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      Recurrent Signature Patterns in HIV-1 B Clade Envelope Glycoproteins Associated with either Early or Chronic Infections


      1 , 1 , 2 , 1 , 3 , 4 , 1 , 1 , 1 , 5 , 1 , 1 , 4 , 4 , 4 , 4 , 6 , 7 , 7 , 8 , 8 , 8 , 8 , 9 , 4 , 4 , 8 , 7 , 10 , 7 , 11 , 11 , 12 , 13 , 13 , 13 , 14 , 14 , 15 , 1 , 16 , 7 , 17 , 7 , 4 , 4 , 1 , 2 , *

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          Here we have identified HIV-1 B clade Envelope (Env) amino acid signatures from early in infection that may be favored at transmission, as well as patterns of recurrent mutation in chronic infection that may reflect common pathways of immune evasion. To accomplish this, we compared thousands of sequences derived by single genome amplification from several hundred individuals that were sampled either early in infection or were chronically infected. Samples were divided at the outset into hypothesis-forming and validation sets, and we used phylogenetically corrected statistical strategies to identify signatures, systematically scanning all of Env. Signatures included single amino acids, glycosylation motifs, and multi-site patterns based on functional or structural groupings of amino acids. We identified signatures near the CCR5 co-receptor-binding region, near the CD4 binding site, and in the signal peptide and cytoplasmic domain, which may influence Env expression and processing. Two signatures patterns associated with transmission were particularly interesting. The first was the most statistically robust signature, located in position 12 in the signal peptide. The second was the loss of an N-linked glycosylation site at positions 413–415; the presence of this site has been recently found to be associated with escape from potent and broad neutralizing antibodies, consistent with enabling a common pathway for immune escape during chronic infection. Its recurrent loss in early infection suggests it may impact fitness at the time of transmission or during early viral expansion. The signature patterns we identified implicate Env expression levels in selection at viral transmission or in early expansion, and suggest that immune evasion patterns that recur in many individuals during chronic infection when antibodies are present can be selected against when the infection is being established prior to the adaptive immune response.

          Author Summary

          A single virus most often establishes HIV-1 infection. As a consequence, virus sampled early in infection is usually very homogeneous. A few months into the infection, the virus begins to accumulate mutations as it evolves to evade HIV-specific immune responses mounted by the infected host. During chronic infection, the viral population diversifies, reflecting the history of mutations that arose within that infected individual. We hypothesized that particular amino acids might confer a selective advantage during transmission or early infection, and others might recur during chronic infection because they provide common and effective strategies of immune escape. We compared a large number of viral sequences from several hundred infected people sampled soon after transmission or during chronic infection to identify such infection-status “signature” patterns. A particularly robust signature was identified in the signal peptide of Envelope, a region that regulates its expression. Other signatures were found in regions of Envelope that interact with its cellular receptors, or are implicated in immune escape.

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          Most cited references 101

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          Multiple alignment of DNA sequences with MAFFT.

          Multiple alignment of DNA sequences is an important step in various molecular biological analyses. As a large amount of sequence data is becoming available through genome and other large-scale sequencing projects, scalability, as well as accuracy, is currently required for a multiple sequence alignment (MSA) program. In this chapter, we outline the algorithms of an MSA program MAFFT and provide practical advice, focusing on several typical situations a biologist sometimes faces. For genome alignment, which is beyond the scope of MAFFT, we introduce two tools: TBA and MAUVE.
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            The immune response during acute HIV-1 infection: clues for vaccine development

            Key Points The early virological factors in HIV-1 infection, including transmission and the nature of the founder virus, can affect the time course of viraemia through the early peak to set point. The identification of patients within the first few weeks of HIV-1 infection has provided early evidence of immune system damage, including massive apoptosis of CD4+ T cells, which is associated with the presence of apoptotic microparticles and TRAIL (tumour necrosis factor-related apoptosis-inducing ligand) in the blood, and damage to germinal centres in mucosal lymphoid tissues. The first innate immune responses include the appearance of acute-phase proteins, early cytokine storm and activation of natural killer (NK) cells. An innate immune response to HIV-1 can be damaging, however, as it can draw susceptible T cells to the infection foci. The first T cell response controls the founder virus by killing infected T cells. However, the T cell response also selects mutational changes in the founder virus, allowing immune evasion. The first B cell response consists of early immune complexes, followed by non-neutralizing antibodies against the founder virus and then the slow development of broadly acting neutralizing antibodies. Development of vaccines that rapidly induce broadly acting neutralizing antibodies might be beneficial in preventing HIV infection. Understanding the early events and immune responses is crucial to devising vaccine strategies that can improve the weak protection offered by current HIV vaccines that are being trialled, such as the RV144 (Thai) efficacy trial.
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              The first T cell response to transmitted/founder virus contributes to the control of acute viremia in HIV-1 infection

