1887

Abstract

A CD8+ cell non-cytotoxic antiviral response (CNAR), mediated by a CD8+ cell antiviral factor (CAF), is associated with a long-term healthy state in human immunodeficiency virus (HIV) infection. CNAR/CAF reduces viral transcription without a known effect on specific viral sequences in the HIV genome. In studies to define the mechanism involved in the block in viral transcription, we now report that transcription from the HIV-LTR reporter is reduced in infected CD4+ cells upon treatment with CAF. In agreement with this observation, the amount of RNA polymerase II (RNAPII) on the HIV promoter and other viral regions was strongly diminished in HIV-infected CD4+ cells co-cultivated with CNAR-expressing CD8+ cells. These results demonstrate further that CNAR/CAF has a specific role in regulating HIV transcription and a step during the preinitiation complex assembly appears to be sensitive to CNAR/CAF.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/jgv.0.000326
2016-01-01
2024-04-19
Loading full text...

Full text loading...

/deliver/fulltext/jgv/97/1/220.html?itemId=/content/journal/jgv/10.1099/jgv.0.000326&mimeType=html&fmt=ahah

References

  1. Barker E., Mackewicz C. E., Reyes-Terán G., Sato A., Stranford S. A., Fujimura S. H., Christopherson C., Chang S. Y., Levy J. A. 1998; Virological and immunological features of long-term human immunodeficiency virus-infected individuals who have remained asymptomatic compared with those who have progressed to acquired immunodeficiency syndrome. Blood 92:3105–3114[PubMed]
    [Google Scholar]
  2. Blazek D., Barboric M., Kohoutek J., Oven I., Peterlin B. M. 2005; Oligomerization of HEXIM1 via 7SK snRNA and coiled-coil region directs the inhibition of P-TEFb. Nucleic Acids Res 33:7000–7010 [View Article][PubMed]
    [Google Scholar]
  3. Blazek D., Kohoutek J., Bartholomeeusen K., Johansen E., Hulinkova P., Luo Z., Cimermancic P., Ule J., Peterlin B. M. 2011; The Cyclin K/Cdk12 complex maintains genomic stability via regulation of expression of DNA damage response genes. Genes Dev 25:2158–2172 [View Article][PubMed]
    [Google Scholar]
  4. Bonneau K. R., Ng S., Foster H., Choi K. B., Berkhout B., Rabson A., Mackewicz C. E., Levy J. A. 2008; Derivation of infectious HIV-1 molecular clones with LTR mutations: sensitivity to the CD8+ cell noncytotoxic anti-HIV response. Virology 373:30–38 [View Article][PubMed]
    [Google Scholar]
  5. Brady J., Kashanchi F. 2005; Tat gets the green light on transcription initiation. Retrovirology 2:69 [View Article][PubMed]
    [Google Scholar]
  6. Brinchmann J. E., Gaudernack G., Vartdal F. 1990; CD8+ T cells inhibit HIV replication in naturally infected CD4+ T cells. Evidence for a soluble inhibitor. J Immunol 144:2961–2966[PubMed]
    [Google Scholar]
  7. Chao S. H., Fujinaga K., Marion J. E., Taube R., Sausville E. A., Senderowicz A. M., Peterlin B. M., Price D. H. 2000; Flavopiridol inhibits P-TEFb and blocks HIV-1 replication. J Biol Chem 275:28345–28348 [View Article][PubMed]
    [Google Scholar]
  8. Chen C. H., Weinhold K. J., Bartlett J. A., Bolognesi D. P., Greenberg M. L. 1993; CD8+ T lymphocyte-mediated inhibition of HIV-1 long terminal repeat transcription: a novel antiviral mechanism. AIDS Res Hum Retroviruses 9:1079–1086 [View Article][PubMed]
    [Google Scholar]
  9. Gómez A. M., Smaill F. M., Rosenthal K. L. 1994; Inhibition of HIV replication by CD8+ T cells correlates with CD4 counts and clinical stage of disease. Clin Exp Immunol 97:68–75 [View Article][PubMed]
    [Google Scholar]
  10. Hoffman A. D., Banapour B., Levy J. A. 1985; Characterization of the AIDS-associated retrovirus reverse transcriptase and optimal conditions for its detection in virions. Virology 147:326–335 [View Article][PubMed]
