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• W1965541741 abstract "Persistence of latently infected CD4+ T cell “reservoirs” presents a major obstacle for current HIV-1 antiretroviral therapies. In Cell Host & Microbe, two separate studies use model systems of latent infection to dissect the influence of host genes on HIV-1 transcription, yielding intriguing, though partially contradictory, conclusions. Persistence of latently infected CD4+ T cell “reservoirs” presents a major obstacle for current HIV-1 antiretroviral therapies. In Cell Host & Microbe, two separate studies use model systems of latent infection to dissect the influence of host genes on HIV-1 transcription, yielding intriguing, though partially contradictory, conclusions. HIV-1 latency is established when a small subset of CD4+ lymphoblasts exit the cell cycle after proviral integration into the genome (Finzi et al., 1999Finzi D. Blankson J. Siliciano J.D. Margolick J.B. Chadwick K. Pierson T. Smith K. Lisziewicz J. Lori F. Flexner C. et al.Nat. Med. 1999; 5: 512-517Crossref PubMed Scopus (1652) Google Scholar). This long-lived cell population harbours a HIV-1 reservoir, where replication-competent provirus retains the ability to reactivate into productive infection while remaining shielded from the immune system by effective and reversible silencing. Latently infected cells are inadvertently maintained by a suboptimal cellular environment for HIV-1 expression, including several mechanisms (Marcello, 2006Marcello A. Retrovirology. 2006; 3: 7Crossref PubMed Scopus (95) Google Scholar) operating at posttranscriptional (i.e, inefficient viral mRNA transport, inhibitory miRNAs) and transcriptional levels (i.e., absence of cellular [Sp1, NF-κB] and viral [Tat] activators; repressive chromatin environment). These processes are of interest given their potential to be manipulated to render latent HIV-1 susceptible to antiretroviral therapy. An alternative transcriptional basis for latency arose from studies indicating that HIV-1 preferentially integrates into active transcription units (Han et al., 2004Han Y. Lassen K. Monie D. Sedaghat A.R. Shimoji S. Liu X. Pierson T.C. Margolick J.B. Siliciano R.F. Siliciano J.D. J. Virol. 2004; 78: 6122-6133Crossref PubMed Scopus (254) Google Scholar, Lewinski et al., 2005Lewinski M.K. Bisgrove D. Shinn P. Chen H. Hoffmann C. Hannenhalli S. Verdin E. Berry C.C. Ecker J.R. Bushman F.D. J. Virol. 2005; 79: 6610-6619Crossref PubMed Scopus (210) Google Scholar, Schroder et al., 2002Schroder A.R. Shinn P. Chen H. Berry C. Ecker J.R. Bushman F. Cell. 2002; 110: 521-529Abstract Full Text Full Text PDF PubMed Scopus (1324) Google Scholar). This finding opened up the possibility that host genes mediate proviral gene silencing by transcriptional interference (TI). Although TI can be technically applied to describe any process that interferes with transcriptional machinery or its product, it usually refers to the direct negative impact of one gene on another in cis. In latently infected cells, viral integrates residing in introns of actively transcribed genes may be subjected to TI by host gene “readthrough,” preventing preinitiation complex (PIC) formation on the 5′ long terminal repeat (LTR) viral promoter. Although TI acts in a uniformly inhibitory manner when genes are convergently transcribed, it is possible that host gene transcription may confer positive effects on HIV-1 expression when the provirus is integrated in the same orientation as the host gene. In this issue of Cell Host & Microbe, studies by Lenasi and colleagues (Lenasi et al., 2008Lenasi T. Contreras X. Peterlin B.M. Cell Host Microbe. 2008; 4 (this issue): 123-133Abstract Full Text Full Text PDF PubMed Scopus (175) Google Scholar) and Han and colleagues (Han et al., 2008Han Y. Lin Y.B. An W. Xu J. Yang H.-C. O'Connell K. Dordai D. Boeke J.D. Siliciano J.D. Siliciano R.F. Cell Host Microbe. 