Biology Of Htlv

Human T lymphotropic virus was first isolated by Robert Gallo's group1,2 and was the first human retrovirus for which a disease association was made. This new virus was classified as human T cell lymphotrophic/ leukemic virus type 1, or HTLV-I. Shortly after the discovery of HTLV-I, Kalyanaraman et al. isolated another human T cell leukemia virus, designated HTLV-II.3 HTLV-I is the causal agent of adult T cell leukemia and HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP) . Although a clear disease association for HTLV-II infection has not been established, some researchers suggest that it may be associated with a neurodegenerative disorder similar to HAM/TSP.4

Both HTLV-I and HTLV-II are members of the oncovirinae subfamily of retroviruses and have recently been reclassified as members of the group of viruses which includes bovine leukemia virus (BLV).1 The discovery and characterization of HTLV-I and II greatly facilitated the characterization of the etiological agents for another retrovirus, human immunodeficiency virus types 1 and 2 (HIV-1 and HIV-2), a member of the subfamily of lenti-viruses.4 HTLV shares many biological and molecular characteristics of HIV including routes of transmission, a general T-cell tropism, syncytia induction, and the presence of viral-encoded core proteins that function at both the transcriptional and posttranscriptional level.

The HTLV-I proviral genome consists of9032 nucleotides and includes regions coding for the structural proteins (gag and env) and the viral protease and polymerase (pol), similar to HIV-1 (Fig. 1). The genome also contains an additional sequence designated pX. This region is adjacent to the envelope (env) gene and contains three overlapping regulatory genes that encode the transactivator protein (Tax p40), transmodulator protein (Rex p27), and a third gene which encodes for the protein p21. The tax and rex genes are two regulatory genes that positively and negatively control viral gene expression and replication. The function of p21 is not known.5-7

HTLV-I and HTLV-II share a 66% sequence homology. HTLV also shares high sequence homologies with other retroviruses such as bovine leukemia virus (BLV) and the simian T cell leukemia virus (STLV) . Unlike other oncoviruses, HTLV-I does not express an analogue of any known

pol

FIGURE 1. The HTLV genome.

cellular oncogene, nor does it insert its proviral genome into a specific regulatory region of the host DNA. Rather, the provirus acts randomly, taking up residence in any open region provided by the host cell's transcrip-tional activity.

The env gene of HTLV encodes a glycoprotein precursor, gp61, which is cleaved to the gp46 external and gp21 transmembrane glycoproteins. These glycoproteins are present on mature virions and are expressed on the infected cells.8-9 Similar to other viruses, HTLV infects target cells by fusion with the cell membrane mediated by way of binding through its envelope glycoprotein to a cell surface. HTLV is unusual in its necessity for direct cell contact for efficient infection, possibly a result of the interactions of the Env proteins with currently unidentified cellular receptor or receptors. Culture media from HTLV-transformed cells have been shown to contain large amounts of free gp46 which are shed from the surface of cells.9

Although the mechanisms involved in the oncogenic transformation of infected cells are poorly understood, it is thought that the HTLV-I transacti-vation protein Tax may play an indirect role in cell transformation. The tax gene is capable of positively regulating HTLV gene expression and can also affect a number of transcription factors. As mentioned earlier, tax is located in the pX region. Tax activates the nuclear factor (NF)-KB-binding site of the interleukin-2 (IL-2) receptor alpha gene, the serum-responsive element (SRE) of the c-fos and c-egr protooncogenes, and the 21-bp enhancer of HTLV-I. The mechanism of the activation was shown to be the binding of Tax to transcription factors that bind to specific enhancers10-13 (Fig. 2). Tax has the ability to associate with host cell enhancer-binding proteins such as the cyclic AMP-responsive element (CRE)-binding protein (CREB) , the CRE modulator protein (CREM) , the p50 subunit ofNF-KB, and the serum-responsive factor (SW) .13 Expression of Tax alone has been shown to transform a number of cell lines in vitro and cause these primary T cells to exhibit many of the features similar to those of T cells transformed by HTLV-I.

In addition, the tax gene can activate the expression of several other cellular genes such as those for the IL-2 receptor (IL-2R) y chain, granulocyte-macrophage colony-stimulating factor (GM-CSF) , and IL-6.14 This characteristic may explain how Tax is responsible for making HTLV-I-infected cells

Transcriptional Factors

Transcriptional Factors

FIGURE 2. Binding of Tax to the enhancer-binding proteins CREB, CREM, NF-KB p50, and SFW. Indirect association of Tax protein to the enhancer DNA through each enhancer-binding protein, or increase of the active NF-KB p50 through binding to the precursor, seems to be the activation mechanism of Tax. Indirect binding of Tax to the three different classes of transcriptional enhancers promotes transcription.

FIGURE 2. Binding of Tax to the enhancer-binding proteins CREB, CREM, NF-KB p50, and SFW. Indirect association of Tax protein to the enhancer DNA through each enhancer-binding protein, or increase of the active NF-KB p50 through binding to the precursor, seems to be the activation mechanism of Tax. Indirect binding of Tax to the three different classes of transcriptional enhancers promotes transcription.

more susceptible to IL-2-dependent growth. Typically, HTLV-I-infected cells upregulate the expression of not only IL-2R, but also other molecules involved in T cell activation such as major histocompatibility class (MHC) class II antigens, adhesion molecules, and costimulatory molecules. Infected cells also have the ability to stimulate the proliferation of uninfected T cells.15 Recently, researchers have found that HTLV-I Tax induces expression of gp34 and 0X40.16 0X40 is expressed on activated T cells and is involved in T-cell proliferation. A member of the tumor necrosis factor (TNF) receptor family, 0X40 is a ligand for gp34. Since Tax-positive cell lines express higher levels of both gp34 and 0x40, this system may possibly play an important role in the process of malignant transformation of HTLV-I-infected cells.16

The rex gene is another unique gene found in the pX sequence of the HTLV genome. Like Tax, the exact mechanism of Rex action is not clear. The rex gene encodes proteins of 27/21 kDa for HTLV-I and 26/24 kDa for HTLV-II. The Rex protein is essential for HTLV replication and control of gene expression. While Rex does not directly regulate RNA transcription, it has been shown to act at the posttranscriptional level to regulate viral gene expression by processing viral RNA.17 It is also believed that Rex can play a role in the process of cell transformation. Researchers have shown that Rex, like Tax, increases the expression of IL-2R by prolonging the IL-2R mRNA half-life.1819

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