    [Google Scholar]
  11. Levy J. A. 1993; HIV pathogenesis and long-term survival. AIDS 7:1401–1410 [View Article][PubMed]
    [Google Scholar]
  12. Levy J. A. 2003; The search for the CD8+ cell anti-HIV factor (CAF). Trends Immunol 24:628–632 [View Article][PubMed]
    [Google Scholar]
  13. Levy J. A., Mackewicz C. E., Barker E. 1996; Controlling HIV pathogenesis: the role of the noncytotoxic anti-HIV response of CD8+ T cells. Immunol Today 17:217–224 [View Article][PubMed]
    [Google Scholar]
  14. Mackewicz C. E., Ortega H. W., Levy J. A. 1991; CD8+ cell anti-HIV activity correlates with the clinical state of the infected individual. J Clin Invest 87:1462–1466 [View Article][PubMed]
    [Google Scholar]
  15. Mackewicz C. E., Ortega H., Levy J. A. 1994; Effect of cytokines on HIV replication in CD4+ lymphocytes: lack of identity with the CD8+ cell antiviral factor. Cell Immunol 153:329–343 [View Article][PubMed]
    [Google Scholar]
  16. Mackewicz C. E., Blackbourn D. J., Levy J. A. 1995; CD8+T cells suppress human immunodeficiency virus replication by inhibiting viral transcription. Proc Natl Acad Sci U S A 92:2308–2312 [View Article][PubMed]
    [Google Scholar]
  17. Mackewicz C. E., Patterson B. K., Lee S. A., Levy J. A. 2000; CD8+ cell noncytotoxic anti-human immunodeficiency virus response inhibits expression of viral RNA but not reverse transcription or provirus integration. J Gen Virol 81:1261–1264 [View Article][PubMed]
    [Google Scholar]
  18. Ott M., Geyer M., Zhou Q. 2011; The control of HIV transcription: keeping RNA polymerase II on track. Cell Host Microbe 10:426–435 [View Article][PubMed]
    [Google Scholar]
  19. Peterlin B. M., Price D. H. 2006; Controlling the elongation phase of transcription with P-TEFb. Mol Cell 23:297–305 [View Article][PubMed]
    [Google Scholar]
  20. Raha T., Cheng S. W., Green M. R. 2005; HIV-1 Tat stimulates transcription complex assembly through recruitment of TBP in the absence of TAFs. PLoS Biol 3:e44 [View Article][PubMed]
    [Google Scholar]
  21. Rahl P. B., Lin C. Y., Seila A. C., Flynn R. A., McCuine S., Burge C. B., Sharp P. A., Young R. A. 2010; c-Myc regulates transcriptional pause release. Cell 141:432–445 [View Article][PubMed]
    [Google Scholar]
  22. Shridhar V., Chen Y., Gupta P. 2014; The CD8 antiviral factor (CAF) can suppress HIV-1 transcription from the long terminal repeat (LTR) promoter in the absence of elements upstream of the CATATAA box. Virol J 11:130 [View Article][PubMed]
    [Google Scholar]
  23. Taube R., Lin X., Irwin D., Fujinaga K., Peterlin B. M. 2002; Interaction between P-TEFb and the C-terminal domain of RNA polymerase II activates transcriptional elongation from sites upstream or downstream of target genes. Mol Cell Biol 22:321–331 [View Article][PubMed]
    [Google Scholar]
  24. Tomaras G. D., Lacey S. F., McDanal C. B., Ferrari G., Weinhold K. J., Greenberg M. L. 2000; CD8+ T cell-mediated suppressive activity inhibits HIV-1 after virus entry with kinetics indicating effects on virus gene expression. Proc Natl Acad Sci U S A 97:3503–3508 [View Article][PubMed]
    [Google Scholar]
  25. Walker C. M., Levy J. A. 1989; A diffusible lymphokine produced by CD8+ T lymphocytes suppresses HIV replication. Immunology 66:628–630[PubMed]
    [Google Scholar]
  26. Walker C. M., Moody D. J., Stites D. P., Levy J. A. 1986; CD8+ lymphocytes can control HIV infection in vitro by suppressing virus replication. Science 234:1563–1566 [View Article][PubMed]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/jgv.0.000326
Loading
/content/journal/jgv/10.1099/jgv.0.000326
Loading

Data & Media loading...

Supplements

Supplementary Data

PDF
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error