**4. HTLV type 1 (HTLV-1)**

Another important human carcinogenic virus is human T-cell leukemia virus type 1 (HTLV-1). This virus has the potential to cause adult T-cell leukemia/lymphoma (ATL), HTLV-1-associated myelopathy (HAM), and HTLV-1 uveitis (HU). These diseases develop in HTLV-1 carriers after prolonged latent infection. HTLV-1 carriers are particularly prevalent in southwest Japan, including Kyushu, Shikoku, and Okinawa. HTLV-1 was isolated and reported by Gallo R as the first human pathogenic retrovirus in 1980. Yorio Hinuma of Kyoto University in Japan precisely analyzed the genomic structure and identified the HTLV-1 [34]. HTLV-1 is a weakly infective virus particle, and cell-to-cell transmission is the main route of infection.

#### **4.1 Molecular biology of HTLV-1**

ATL is a hematologic malignancy in which abnormal lymphocytes appear in peripheral blood and infiltrate various organs throughout the body. Kiyoshi Takatsuki of Kumamoto University in Japan and Taku Uchiyama of Kyoto University collected samples. In 1981, Hinuma identified HTLV-1 to be the causative virus of ATL; this was the first report on tumor-induced retrovirus in humans. Most infected cells are CD4 + CD25 + T cells. Viral receptors are thought to involve other proteins and heparan sulfate. HTLV-1 is an approximately spherical virus particle about 100 nm in diameter and has an envelope. It has an RNA genome composed of the genes common to retroviruses such as *gag*, *pro*, *pol*, and *env*, as well as the gene encoding pX. It selectively uses the splicing and translation initiation sites in a region less than 2 kb called pX located between the env gene and the 3′ LTR [35] and uses the plus and minus strands relative to the transcription direction and efficiently. It often encodes several regulatory and accessory genes. As described later, this pX is involved in the action of HTLV-1 encoding HTLV-1 bZIP factor (HBZ).

Tax and HBZ may be the carcinogenic potentials of HTLV-1. Tax is a potent transactivator essential for the activation of the viral promoter 5′ LTR. After entering the cell by infection, the virus particle capsid is lost, and the HTLV-1 genomic RNA is reverse transcribed to form genomic duplex DNA. Thereafter, the integrase encoded by the viral genome and the DNA end forms a complex, which contacts the genomic DNA on the cell side, and inserts by catalytic reaction. The 5-base-long sequence of the targeted host cell genome is duplicated at both ends of the inserted viral genome in the insertion process. Tax, the transcript of TLV-1 regulatory gene tax, not only binds to the HTLV-1 promoter to promote viral transcription and expression but also interacts with cell-side transcription factors to activate host gene transcription activity. Therefore, *tax* is implicated in the early stages of tumorigenesis of infected cells. However, in peripheral blood of most ATL patients, Tax is suppressed by its promoter 5′ LTR deletion and epigenetic modification. Thus, Tax is not essential, at least at the final stage of carcinogenesis. Recently, Matsuoka has suggested that Tax is constitutively expressed in a small fraction of leukemia cells, and this fraction triggers an anti-apoptotic mechanism to establish sustained infection and induces oncogenesis [36]. Tax is induced by a variety of cytotoxic stresses and also promotes HTLV-1 replication. Thus, it protects infected cells from apoptosis and increases the chance of viral infection at the critical phase of disease in the carrier. Another HBZ gene is expressed in all ATL patients causing and promoting the growth of ATL cells; therefore, it may be the gene responsible for ATL.
