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Chapter 12 : HIV Infection and Development of Cancer
Category: Viruses and Viral Pathogenesis
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Cancer will occur in about 40% of individuals with HIV infection. This chapter reviews studies of the four cancers frequently associated with HIV infection: Kaposi’s sarcoma (KS), B-cell lymphoma, anal carcinoma, and cervical carcinoma. Other tumors that could become more prominent in the HIV-infected host are discussed briefly. For instance, all of the following have shown an increased incidence in HIV infection: Hodgkin’s disease, potentially involving Epstein-Barr virus (EBV) in several cases; multiple myelomas; and seminomas. The mechanisms involved could include either immune suppression or immune enhancement associated with virus infection. A major consideration, because of the potential approaches to therapy, is the role of cytokines in these diseases. B cells, endothelial cells, and epithelial cells could proliferate as a result of cytokine production and could give rise to lymphomas, KS, and anal carcinomas. The chromosomal changes that take place can result from this stimulated growth or directly from an infectious agent, and eventually the malignancy is established. In some cases (e.g., polyclonal B-cell lymphoma), the persistent growth into a cancer could be caused solely by cytokine production. In the presence of immunologic disorders, tumors, such as cervical carcinoma, could spread more readily.
Key Concept Ranking
- Herpes simplex virus 2
Potential role of viruses in induction of malignant disease. Virus can infect host cells, and in the case presented, immune cell cytokine production is induced that promotes proliferation of certain target cells (e.g., endothelial, epithelial, or B cells). With increased replication of cells, other factors can cause chromosomal changes leading to autonomous growth and malignant transformation. Adapted from The Lancet (2523), copyright 1995, with permission from Elsevier.
Tumor development appears to be a multistep phenomenon. A variety of agents can initiate the process, which is then promoted often by cellular products such as cy-tokines or hormones. Finally, a transforming event occurs which generally involves chromosomal changes. This event can be induced directly by virus.
HIV infection and cancer development. HIV infection can lead to immune disorders that result in either an increase or a decrease in immune responses. Both processes could be involved in cancer development.
A phylogenetic tree for primate herpesvirus lineages. The tree shown is derived from the data set and analyses described in reference 2924. The tree was obtained by a maximum-likelihood method with molecular clock imposed and an input alignment of amino acid sequences for six genes; the species depicted were selected from a total set of 40 species. The root locus is marked with a circle. A divergence scale (substitutions per site) is shown. HSV, herpes simplex virus; VZV, varicella-zoster virus: HCMV, human cytomegalovirus; HVS, herpesvirus saimiri; SVV, simian varicella virus; CCMV, chimpanzee cytomegalovirus; OW, Old World; NW, New World; RV rhadinovirus; LCV, lymphocryptovirus. Figure provided by D. McGeoch.
Natural history of human herpesvirus 8 (HHV-8) infection: clinical stages and determinants of progression. KS, Kaposi’s sarcoma. Reprinted from reference 1145 with permission.
Schematic representation of the 137-kb unique region of the Kaposi’s sarcoma-associated herpesvirus/human herpesvirus 8 (KSHV/HHV-8) genome, which contains all the known protein-coding regions. The unique region is flanked at each end by multiple copies of a high-GC 801-bp terminal direct repeat (not shown) to give a total genome size of about 170 kbp. The genome termini probably ligate together to circularize the genome during the cellular portion of the viral replicative cycle. The unique region consists of portions containing genes that are widely conserved in other herpesviruses (grey portions) and portions containing genes unique to HHV-8 and, in some cases, its close relatives (white portions). Several genes are regulatory, cytokine, and DNA metabolism genes that are homologous to cellular genes, and many of these are unique to HHV-8. KCP, KSHV complement-binding protein; POL, DNA polymerase; vIL-6, viral IL-6 homolog; DHFR, di-hydrofolate reductase; TS, thymidylate synthase; vCCL-1, -2, and -3, viral IL-8-like CC chemokine homologues; vBcl-2, viral Bcl-2 homologues; TK, thymidine kinase; UNG, uracil-DNA glycosylase; DUT, dUTPase; vIRF-1, -2, -3, and -4, viral interferon regulatory factor homologues; RR1 and RR2, subunits of ribonucleotide reductase; vFLIP, viral FLIPlike inhibitor of apoptosis homologue; vCYC, viral D-type cyclin homologue; vOX2, viral OX2 homologue; vGPCR, viral GPCR homologue resembling IL-8Rα; FGARAT, formyl-glycinamide ribotide amidotransferase. Also shown are T1.1 and T0.7, two highly expressed transcripts, and KS330Bam and KS631Bam sequences, originally found by representational difference analysis of an AIDS KS lesion. Provided by A. Davison.
