Blog
About

81
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: not found

      Rapid Seeding of the Viral Reservoir Prior to SIV Viremia in Rhesus Monkeys

      Read this article at

      ScienceOpenPublisherPMC
      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 viral reservoir represents a critical challenge facing HIV-1 eradication strategies 15 . However, it remains unclear when and where the viral reservoir is seeded during acute infection and the extent to which it is susceptible to early antiretroviral therapy (ART). Here we show that the viral reservoir is seeded very early following mucosal SIV infection of rhesus monkeys and prior to systemic viremia. We initiated suppressive ART in groups of monkeys on days 3, 7, 10, and 14 following intrarectal SIVmac251 infection. Treatment on day 3 blocked the emergence of viral RNA and proviral DNA in peripheral blood and also substantially reduced levels of proviral DNA in lymph nodes and gastrointestinal mucosa as compared with treatment at later timepoints. In addition, treatment on day 3 abrogated the induction of SIV-specific humoral and cellular immune responses. Nevertheless, following discontinuation of ART after 24 weeks of fully suppressive therapy, virus rebounded in all animals, although animals treated on day 3 exhibited a delayed viral rebound as compared with animals treated on days 7, 10 and 14. The time to viral rebound correlated with total viremia during acute infection and with proviral DNA at the time of ART discontinuation. These data demonstrate that the viral reservoir is seeded very early following intrarectal SIV infection of rhesus monkeys, during the “eclipse” phase, and prior to viremia. This strikingly early seeding of the refractory viral reservoir raises important new challenges for HIV-1 eradication strategies.

          Related collections

          Most cited references 29

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

          Quantification of latent tissue reservoirs and total body viral load in HIV-1 infection.

          The capacity of HIV-1 to establish latent infection of CD4+ T cells may allow viral persistence despite immune responses and antiretroviral therapy. Measurements of infectious virus and viral RNA in plasma and of infectious virus, viral DNA and viral messenger RNA species in infected cells all suggest that HIV-1 replication continues throughout the course of infection. Uncertainty remains over what fraction of CD4+ T cells are infected and whether there are latent reservoirs for the virus. We show here that during the asymptomatic phase of infection there is an extremely low total body load of latently infected resting CD4+ T cells with replication-competent integrated provirus (<10(7) cells). The most prevalent form of HIV-1 DNA in resting and activated CD4+ T cells is a full-length, linear, unintegrated form that is not replication competent. The infection progresses even though at any given time in the lymphoid tissues integrated HIV-1 DNA is present in only a minute fraction of the susceptible populations, including resting and activated CD4+ T cells and macrophages.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Replication-competent noninduced proviruses in the latent reservoir increase barrier to HIV-1 cure.

            Antiretroviral therapy fails to cure HIV-1 infection because latent proviruses persist in resting CD4(+) T cells. T cell activation reverses latency, but <1% of proviruses are induced to release infectious virus after maximum in vitro activation. The noninduced proviruses are generally considered defective but have not been characterized. Analysis of 213 noninduced proviral clones from treated patients showed 88.3% with identifiable defects but 11.7% with intact genomes and normal long terminal repeat (LTR) function. Using direct sequencing and genome synthesis, we reconstructed full-length intact noninduced proviral clones and demonstrated growth kinetics comparable to reconstructed induced proviruses from the same patients. Noninduced proviruses have unmethylated promoters and are integrated into active transcription units. Thus, it cannot be excluded that they may become activated in vivo. The identification of replication-competent noninduced proviruses indicates that the size of the latent reservoir-and, hence, the barrier to cure-may be up to 60-fold greater than previously estimated. Copyright © 2013 Elsevier Inc. All rights reserved.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy.

              Combination therapy for HIV-1 infection can reduce plasma virus to undetectable levels, indicating that prolonged treatment might eradicate the infection. However, HIV-1 can persist in a latent form in resting CD4+ T cells. We measured the decay rate of this latent reservoir in 34 treated adults whose plasma virus levels were undetectable. The mean half-life of the latent reservoir was very long (43.9 months). If the latent reservoir consists of only 1 x 10(5) cells, eradication could take as long as 60 years. Thus, latent infection of resting CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective anti-retroviral therapy.
                Bookmark

                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                Nature
                0028-0836
                1476-4687
                21 June 2014
                20 July 2014
                7 August 2014
                07 February 2015
                : 512
                : 7512
                : 74-77
                Affiliations
                [1 ]Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
                [2 ]Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA
                [3 ]Program for Evolutionary Dynamics, Harvard University, Cambridge, MA 02138 USA
                [4 ]Bioqual, Rockville, MD 20852, USA
                [5 ]Gilead Sciences, Foster City, CA 94404
                [6 ]U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD 20910
                Author notes
                [* ]Correspondence: Dan H. Barouch ( dbarouch@ 123456bidmc.harvard.edu )
                Article
                NIHMS607084
                10.1038/nature13594
                4126858
                25042999
                Categories
                Article

                Uncategorized

                Comments

                Comment on this article