Retroviruses

Human T-Cell Leukemia Virus Types I and II

Human T-cell leukemia viruses type I (HTLV-I) and type II (HTLV-II) belong to the subfamily Oncovirinae of the family Retroviridae. HTLV-I infection is endemic in Japan, other regions of Asia such as the Philippines, the Caribbean region, central Africa, and some areas of Australia and New Guinea. In these areas of the world, the seroprevalence rate of antibodies to HTLV-I is 5% to 33% in the normal human popu-lation.207 HTLV-I is associated with adult T-cell leukemia and lymphoma (ATL),222,223 as well as with its cutaneous variants, mycosis fungoides and Sezary's syndrome. HTLV-I is also the etiologic agent of HTLV-I-associated myelopathy or tropical spastic paraparesis. HTLV-II is associated with an atypical form of hairy cell leukemia.30,222,224 Monoclonal integration of HTLV-I proviral DNA was demonstrated in ATL neoplastic cells, and all individuals with ATL have antibodies to HTLV-I.225,226 HTLV-I, at variance from the avian and rodent retro-viruses, immortalizes T lymphocytes much like the oncogenic deoxyriboviruses, that is, through the product of a viral oncogene, the tax gene. The Tax protein has pleiotropic effects because it is able to activate or repress the expression of a wide array of cellular genes.227 Tax does not bind directly to DNA, but it interacts with cellular transcription factors or modulators of cellular functions. Binding of Tax to NF-KB results in transcriptional activation of IL-2a and IL-2a receptor genes, leading to autocrine stimulation of T-cell proliferation.228,229 Interaction of Tax with serum responsive factor (SRF) activates the expression of c-fos and of the early growth response genes egr-1 and egr-2.230 Other cellular genes activated by Tax include the GM-CSF, IL-1, IL-3, IL-6, PDGF, TGF-fi1, TNF-b, and NGF.231 Conversely, Tax represses transcription of the DNA polymerase b gene232 encoding a cellular enzyme involved in host cell DNA repair. This finding suggests a possible correlation between HTLV-I infection and host cell chromosomal damage, which is often observed in ATL. Tax inhibits the expression of the lck gene,233 encoding a tyrosine kinase of the src family, which plays a major role in the regulation of T-cell activation.233 Tax also dysregulates the cell cycle by binding and inactivating p16INK4, a key inhibitor of CDK4 and CDK6.234 In HTLV-I-infected cells, Tax is responsible for the stabilization and inactivation of p53 protein by phosphorylation at Ser15, which blocks p53 interaction with transcription factors.227,235 Tax also targets the mitotic checkpoint protein MAD-1, an important control protein for the formation of the mitotic spindle.227,236 The block of p53 and MAD-1 functions may be responsible for the genetic instability, aneuploidy, and chromosomal rearrangements that have been reported in ATL cells,226,227 and may affect oncogenes, tumor suppressor and DNA repair genes. Also, Tax expression enhances the mutation frequency in chromosomal DNA after transfection of the tax gene into the rat fibroblastic cell line Rat 2.237 These diverse effects of Tax suggest a scenario where ATL cells are initially dependent on Tax expression for proliferation. After the appearance of chromosomal aberrations and mutations involving genes crucial in oncogenesis, the neoplastic cells grow independently from Tax and ATL progresses toward a more malignant phenotype.

