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      Retroviral DNA Integration

      review-article
      Author(s): † , ‡ , , † , § ,
      Publication date (Electronic):
      Journal: Chemical Reviews
      Publisher: American Chemical Society

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          Abstract

          The integration of a DNA copy of the viral RNA genome into host chromatin is the defining step of retroviral replication. This enzymatic process is catalyzed by the virus-encoded integrase protein, which is conserved among retroviruses and LTR-retrotransposons. Retroviral integration proceeds via two integrase activities: 3′-processing of the viral DNA ends, followed by the strand transfer of the processed ends into host cell chromosomal DNA. Herein we review the molecular mechanism of retroviral DNA integration, with an emphasis on reaction chemistries and architectures of the nucleoprotein complexes involved. We additionally discuss the latest advances on anti-integrase drug development for the treatment of AIDS and the utility of integrating retroviral vectors in gene therapy applications.

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          Detection and isolation of type C retrovirus particles from fresh and cultured lymphocytes of a patient with cutaneous T-cell lymphoma.

          B Poiesz, F Ruscetti, A Gazdar … (1980)
          Retrovirus particles with type C morphology were found in two T-cell lymphoblastoid cell lines, HUT 102 and CTCL-3, and in fresh peripheral blood lymphocytes obtained from a patient with a cutaneous T-cell lymphoma (mycosis fungoides). The cell lines continuously produce these viruses, which are collectively referred to as HTLV, strain CR(HTLV(CR)). Originally, the production of virus from HUT 102 cells required induction with 5-iodo-2'-deoxyuridine, but the cell line became a constitutive producer of virus at its 56th passage. Cell line CTCL-3 has been a constitutive producer of virus from its second passage in culture. Both mature and immature extracellular virus particles were seen in thin-section electron micrographs of fixed, pelleted cellular material; on occasion, typical type C budding virus particles were seen. No form of intracellular virus particle has been seen. Mature particles were 100-110 nm in diameter, consisted of an electron-dense core surrounded by an outer membrane separated by an electron-lucent region, banded at a density of 1.16 g/ml on a continuous 25-65% sucrose gradient, and contained 70S RNA and a DNA polymerase activity typical of viral reverse transcriptase (RT; RNA-dependent DNA nucleotidyltransferase). Under certain conditions of assay, HTLV(CR) RT showed cation preference for Mg(2+) over Mn(2+), distinct from the characteristics of cellular DNA polymerases purified from human lymphocytes and the RT from most type C viruses. Antibodies to cellular DNA polymerase gamma and anti-bodies against RT purified from several animal retroviruses failed to detectably interact with HTLV(CR) RT under conditions that were positive for the respective homologous DNA polymerase, demonstrating a lack of close relationship of HTLV(CR) RT to cellular DNA polymerases gamma or RT of these viruses. Six major proteins, with sizes of approximately 10,000, 13,000, 19,000, 24,000, 42,000, and 52,000 daltons, were apparent when doubly banded, disrupted HTLV(CR) particles were chromatographed on a NaDodSO(4)/polyacrylamide gel. The number of these particle-associated proteins is consistent with the expected proteins of a retrovirus, but the sizes of some are distinct from those of most known retroviruses of the primate subgroups.
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            HIV reproducibly establishes a latent infection after acute infection of T cells in vitro.

            Albert Jordan, Dwayne Bisgrove, Eric Verdin (2003)
            The presence of latent reservoirs has prevented the eradication of human immunodeficiency virus (HIV) from infected patients successfully treated with anti-retroviral therapy. The mechanism of postintegration latency is poorly understood, partly because of the lack of an in vitro model. We have used an HIV retroviral vector or a full-length HIV genome expressing green fluorescent protein to infect a T lymphocyte cell line in vitro and highly enrich for latently infected cells. HIV latency occurred reproducibly, albeit with low frequency, during an acute infection. Clonal cell lines derived from latent populations showed no detectable basal expression, but could be transcriptionally activated after treatment with phorbol esters or tumor necrosis factor alpha. Direct sequencing of integration sites demonstrated that latent clones frequently contain HIV integrated in or close to alphoid repeat elements in heterochromatin. This is in contrast to a productive infection where integration in or near heterochromatin is disfavored. These observations demonstrate that HIV can reproducibly establish a latent infection as a consequence of integration in or near heterochromatin.
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              HIV-1 dynamics in vivo: virion clearance rate, infected cell life-span, and viral generation time.

              Victor Markowitz, Alan Perelson, Anthony Ho … (1996)
              A new mathematical model was used to analyze a detailed set of human immunodeficiency virus-type 1 (HIV-1) viral load data collected from five infected individuals after the administration of a potent inhibitor of HIV-1 protease. Productively infected cells were estimated to have, on average, a life-span of 2.2 days (half-life t 1/2 = 1.6 days), and plasma virions were estimated to have a mean life-span of 0.3 days (t 1/2 = 0.24 days). The estimated average total HIV-1 production was 10.3 x 10(9) virions per day, which is substantially greater than previous minimum estimates. The results also suggest that the minimum duration of the HIV-1 life cycle in vivo is 1.2 days on average, and that the average HIV-1 generation time--defined as the time from release of a virion until it infects another cell and causes the release of a new generation of viral particles--is 2.6 days. These findings on viral dynamics provide not only a kinetic picture of HIV-1 pathogenesis, but also theoretical principles to guide the development of treatment strategies.
              Article 0 comments Cited 305 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Chem Rev
                Journal ID (iso-abbrev): Chem. Rev
                Journal ID (publisher-id): cr
                Journal ID (coden): chreay
                Title: Chemical Reviews
                Publisher: American Chemical Society
                ISSN (Print): 0009-2665
                ISSN (Electronic): 1520-6890
                Publication date (Electronic): 20 May 2016
                Publication date (Print): 26 October 2016
                Volume: 116
                Issue: 20 , Genome Modifying Mechanisms
                Pages: 12730-12757
                Affiliations
                [† ]Clare Hall Laboratories, The Francis Crick Institute , Blanche Lane, South Mimms, EN6 3LD, U.K.
                [‡ ]Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute and Department of Medicine, Harvard Medical School , 450 Brookline Avenue, Boston, Massachusetts 02215 United States
                [§ ]Imperial College London , St-Mary’s Campus, Norfolk Place, London, W2 1PG, U.K.
                Author notes
                Article
                DOI: 10.1021/acs.chemrev.6b00125
                PMC ID: 5084067
                PubMed ID: 27198982
                SO-VID: 5159c67e-45f6-4f6d-a64e-505826adab09
                Copyright © Copyright © 2016 American Chemical Society
                License:

                This is an open access article published under a Creative Commons Attribution (CC-BY) License, which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.

                History
                Date received : 18 February 2016
                Categories
                Subject: Review
                Custom metadata
                document-id-old-9 cr6b00125
                document-id-new-14 cr-2016-001253
                ccc-price

                ScienceOpen disciplines: Chemistry
                Data availability:
                ScienceOpen disciplines: Chemistry

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