HTLV-1 and apoptosis: role in cellular transformation and recent advances in therapeutic approaches

Abstract

A universal cellular defense mechanism against viral invasion is the elimination of infected cells through apoptotic cell death. To counteract host defenses many viruses have evolved complex apoptosis evasion strategies. The oncogenic human retrovirus HTLV-I is the etiological agent of adult-T-cell leukemia/lymphoma (ATLL) and the neurodegenerative disease known as HTLVassociated myelopathy/tropical spastic paraparesis (HAM/TSP). The poor prognosis in HTLV-Iinduced ATLL is linked to the resistance of neoplastic T cells against conventional therapies and the immunocompromised state of patients. Nevertheless, several studies have shown that the apoptotic pathway is largely intact and can be reactivated in ATLL tumor cells to induce specific killing. A better understanding of the molecular mechanisms employed by HTLV-I to counteract cellular death pathways remains an important challenge for future therapies and the treatment of HTLV-Iassociated diseases.

Common Threads in Persistent Viral Infections

“…The tumor suppressor protein p53 is an attractive target for many viruses; most notably, the SV40 large T antigen (LT) is known to bind and inactivate p53, thereby preventing apoptosis (47,52,54). Among retroviruses, the HLTV-1 Tax protein prevents apoptosis through activation of the NF-B and Akt cellular prosurvival pathways and neg- ative regulation of p53 (85), while the HIV accessory protein Tat thwarts apoptosis through inhibition of p53 transcription (29). The antiapoptotic HCV protein NS3 has also been shown to target p53 and inhibit its function (22).…”

NK314 potentiates antitumor activity with adult T-cell leukemia-lymphoma cells by inhibition of dual targets on topoisomerase IIα and DNA-dependent protein kinase

“…Based on these studies, targeting therapies for various molecules, such as Tax, NF-B, Akt/PKB, mTOR, CD25, CD52, and chemokine receptor-4, have been developed under clinical or preclinical investigations using small molecules or monoclonal antibodies. [12][13][14][15][16][17][18][19][20][21][22][23] The DNA repair system is also a promising target for sensitization of cancer treatment. [24][25][26] Although genetic instability of proliferating cells is necessary for most cell types to become malignant, cells that are overly unstable genetically will die.…”

The Major Histocompatibility Complex Class II Transactivator CIITA Inhibits the Persistent Activation of NF-κB by the Human T Cell Lymphotropic Virus Type 1 Tax-1 Oncoprotein

“…Both the HTLV-1 and HTLV-2 genomes encode homologous transcription activators, designated Tax-1 and Tax-2, respectively, that control viral gene expression and viral replication (8)(9)(10)(11)(12)(13)(14)(15)(16)(17). Besides promoting proviral transcription, Tax-1 is a pivotal player in HTLV-1-induced T cell transformation, modulating the expression of cellular genes and deregulating cell signaling pathways involved in cell proliferation, cell cycle control, DNA damage repair, and apoptosis (4,8,(18)(19)(20)(21)(22)(23). The oncogenic potential of Tax-1 is due mostly to its ability to constitutively activate the nuclear factor kappa B (NF-B) pathway (24)(25)(26)(27)(28).…”