load, correlate with development of large-cell lymphoma in HIV-infected patients (30).

In addition to EBV, dysregulation of bcl-6 has also been described in approx 70% of diffuse large B-cell lymphoma, in both HIV-infected and uninfected patients (31). Bcl-6 expression is restricted to B cells of the germinal center, and is essential for germinal center formation (32). The protooncogene functions as a zinc-finger transcriptional repressor (33). Bcl-6 may be deregulated in lymphoma by means of chromosomal rearrangements or mutations of the 5' regulatory sequences (31,34). Although bcl-6 deregulation appears to be the most common mutational aberration in AIDS-related diffuse large B-cell lymphoma, such deregulation is not common in AIDS-related immunoblastic lymphoma, consistent with the postgerminal center derivation of these cells (20).

The molecular pathogenesis of PEL has not yet been fully ascertained, although the tumor is clearly associated with infection by HHV-8 (12). Of importance, the HHV8 genome carries structural and functional homologs of the human bcl-2, IL-6, and cyclin D genes, each of which may contribute to the development of lymphoid malignancy (35). In addition, the majority of PEL cases are also infected with EBV, providing another potential mechanism for lymphomagenesis.

Hepatitis C (HCV) infection has been associated with a variety of lymphoprolifera-tive disorders, and a high prevalence of HCV infection has been noted in HIV-negative patients with malignant lymphoma (36). Because HCV has been demonstrated in as many as 40% of HIV-infected patients, Levine and colleagues studied the relationship, if any, between chronic HCV infection and the subsequent development of AIDS-related lymphoma (37). Of interest, the study demonstrated no relationship between dual infection by HIV and HCV, and subsequent increased risk of lymphoma (37).

In summary, essentially all AIDS-lymphomas develop in the setting of ongoing B-cell stimulation and proliferation. The development of specific mutational errors in these proliferating cells provides a mechanism for clonal selection, with evolution from polyclonal B-cell response to monoclonal B-cell lymphoma. The specific pathologic types of AIDS-lymphoma are associated with different genetic alterations, each of which may lead to malignant transformation.

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