Human Immunodeficiency Virus Type 1

Human immunodeficiency virus type 1 (HIV-1) belongs to the subfamily Lentivirinae of the family Retroviridae. In the course of HIV-1 infection, an opportunistic neoplastic pathology develops that is mainly due to immunosuppression, leading to decrease of the immune surveillance against tumors and latent viruses. Indeed, most cancers arising during AIDS are associated with oncogenic viruses (Table 17.3), because HIV-1 infection provides the immunologic background on which other viruses can escape immune control and induce tumors.238 However, a large body of evidence indicates that HIV-1 itself may be oncogenic through the expression of the Tat protein, the product of the early HIV-1 tat gene.239,240 The Tat protein of HIV-1 is a small polypeptide of 14 to 15kDa containing 86 to 102 amino acids, depending on the viral strains. Tat is a potent transactivator of the HIV-1 LTR and is also able to activate the expression of many cellular genes, thereby affecting cellular functions and inducing angiogenesis, cell proliferation, inhibition of apoptosis, and oncogenesis.239,240 A remarkable property of Tat protein is that it is released from HIV-1-infected cells, circulates in the bloodstream and in extracellular fluids, and is taken up by uninfected cells where it exerts its biologic effects.241-243 Tat induces neoangiogenesis in vivo240,244 and has a synergic effect with bFGF on the induction of KS-like lesions in nude mice.245 During neoangiogene-sis and cell growth, Tat activates the expression of cytokines, chemokines, and growth factors (IL-1 a, IL-1 b, IL-2, IL-6, IL-8, IFN-g, TNF-a, TNF-b, MCP-1, bFGF, VEGF, GM-CSF, PDGF, SF/HGF, and TGF-b) by KS cells and induces the activity of urokinase and collagenase IV, which allow endothelial cells to invade underlying tissues.239 The multiple angiogenic and growth-stimulating effects of Tat, together with the profound immunodeficiency associated with AIDS, may be responsible for the more aggressive and invasive behavior of AIDS-KS compared to the other forms of this tumor.46,49 When Tat is transfected under the control of the HIV-1 long terminal repeat, it efficiently transforms immortalized keratinocytes to a neoplastic phenotype.246 Moreover, Tat inhibits expression of the manganese-dependent superoxide dismutase (Mn-SOD) gene by direct interaction with Mn-SOD transcripts,247 thereby contributing to the establishment and maintenance

TABLE 17.3. Tumors with increased incidence in acquired immunodeficiency syndrome (AIDS).

Tumor

Associated virus

Kaposi's sarcoma3

Human herpesvirus 8 and HIV-1 Tat

Primary effusion lymphoma

Human herpesvirus 8

Multiple myeloma

Human herpesvirus 8 (?)

B-cell non-Hodgkin's lymphoma8 (mostly systemic and brain lymphomas)

Epstein-Barr virus

Hodgkin's disease

Epstein-Barr virus

Leiomyoma and leiomyosarcoma (in children)

Epstein-Barr virus

Cervical carcinoma and squamous cell neoplasia of oropharynx and anus

Human papillomavirus

aTumors whose frequency is significantly increased in AIDS patients.

aTumors whose frequency is significantly increased in AIDS patients.

of oxidative stress. Mn-SOD has been shown to control cell proliferation by regulation of the oxidative metabolism248 and is a candidate tumor suppressor gene involved in the patho-genesis of melanoma and other human tumors.249 The onco-genic activity of Tat may be related also to its ability to downregulate p53 expression250,251 as well as to upregulate IL-2, bcl-2, and IL-6 gene transcription.252-255 The angiogenic and tumorigenic effects of Tat are confirmed and recapitulated in tat-transgenic mice.256,257 These animals develop angiogenic proliferation in the derma, resembling the early phases of KS. In addition, they develop skin papillomas and carcinomas, adenocarcinomas of subcutaneous glands, lymphoid hyper-plasia and lymphomas, liver dysplasia and hepatocarcinomas, polyps of the rectum, and squamous cell hyperplasia of the anal orifice and adjacent perianal skin. Liver dysplasia affects about 40% of tat-transgenic mice256,257 and represents a pre-neoplastic state, predisposing to liver tumorigenesis induced by chemical carcinogens.258,259 In conclusion, the HIV-1 Tat protein is oncogenic and may be a cofactor in AIDS-related malignancies, especially in KS and PELs where Tat may cooperate with HHV-8 in the angiogenic and oncogenic effects.46-49,239

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