2008; 4 (this issue): 134-146Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar) utilize model systems to determine if host genes play a contributing role in maintaining proviral latency. Lenasi and colleagues investigated whether host gene TI mediates HIV-1 silencing by using two clonal cell lines isolated from an established Jurkat CD4+ T cell model of postintegration latency (Jordan et al., 2003Jordan A. Bisgrove D. Verdin E. EMBO J. 2003; 22: 1868-1877Crossref PubMed Scopus (584) Google Scholar). Both clones contain GFP-labeled HIV-1 integrated in a single allele of a constitutively expressed host gene (protein phosphatase 5 gene [PP5] and SUMO-activating enzyme subunit-2 [UBA2]; Figure 1A). In unstimulated cells, the authors demonstrate through quantitative RT-PCR and chromatin immunoprecipitation (ChIP) analysis that elongating RNA polymerase (RNAPII-Ser2) resided over the 5′LTR and was accompanied by a concurrent depletion of Sp1 (a transcription factor indicating PIC assembly). This transcriptional profile suggests TI with two interesting consequences. First, elongating RNAPII, originating from the host gene, renders the 5′LTR promoter inaccessible to the PIC. Second, chimeric transcripts are created by 5′LTR polyA site use together with a proximal cryptic splice acceptor site. Proviral stimulation by viral (Tat) or cellular (TNF-α) factors caused a large increase of both initiating and elongating polymerase (RNAPII-Ser5/Ser2) and Sp1 at the 3′LTR. Ironically, this is a “knockon” effect, where downregulation by TI at the 5′LTR encourages transcription initiation at the 3′LTR due to the loss of TI normally applied by elongating RNAPII originating from the 5′LTR. A strategy was devised to determine if this phenomenon naturally occurs in infected primary CD4+ cells containing multiple proviral insertion sites, presumably resulting in different transcriptional attributes. Significant levels of host-viral chimeric transcripts were detected, indicating viral transcription is subjected to TI in CD4+ T cells. Can release of host gene-mediated TI be exploited to devise a strategy for eliminating the latent HIV-1 reservoir? Two different approaches for release of TI were used (Figure 1B), the first targeted the estrogen receptor-dependent PP5 promoter. Stably transfected shRNAmir was used to deplete estrogen-receptor mRNA, then potential TI release of the HIV-1 provirus was assessed by GFP epifluorescence (indicating active 5′LTR transcription). GFP production increased to 20% of cells, indicating partial alleviation of host-mediated TI. Not all host genes can be directly targeted in this fashion, so a second strategy used direct proviral stimulation (TNF-α for initiation; HMBA/Tat for elongation). As synergistic activation of TNF-α with HMBA/Tat-increased GFP-positive cells to almost 60%, combinations of viral transcriptional activators appear to overpower any transcriptional influence originating from the host gene. Han and colleagues, similarly to Lenasi and colleagues, propose that transcriptional readthrough in host cells is important in modulating viral transcription by TI. Their approach was to develop an elegantly designed model system in which HIV-1 transcription could be measured and compared under conditions where host gene readthrough can be selectively permitted or blocked using a removable triple polyA sequence/spacer region (Han et al., 2008Han Y. Lin Y.B. An W. Xu J. Yang H.-C. O'Connell K. Dordai D. Boeke J.D. Siliciano J.D. Siliciano R.F. Cell Host Microbe. 2008; 4 (this issue): 134-146Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar). Using homologous recombination, a cassette containing a GFP-labeled HIV-1 genome was inserted into an intron of the HPRT gene in HCT116 (colon carcinoma) cells. Potential orientation effects could also be analyzed—an important consideration in keeping with prior studies where HIV-1 integration did not exhibit orientation preferences relative to host gene transcription (Lewinski et al., 2005Lewinski M.K. Bisgrove D. Shinn P. Chen H. Hoffmann C. Hannenhalli S. Verdin E. Berry C.C. Ecker J.R. Bushman F.D. J. Virol. 