January 2006
Volume 5
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January 2006
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Contents
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Human T-Cell Leukemia/Lymphoma Virus Type 1: Playing Hide and Seek
The human T-cell leukemia/lymphoma virus type 1 (HTLV-1) (Figure 1, part A) is transmitted sexually or through breastfeeding and causes adult T-cell leukemia/lymphoma (ATLL) or a progressive demyelinating disease called tropical spastic paraparesis/HTLV-1–associated myelopathy (TSP/HAM). The HTLV-1 genome is composed of two copies of a single-stranded RNA virus whose genome is copied into a double-stranded DNA form that integrates into the host cell genome, at which point the virus is referred to as a provirus. Molecular epidemiological studies indicate a direct correlation between the proviral DNA level and disease occurrence, and some scientists believe that proviral amplification occurs mainly through cell division. HTLV-1 infects memory (antigen-experienced) CD4+ T cells that are programmed to quickly enter the cell cycle and undergo cell division upon antigen reencounter. Depending on reexposure to an antigen, the CD4+ T cells could divide at any moment and amplify the provirus. However, the viral transcripts in the infected cells should be quickly recognized and the cells eliminated by the host immune system. Yet, most T cells carrying the HTLV-1 provirus do not produce detectable viral transcripts. We hypothesized that HTLV-1 might have evolved one or more mechanisms to control its own expression rather than leaving it to the cell cycle process. HTLV-1 genome expression (Figure 1, part B) begins by transcription from the viral promoter within the long terminal repeat (LTR). The genomic RNA encodes the structural protein Gag and the enzymatic protein Pol, whereas a singly spliced mRNA encodes the Env protein. A unique doubly spliced mRNA encodes two positive regulators of viral expression, Tax and Rex (Figure 1, part B). Increasing levels of Tax during infection leads to the recruitment of highly effective transcription complexes to the viral promoter (Figure 1, part C) and full-fledged viral expression. The genomic RNA that encodes the protease, reverse transcriptase, and integrase, as well as the Env protein, is necessary for the production of infectious viral particles. Rex’s function is essential in transporting the singly spliced Env and the unspliced genomic mRNAs to the cytoplasm (Figure 1, part C). Figure 1. Human T-cell leukemia/lymphoma virus type 1 (HTLV-1) morphology, genomic organization, and replication. A) Structure of HTLV-1. B) The spliced mRNA encoding the Tax, Rex, and p30II proteins. C) A simplified transcription complex on the viral promoter. D and E) Tax and Rex production and Rex’s effect on the transport of singly spliced and unspliced viral RNAs. F) The p30II protein is depicted binding to the Tax/Rex mRNA—it is unknown whether the binding is direct or indirect—and retaining it in the nucleus. LTR, long terminal repeat; CBP/p300, a transcriptional co-activator; PCAF, a transcriptional co-activator; CREB, cAMP response element binding protein; TRE, transcription response element; CRE, cAMP response element; TFIIB, transcription initiation factor IIB; TFIID, transcription initiation factor IID; TFIIA, transcription initiation factor IIA. We have previously found that HTLV-1 encodes a protein, called p30II, which is generated from a doubly spliced mRNA from the HTLV-1 ORF II proviral sequence (Figure 1, part B) (Koralnik I et al. Proc Natl Acad Sci U S A 89: 8813–7, 1992). More recently, we have demonstrated that p30II is a negative regulator of viral expression. The negative effect of p30II on viral replication is not attributable to interference with Tax-mediated transcription from the viral promoter, as overexpression of Tax or Rex cDNA alone is unable to counteract the negative effect of p30II on proviral expression. However, when Tax and Rex are expressed from the unique doubly spliced mRNA derived from the proviral clone, p30II exerts a negative post-transcriptional effect. Quantitative reverse transcriptase (RT)–PCR analysis of viral messenger mRNA species demonstrated that the cytoplasmic level of the Tax/Rex mRNA is decreased by p30II. Importantly, we found that p30II is a nuclear-resident protein unable to shuttle in and out of the nucleus. In addition, we demonstrated that p30II binds to the doubly spliced Tax/Rex mRNA. Therefore, the Tax/Rex mRNA is retained in the nucleus. As expected, overexpression of p30II in HTLV-1–infected T-cell lines also decreases viral replication by decreasing the level of Tax. Immune T cells continuously patrol lymphoid and nonlymphoid tissues in search of “foreign” signals. We propose that p30II may help HTLV-1 to hide when cells divide. This hypothesis could explain the paradox that most T cells carrying the provirus do not produce detectable viral transcripts. How p30II expression is regulated and whether inhibition of p30II function may reveal hidden infected cells to immune surveillance are unknown. Thus, further investigation on the basic molecular mechanisms of p30II activity might teach us how to reduce or even eradicate virus-infected cells and prevent disease. back to top
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umans
have specialized immunologic machinery, such as cytolytic T cells, cytokines,
chemokines, and antibodies, to fight intracellular and extracellular pathogens.
Many pathogens, however, have sophisticated mechanisms to escape human
immune surveillance.