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      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

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          Abstract

          Background

          The CD8 Antiviral Factor (CAF) suppresses viral transcription from the HIV-1 Long Terminal Repeat (LTR) promoter in a non-cytolytic manner. However, the region on the LTR upon which CAF acts is unknown. Our objective was to determine the region on the LTR upon which CAF acts to suppress HIV-1 transcription.

          Methods

          Serial deletions of the LTR from the 5’ end and inactivating point mutations were made.

          Results

          Serial deletions of the LTR from the 5’ end indicated the importance of a short ~120 bp segment, containing the 3 SpI sites, CATA box (used by HIV-1 instead of the TATA box) and TAR region, in the suppressive process. Introduction of deletions or inactivating point mutations in the SpI sites or deletion of the TAR region did not abolish CAF-mediated transcriptional suppression. Yet, CAF-mediated transcriptional suppression was still retained in the HIV-1 CATA-TAR segment.

          Conclusion

          CAF is able to suppress transcription from the LTR lacking all the elements upstream of the CATA box. Our results suggest that the HIV-1 CATA box may be responsible for CAF-mediated suppression of transcription from the HIV-1 LTR.

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          Most cited references35

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          Identification of RANTES, MIP-1 alpha, and MIP-1 beta as the major HIV-suppressive factors produced by CD8+ T cells.

          Evidence suggests that CD8+ T lymphocytes are involved in the control of human immunodeficiency virus (HIV) infection in vivo, either by cytolytic mechanisms or by the release of HIV-suppressive factors (HIV-SF). The chemokines RANTES, MIP-1 alpha, and MIP-1 beta were identified as the major HIV-SF produced by CD8+ T cells. Two active proteins purified from the culture supernatant of an immortalized CD8+ T cell clone revealed sequence identity with human RANTES and MIP-1 alpha. RANTES, MIP-1 alpha, and MIP-1 beta were released by both immortalized and primary CD8+ T cells. HIV-SF activity produced by these cells was completely blocked by a combination of neutralizing antibodies against RANTES, MIP-1 alpha, and MIP-1 beta. Recombinant human RANTES, MIP-1 alpha, and MIP-1 beta induced a dose-dependent inhibition of different strains of HIV-1, HIV-2, and simian immunodeficiency virus (SIV). These data may have relevance for the prevention and therapy of AIDS.
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            CD8+ lymphocytes can control HIV infection in vitro by suppressing virus replication.

            Lymphocytes bearing the CD8 marker were shown to suppress replication of human immunodeficiency virus (HIV) in peripheral blood mononuclear cells. The effect was dose-dependent and most apparent with autologous lymphocytes; it did not appear to be mediated by a cytotoxic response. This suppression of HIV replication could be demonstrated by the addition of CD8+ cells at the initiation of virus production as well as after several weeks of virus replication by cultured cells. The observations suggest a potential approach to therapy in which autologous CD8 lymphocytes could be administered to individuals to inhibit HIV replication and perhaps progression of disease.
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              HIV-1 Tat protein increases transcriptional initiation and stabilizes elongation.

              We studied regulation of human immunodeficiency virus-1 (HIV-1) transcription by Tat and, for comparative purposes, by the adenovirus E1A protein. These two trans-activators exerted different effects. Two classes of HIV-1-promoted cytoplasmic RNA were detected, one class corresponding to full-length transcripts and the other to transcripts ending 55 and 59 nucleotides from the transcription start. Tat increased the level of the full-length class only, whereas E1A increased the levels of both classes of RNA. We also measured the effects of Tat and E1A on RNA synthesis rates. Without trans-activators, HIV-1-directed transcription was relatively weak and exhibited a marked polarity. Both Tat and E1A dramatically increased promoter-proximal transcription, while only Tat suppressed transcriptional polarity. Mutations in the TAR element did not influence basal transcription rates or the response to E1A, but eliminated trans-activation by Tat. We propose that Tat acts through TAR to increase initiation complex formation on the HIV-1 promoter and to stabilize complexes during elongation.
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                Author and article information

                Contributors
                Journal
                Virol J
                Virol. J
                Virology Journal
                BioMed Central
                1743-422X
                2014
                21 July 2014
                : 11
                : 130
                Affiliations
                [1 ]Currently at the Department of Obstetrics and Gynecology, Magee Women’s Research Institute, University of Pittsburgh, Pittsburgh, USA
                [2 ]Pittsburgh Retrovirology Laboratory, Department of Infectious Diseases and Microbiology, University of Pittsburgh Graduate School of Public Health, 426, Parran Hall, 130, DeSoto Street, Pittsburgh 15261, USA
                Article
                1743-422X-11-130
                10.1186/1743-422X-11-130
                4223764
                25048949
                896b03d7-63a9-4c9b-b48c-0bc970f389d6
                Copyright © 2014 Shridhar et al.; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 26 February 2014
                : 6 June 2014
                Categories
                Research

                Microbiology & Virology
                cd8 antiviral factor,hiv-1,long terminal repeat,transcription suppression

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