2005; 79: 6610-6619Crossref PubMed Scopus (210) Google Scholar). The effect of host gene readthrough when HIV-1 lies in the opposing orientation was assessed using steady-state viral mRNA and ChIP analysis (Figure 1C). In this convergent setting, HIV-1 transcription declined, along with ChIP signals detecting RNAPII and other relevant transcription factors over the 5′LTR. This observation is in agreement with numerous studies in which TI between convergent promoters results in a uniformly negative effect. In this study, TI appears to act upon 5′LTR binding factors without affecting steady-state HPRT transcript levels, indicating that nonreciprocal collision of converging elongating complexes or promoter occlusion/transcription factor “dislodging” is accountable. However, the striking aspect of the Han et al. paper relates to analysis of constructs where HIV-1 is orientated in the same direction as HPRT (Figure 1D). In readthrough clones, proviral transcription was enhanced approximately 4-fold and was accompanied by an increase in GFP expression measured by flow cytometry. These results are at odds with prior studies that infer an integral role of TI in repressing viral promoters in the same orientation as an upstream promoter (Cullen et al., 1984Cullen B.R. Lomedico P.T. Ju G. Nature. 1984; 307: 241-245Crossref PubMed Scopus (213) Google Scholar, Greger et al., 1998Greger I.H. Demarchi F. Giacca M. Proudfoot N.J. Nucleic Acids Res. 1998; 26: 1294-1301Crossref PubMed Scopus (92) Google Scholar, Lewinski et al., 2005Lewinski M.K. Bisgrove D. Shinn P. Chen H. Hoffmann C. Hannenhalli S. Verdin E. Berry C.C. Ecker J.R. Bushman F.D. J. Virol. 2005; 79: 6610-6619Crossref PubMed Scopus (210) Google Scholar) and the findings of Lenasi et al., 2008Lenasi T. Contreras X. Peterlin B.M. Cell Host Microbe. 2008; 4 (this issue): 123-133Abstract Full Text Full Text PDF PubMed Scopus (175) Google Scholar in this issue. Furthermore, these results imply that latent HIV-1 should exhibit a trend toward convergent integration, which does not appear to be the case (Han et al., 2004Han Y. Lassen K. Monie D. Sedaghat A.R. Shimoji S. Liu X. Pierson T.C. Margolick J.B. Siliciano R.F. Siliciano J.D. J. Virol. 2004; 78: 6122-6133Crossref PubMed Scopus (254) Google Scholar, Lewinski et al., 2005Lewinski M.K. Bisgrove D. Shinn P. Chen H. Hoffmann C. Hannenhalli S. Verdin E. Berry C.C. Ecker J.R. Bushman F.D. J. Virol. 2005; 79: 6610-6619Crossref PubMed Scopus (210) Google Scholar). Is there an underlying cause of this contrary influence of same-orientation host gene readthrough on HIV-1 transcription? Position effects may play some role. Alternatively, different transcriptional mechanisms may be employed in resting CD4+ cells than in HCT116 cells to repress HIV-1 integrates in actively transcribed host genes. It will be of interest if this phenomenon occurs naturally and, if so, what strategies are employed by latent cells to maintain proviral silencing. It is clear that multiple mechanisms contribute to maintaining HIV-1 latency at the transcription level, and the key may lie in unraveling the complex processes by which host genes regulate a viral genome within their own. Transcriptional Interference Antagonizes Proviral Gene Expression to Promote HIV LatencyLenasi et al.Cell Host & MicrobeAugust 14, 2008In BriefEradication of the latent HIV reservoir remains a major barrier to curing AIDS. However, the mechanisms that direct viral persistence in the host are not well understood. Studying a model system of postintegration latency, we found that viral integration into the actively transcribed host genes led to transcriptional interference (TI) caused by the elongating RNA polymerase II (RNAPII) transcribing through the viral promoter. The resulting physical exclusion of preinitiation complex formation on the 5′ long terminal repeat (LTR) promoted the silencing of HIV transcription. Full-Text PDF Open ArchiveOrientation-Dependent Regulation of Integrated HIV-1 Expression by Host Gene Transcriptional ReadthroughHan et al.Cell Host & MicrobeAugust 14, 2008In BriefIntegrated HIV-1 genomes are found within actively transcribed host genes in latently infected CD4+ T cells. Readthrough transcription of the host gene might therefore suppress HIV-1 gene expression and promote the latent infection that allows viral persistence in patients on therapy. To address the effect of host gene readthrough, we used homologous recombination to insert HIV-1 genomes in either orientation into an identical position within an intron of an actively transcribed host gene, hypoxanthine-guanine phosphoribosyltransferase (HPRT). Full-Text PDF Open Archive" @default.
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• W1965541741 title "An Ungracious Host for an Unwelcome Guest" @default.
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