Abstract
Human T-cell leukemia virus types 1 and 2 (HTLV-1 and HTLV-2) are delta retroviruses that share a common overall genetic organization, splicing pattern, and ability to infect and immortalize T-cells in vitro. However, HTLV-1 and HTLV-2 exhibit a clearly distinct pathogenic potential in infected patients. To find clues to the possible viral determinants of the biology of these viruses, recent studies investigated the timing of expression and the intracellular compartmentalization of viral transcripts in ex-vivo samples from infected patients. Results of these studies revealed a common overall pattern of expression of HTLV-1 and -2 with a two-phase kinetics of expression and a nuclear accumulation of minus-strand transcripts. Studies in cells transfected with HTLV-1 molecular clones demonstrated the strict Rex-dependency of this “two-phase” kinetics. These studies also highlighted interesting differences in the relative abundance of transcripts encoding the Tax and Rex regulatory proteins, and that of the accessory proteins controlling Rex expression and function, thus suggesting a potential basis for the different pathobiology of the two viruses.
Highlights
Human T-cell leukemia virus types 1 and 2 (HTLV-1 and HTLV-2) are genetically related deltaretroviruses (Lairmore and Franchini, 2007)
HTLV2 infection is associated with an increase in lymphocytes counts (Bartman et al, 2008) and coinfection with HTLV-2 plays an important role in the progression of HIV-infected patients to AIDS (Casoli et al, 2007)
TEMPORAL ANALYSIS OF HTLV-1 EXPRESSION An early study by Hidaka et al (Hidaka et al, 1988) established that HTLV-1 expression is controlled by two key regulatory circuits: a positive feedback provided by the viral transactivator Tax, which drives transcription of the viral genome, and a post-transcriptional regulatory loop provided by Rex, which binds to the Rex-responsive element (RXRE) present at the 3 end of HTLV-1 transcripts and enhances the nuclear export and expression of a subset of mRNAs coding for the virion-associated proteins Gag-Pol and Env
Summary
Human T-cell leukemia virus types 1 and 2 (HTLV-1 and HTLV-2) are genetically related deltaretroviruses (Lairmore and Franchini, 2007). The hbz and aph2 transcripts were detected mainly in the nucleus of infected cells (Rende et al, 2011; Bender et al, 2012), supporting the notion of their possible role as non-coding RNAs. TEMPORAL ANALYSIS OF HTLV-1 EXPRESSION An early study by Hidaka et al (Hidaka et al, 1988) established that HTLV-1 expression is controlled by two key regulatory circuits: a positive feedback provided by the viral transactivator Tax, which drives transcription of the viral genome, and a post-transcriptional regulatory loop provided by Rex, which binds to the Rex-responsive element (RXRE) present at the 3 end of HTLV-1 transcripts and enhances the nuclear export and expression of a subset of mRNAs coding for the virion-associated proteins Gag-Pol and Env. This study was conducted by transfecting wild type and Rex-mutant proviral clones in fibroblast cell lines followed by isolation of nuclear and cytoplasmic mRNAs and analysis by Northern Blot, a technique that was not capable of distinguishing among different mRNAs of similar size.
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