              Identification of the transmitted/founder virus makes possible, for the first time, a genome-wide analysis of host immune responses against the infecting HIV-1 proteome. A complete dissection was made of the primary HIV-1–specific T cell response induced in three acutely infected patients. Cellular assays, together with new algorithms which identify sites of positive selection in the virus genome, showed that primary HIV-1–specific T cells rapidly select escape mutations concurrent with falling virus load in acute infection. Kinetic analysis and mathematical modeling of virus immune escape showed that the contribution of CD8 T cell–mediated killing of productively infected cells was earlier and much greater than previously recognized and that it contributed to the initial decline of plasma virus in acute infection. After virus escape, these first T cell responses often rapidly waned, leaving or being succeeded by T cell responses to epitopes which escaped more slowly or were invariant. These latter responses are likely to be important in maintaining the already established virus set point. In addition to mutations selected by T cells, there were other selected regions that accrued mutations more gradually but were not associated with a T cell response. These included clusters of mutations in envelope that were targeted by NAbs, a few isolated sites that reverted to the consensus sequence, and bystander mutations in linkage with T cell–driven escape.

                Author and article information

                Role: Editor
                PLoS Pathog
                PLoS Pathogens
                Public Library of Science (San Francisco, USA )
                September 2011
                September 2011
                29 September 2011
                : 7
                : 9
                [1 ]Theoretical Biology, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America
                [2 ]Santa Fe Institute, Santa Fe, New Mexico, United States of America
                [3 ]SAIC-Frederick, National Cancer Institute, Frederick, Maryland, United States of America
                [4 ]Departments of Medicine and Microbiology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
                [5 ]Center for Molecular Biophysics and Department of Biochemistry, Cellular & Molecular Biology, University of Tennessee, Knoxville, Tennessee, United States of America
                [6 ]National Engineering Laboratory of AIDS Vaccine School of Life Science, Jilin University, Changchun, China
                [7 ]Duke University Medical Center, the Departments of Medicine and Surgery, and the Duke Human Vaccine Institute, Duke University, Durham, North Carolina, United States of America
                [8 ]Department of Biochemistry and Biophysics and the Division of Infectious Diseases Center for AIDS Research, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
                [9 ]Aaron Diamond AIDS Research Center, an affiliate of the Rockefeller University, New York, New York, United States of America
                [10 ]Institute of Human Virology, University of Maryland, School of Medicine, Baltimore, Maryland, United States of America
                [11 ]Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States of America
                [12 ]Division of Viral Pathogenesis, Department of Medicine, Harvard Medical School, Boston, Massachusetts, United States of America
                [13 ]Vaccine Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United State of America
                [14 ]Department of Biochemistry, University of Washington, Seattle, Washington, United States of America
                [15 ]Arzeda Corporation, Seattle, Washington, United States of America
                [16 ]Department of Epidemiology and Biostatistics, College of Public Health, University of Georgia, Athens, Georgia, United States of America
                [17 ]Dana-Farber Cancer Institute, Department of Cancer Immunology and AIDS, Boston, Massachusetts, United States of America
                The Salk Institute for Biological Studies, United States of America
                Author notes

                Conceived and designed the experiments: BFH GMS BHH BK RS MC NLL JGS. Performed the experiments: BFK HL JMD JFS SW CJ FG JAA LHP GDT MA. Analyzed the data: SG TB MD PTH ASL TS BG PBG ACD CAM WRS YAB MZ MK. Contributed reagents/materials/analysis tools: MC MM PAG MSS JJE CBH WAB KAS. Wrote the paper: BK SG TB BHH GMS BFH.

                This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
                Page count
                Pages: 19
                Research Article

                Infectious disease & Microbiology


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