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      Antibody-based CCR5 blockade protects Macaques from mucosal SHIV transmission

      research-article
      1 , 2 , 1 , 2 , 1 , 2 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 3 , 1 , 2 , 2 , 2 , 2 , 2 , 2 , 2 , 2 , 2 , 4 , 5 , 6 , 6 , 7 , 2 , 1 , 2 , 1 , 1 , 8 , 9 , , 1 , 2 ,
      Nature Communications
      Nature Publishing Group UK
      Antibody therapy, HIV infections

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          Abstract

          In the absence of a prophylactic vaccine, the use of antiretroviral therapy (ART) as pre-exposure prophylaxis (PrEP) to prevent HIV acquisition by uninfected individuals is a promising approach to slowing the epidemic, but its efficacy is hampered by incomplete patient adherence and ART-resistant variants. Here, we report that competitive inhibition of HIV Env-CCR5 binding via the CCR5-specific antibody Leronlimab protects rhesus macaques against infection following repeated intrarectal challenges of CCR5-tropic SHIV SF162P3. Injection of Leronlimab weekly at 10 mg/kg provides significant but partial protection, while biweekly 50 mg/kg provides complete protection from SHIV acquisition. Tissue biopsies from protected macaques post challenge show complete CCR5 receptor occupancy and an absence of viral nucleic acids. After Leronlimab washout, protected macaques remain aviremic, and adoptive transfer of hematologic cells into naïve macaques does not transmit viral infection. These data identify CCR5 blockade with Leronlimab as a promising approach to HIV prophylaxis and support initiation of clinical trials.

          Abstract

          CCR5 is a co-receptor for many transmitted HIV strains. Here, the authors show that biweekly injection of the CCR5-specific antibody Leronlimab protects rhesus macaques against infection following repeated intrarectal challenges of a CCR5-tropic SHIV.

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          Most cited references44

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          Trimmomatic: a flexible trimmer for Illumina sequence data

          Motivation: Although many next-generation sequencing (NGS) read preprocessing tools already existed, we could not find any tool or combination of tools that met our requirements in terms of flexibility, correct handling of paired-end data and high performance. We have developed Trimmomatic as a more flexible and efficient preprocessing tool, which could correctly handle paired-end data. Results: The value of NGS read preprocessing is demonstrated for both reference-based and reference-free tasks. Trimmomatic is shown to produce output that is at least competitive with, and in many cases superior to, that produced by other tools, in all scenarios tested. Availability and implementation: Trimmomatic is licensed under GPL V3. It is cross-platform (Java 1.5+ required) and available at http://www.usadellab.org/cms/index.php?page=trimmomatic Contact: usadel@bio1.rwth-aachen.de Supplementary information: Supplementary data are available at Bioinformatics online.
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            Fast and accurate long-read alignment with Burrows–Wheeler transform

            Motivation: Many programs for aligning short sequencing reads to a reference genome have been developed in the last 2 years. Most of them are very efficient for short reads but inefficient or not applicable for reads >200 bp because the algorithms are heavily and specifically tuned for short queries with low sequencing error rate. However, some sequencing platforms already produce longer reads and others are expected to become available soon. For longer reads, hashing-based software such as BLAT and SSAHA2 remain the only choices. Nonetheless, these methods are substantially slower than short-read aligners in terms of aligned bases per unit time. Results: We designed and implemented a new algorithm, Burrows-Wheeler Aligner's Smith-Waterman Alignment (BWA-SW), to align long sequences up to 1 Mb against a large sequence database (e.g. the human genome) with a few gigabytes of memory. The algorithm is as accurate as SSAHA2, more accurate than BLAT, and is several to tens of times faster than both. Availability: http://bio-bwa.sourceforge.net Contact: rd@sanger.ac.uk
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              Preexposure Chemoprophylaxis for HIV Prevention in Men Who Have Sex with Men

              Antiretroviral chemoprophylaxis before exposure is a promising approach for the prevention of human immunodeficiency virus (HIV) acquisition. We randomly assigned 2499 HIV-seronegative men or transgender women who have sex with men to receive a combination of two oral antiretroviral drugs, emtricitabine and tenofovir disoproxil fumarate (FTC-TDF), or placebo once daily. All subjects received HIV testing, risk-reduction counseling, condoms, and management of sexually transmitted infections. The study subjects were followed for 3324 person-years (median, 1.2 years; maximum, 2.8 years). Of these subjects, 10 were found to have been infected with HIV at enrollment, and 100 became infected during follow-up (36 in the FTC-TDF group and 64 in the placebo group), indicating a 44% reduction in the incidence of HIV (95% confidence interval, 15 to 63; P=0.005). In the FTC-TDF group, the study drug was detected in 22 of 43 of seronegative subjects (51%) and in 3 of 34 HIV-infected subjects (9%) (P<0.001). Nausea was reported more frequently during the first 4 weeks in the FTC-TDF group than in the placebo group (P<0.001). The two groups had similar rates of serious adverse events (P=0.57). Oral FTC-TDF provided protection against the acquisition of HIV infection among the subjects. Detectable blood levels strongly correlated with the prophylactic effect. (Funded by the National Institutes of Health and the Bill and Melinda Gates Foundation; ClinicalTrials.gov number, NCT00458393.).
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                Author and article information

                Contributors
                lndhlovu@med.cornell.edu
                Sacha@ohsu.edu
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                7 June 2021
                7 June 2021
                2021
                : 12
                : 3343
                Affiliations
                [1 ]Vaccine & Gene Therapy Institute, Portland, OR USA
                [2 ]GRID grid.5288.7, ISNI 0000 0000 9758 5690, Oregon National Primate Research Center, , Oregon Health & Science University, ; Portland, OR USA
                [3 ]GRID grid.410445.0, ISNI 0000 0001 2188 0957, University of Hawaii, ; Honolulu, HI USA
                [4 ]IncellDX, Menlo Park, CA USA
                [5 ]Amarex Clinical Research LLC, Germantown, MD USA
                [6 ]CytoDyn Inc., Vancouver, WA USA
                [7 ]GRID grid.168645.8, ISNI 0000 0001 0742 0364, MassBiologics of the University of Massachusetts Medical School, ; Boston, MA USA
                [8 ]GRID grid.447351.0, ISNI 0000 0001 0943 8058, Palm Springs, ; Palm Springs, CA USA
                [9 ]GRID grid.5386.8, ISNI 000000041936877X, Department of Medicine, Division of Infectious Disease, , Weill Cornell Medicine, ; New York, NY USA
                Author information
                http://orcid.org/0000-0001-7101-5160
                http://orcid.org/0000-0002-5868-8085
                http://orcid.org/0000-0002-1773-2406
                http://orcid.org/0000-0003-3369-4662
                http://orcid.org/0000-0001-5427-4187
                http://orcid.org/0000-0002-7633-3122
                Article
                23697
                10.1038/s41467-021-23697-6
                8184841
                34099693
                0d62f904-1cb1-4ac5-b9e8-853d872db30f
                © The Author(s) 2021

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 26 March 2021
                : 11 May 2021
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                © The Author(s) 2021

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                antibody therapy,hiv infections
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                antibody therapy, hiv infections

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