91
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Molecular control of HIV-1 postintegration latency: implications for the development of new therapeutic strategies

      review-article
      1 , 1 ,
      Retrovirology
      BioMed Central

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          The persistence of HIV-1 latent reservoirs represents a major barrier to virus eradication in infected patients under HAART since interruption of the treatment inevitably leads to a rebound of plasma viremia. Latency establishes early after infection notably (but not only) in resting memory CD4 + T cells and involves numerous host and viral trans-acting proteins, as well as processes such as transcriptional interference, RNA silencing, epigenetic modifications and chromatin organization. In order to eliminate latent reservoirs, new strategies are envisaged and consist of reactivating HIV-1 transcription in latently-infected cells, while maintaining HAART in order to prevent de novo infection. The difficulty lies in the fact that a single residual latently-infected cell can in theory rekindle the infection. Here, we review our current understanding of the molecular mechanisms involved in the establishment and maintenance of HIV-1 latency and in the transcriptional reactivation from latency. We highlight the potential of new therapeutic strategies based on this understanding of latency. Combinations of various compounds used simultaneously allow for the targeting of transcriptional repression at multiple levels and can facilitate the escape from latency and the clearance of viral reservoirs. We describe the current advantages and limitations of immune T-cell activators, inducers of the NF-κB signaling pathway, and inhibitors of deacetylases and histone- and DNA- methyltransferases, used alone or in combinations. While a solution will not be achieved by tomorrow, the battle against HIV-1 latent reservoirs is well- underway.

          Related collections

          Most cited references249

          • Record: found
          • Abstract: found
          • Article: not found

          Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy.

          The hypothesis that quiescent CD4+ T lymphocytes carrying proviral DNA provide a reservoir for human immunodeficiency virus-type 1 (HIV-1) in patients on highly active antiretroviral therapy (HAART) was examined. In a study of 22 patients successfully treated with HAART for up to 30 months, replication-competent virus was routinely recovered from resting CD4+ T lymphocytes. The frequency of resting CD4+ T cells harboring latent HIV-1 was low, 0.2 to 16.4 per 10(6) cells, and, in cross-sectional analysis, did not decrease with increasing time on therapy. The recovered viruses generally did not show mutations associated with resistance to the relevant antiretroviral drugs. This reservoir of nonevolving latent virus in resting CD4+ T cells should be considered in deciding whether to terminate treatment in patients who respond to HAART.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            AP-1 function and regulation.

            AP-1 (activating protein-1) is a collective term referring to dimeric transcription factors composed of Jun, Fos or ATF (activating transcription factor) subunits that bind to a common DNA site, the AP-1-binding site. As the complexity of our knowledge of AP-1 factors has increased, our understanding of their physiological function has decreased. This trend, however, is beginning to be reversed due to the recent studies of gene-knockout mice and cell lines deficient in specific AP-1 components. Such studies suggest that different AP-1 factors may regulate different target genes and thus execute distinct biological functions. Also, the involvement of AP-1 factors in functions such as cell proliferation and survival has been made somewhat clearer as a result of such studies. In addition, there has been considerable progress in understanding some of the mechanisms and signaling pathways involved in the regulation of AP-1 activity. In addition to regulation by heterodimerization between Jun, Fos and ATF proteins, AP-1 activity is regulated through interactions with specific protein kinases and a variety of transcriptional coactivators.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              HIV reproducibly establishes a latent infection after acute infection of T cells in vitro.

              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.
                Bookmark

                Author and article information

                Journal
                Retrovirology
                Retrovirology
                BioMed Central
                1742-4690
                2009
                4 December 2009
                : 6
                : 111
                Affiliations
                [1 ]Laboratory of Molecular Virology, Institut de Biologie et de Médecine Moléculaires (IBMM), Université Libre de Bruxelles (ULB), 6041 Gosselies, Belgium
                Article
                1742-4690-6-111
                10.1186/1742-4690-6-111
                2797771
                19961595
                d995329f-e42a-4e79-ae80-51b6e0b954ec
                Copyright ©2009 Colin and Van Lint; 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/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 1 November 2009
                : 4 December 2009
                Categories
                Review

                Microbiology & Virology
                Microbiology & Virology

                Comments

                Comment on this article