Emergence of B-cell lymphomas in HIV-infected individuals. Polyclonal proliferation of B cells can give rise to monoclonal lymphomas. The factors in parentheses can cause the polyclonal expansion of B cells. The latter type may show evidence of c-myc translocation and/or Epstein-Barr virus (EBV) infection. The Burkitt type of lymphoma appears to develop from one malignant cell. EBV and c-myc may be detected in polyclonal lymphomas but at a reduced frequency. Figure provided by B. Herndier.
Potential mechanisms for transformation of B cells into lymphoma. HIV infection of macrophages or CD4+ T cells can result in the production of cytokines that induce the proliferation of B cells. The HIV gp41 envelope protein and EBV can also be involved. The polyclonal activation and chromosomal changes (e.g., c- myc translocation) cause the emergence of an autonomously growing malignant cell.
Schematic presentation of different grades of anal intraepithelial neoplasia (AIN). AIN grade 1 is characterized by 20 and 25% replacement of the epithelium with immature cells with a high nucleus/cytoplasm ratio. AIN grade 2 has approximately 50% replacement with immature cells, and grade 3 has complete or nearly complete replacement of the normal epithelium with immature cells. Microinvasion, shown at the bottom of the figure, takes place when cells traverse the basement membrane. Microinvasion usually occurs with AIN grades 2 to 3 as indicated. Reprinted from reference 3388 with permission.
Cytologic appearance of AIN grade 2. Note the enlarged nuclei with irregular shape (dark arrow) and cross-chromatin. A normal cell with a small nucleus/cytoplasm ratio is seen nearby (open arrow). Magnification, ×500. Reprinted from reference 3388 with permission.
Proposed schema of pathogenesis of anal-genital cancer. Subclinical infection with human papillomavirus establishes viral persistence, and various factors interact to lead to a final transformation event. As with other malignancies, chromosomal changes caused by genomic instability would be involved. Control or regression could be mediated by cellular immune responses that are absent in HIV infection. Reprinted from reference 4985 with permission from Elsevier.
Induction of cancers in HIV infection. Virus infection of macrophages, CD4+ cells, or other cells could lead to production of cytokines that enhance the proliferation of certain target cells, such as B cells, endothelial cells, and epithelial cells. The enhanced replication of these cells—either through aprocrine cytokine production or through subsequent viral infection (Epstein-Barr virus [EBV], human papillomavirus [HPV], or human herpesvirus 8 [HHV-8])—could lead to the eventual development of the malignancies noted. In some cases, such as B-cell lymphomas and Kaposi’s sarcoma, ongoing cytokine production by the tumor cells maintains the malignant state. (See also Figure 12.8 .)
Relationship of HIV transmission group and gender to the percentage of adult AIDS patients in the United States with Kaposi’s sarcoma a
Relation of partner’s HIV transmission group to percentage of infected women with Kaposi’s sarcoma in the United States a
Characteristics of B-cell lymphomas in HIV infection a
B-cell lymphomas associated with underlying HIV infection a
Epstein-Barr virus (EBV) and HIV infection a
Stages in human papillomavirus (HPV) infection a
Disorders induced by HIV infection that could promote cancer development a