Person: Allen, Todd
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Allen
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Allen, Todd
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Publication A genome-to-genome analysis of associations between human genetic variation, HIV-1 sequence diversity, and viral control(eLife Sciences Publications, Ltd, 2013) Bartha, István; Carlson, Jonathan M; Brumme, Chanson J; McLaren, Paul J; Brumme, Zabrina L; John, Mina; Haas, David W; Martinez-Picado, Javier; Dalmau, Judith; López-Galíndez, Cecilio; Casado, Concepción; Rauch, Andri; Günthard, Huldrych F; Bernasconi, Enos; Vernazza, Pietro; Klimkait, Thomas; Yerly, Sabine; O’Brien, Stephen J; Listgarten, Jennifer; Pfeifer, Nico; Lippert, Christoph; Fusi, Nicolo; Kutalik, Zoltán; Allen, Todd; Müller, Viktor; Harrigan, P Richard; Heckerman, David; Telenti, Amalio; Fellay, JacquesHIV-1 sequence diversity is affected by selection pressures arising from host genomic factors. Using paired human and viral data from 1071 individuals, we ran >3000 genome-wide scans, testing for associations between host DNA polymorphisms, HIV-1 sequence variation and plasma viral load (VL), while considering human and viral population structure. We observed significant human SNP associations to a total of 48 HIV-1 amino acid variants (p<2.4 × 10−12). All associated SNPs mapped to the HLA class I region. Clinical relevance of host and pathogen variation was assessed using VL results. We identified two critical advantages to the use of viral variation for identifying host factors: (1) association signals are much stronger for HIV-1 sequence variants than VL, reflecting the ‘intermediate phenotype’ nature of viral variation; (2) association testing can be run without any clinical data. The proposed genome-to-genome approach highlights sites of genomic conflict and is a strategy generally applicable to studies of host–pathogen interaction. DOI: http://dx.doi.org/10.7554/eLife.01123.001Publication Temporal effect of HLA-B*57 on viral control during primary HIV-1 infection(BioMed Central, 2013) Vaidya, Sagar A; Streeck, Hendrik; Beckwith, Noor; Ghebremichael, Musie; Pereyra, F; Kwon, Douglas; Addo, Marylyn M; Rychert, Jenna; Routy, Jean-Pierre; Jessen, Heiko; Kelleher, Anthony D; Hecht, Frederick; Sekaly, Rafick-Pierre; Carrington, Mary; Walker, Bruce; Allen, Todd; Rosenberg, Eric; Altfeld, MarcusBackground: HLA-B alleles are associated with viral control in chronic HIV-1 infection, however, their role in primary HIV-1 disease is unclear. This study sought to determine the role of HLA-B alleles in viral control during the acute phase of HIV-1 infection and establishment of the early viral load set point (VLSP). Findings: Individuals identified during primary HIV-1 infection were HLA class I typed and followed longitudinally. Associations between HLA-B alleles and HIV-1 viral replication during acute infection and VLSP were analyzed in untreated subjects. The results showed that neither HLA-B*57 nor HLA-B*27 were significantly associated with viral control during acute HIV-1 infection (Fiebig stage I-IV, n=171). HLA-B*57 was however significantly associated with a subsequent lower VLSP (p<0.001, n=135) with nearly 1 log10 less median viral load. Analysis of a known polymorphism at position 97 of HLA-B showed significant associations with both lower initial viral load (p<0.01) and lower VLSP (p<0.05). However, this association was dependent on different amino acids at this position for each endpoint. Conclusions: The effect of HLA-B*57 on viral control is more pronounced during the later stages of primary HIV-1 infection, which suggests the underlying mechanism of control occurs at a critical period in the first several months after HIV-1 acquisition. The risk profile of polymorphisms at position 97 of HLA-B are more broadly associated with HIV-1 viral load during primary infection and may serve as a focal point in further studies of HLA-B function.Publication Impact of Pre-adapted HIV Transmission(2016) Carlson, Jonathan M.; Du, Victor Y.; Pfeifer, Nico; Bansal, Anju; Tan, Vincent Y.F.; Power, Karen; Brumme, Chanson J.; Kreimer, Anat; DeZiel, Charles E.; Fusi, Nicolo; Schaefer, Malinda; Brockman, Mark A.; Gilmour, Jill; Price, Matt A.; Kilembe, William; Haubrich, Richard; John, Mina; Mallal, Simon; Shapiro, Roger; Frater, John; Harrigan, P. Richard; Ndung’u, Thumbi; Allen, Susan; Heckerman, David; Sidney, John; Allen, Todd; Goulder, Philip J.R.; Brumme, Zabrina L.; Hunter, Eric; Goepfert, Paul A.Human Leukocyte Antigen class I (HLA) restricted CD8+ T lymphocyte (CTL) responses are critical to HIV-1 control. Although HIV can evade these responses, the longer-term impact of viral escape mutants remains unclear, since these variants can also reduce intrinsic viral fitness. To address this question, we here develop a metric to determine the degree of HIV adaptation to an HLA profile. We demonstrate that transmission of viruses pre-adapted to the HLA molecules expressed in the recipient is associated with impaired immunogenicity, elevated viral load and accelerated CD4 decline. Furthermore, the extent of pre-adaptation among circulating viruses explains much of the variation in outcomes attributed to expression of certain HLA alleles. Thus, viral pre-adaptation exploits “holes” in the immune response. Accounting for these holes may be critical for vaccine strategies seeking to elicit functional responses from viral variants, and to HIV cure strategies requiring broad CTL responses to achieve successful eradication of HIV reservoirs.Publication Efficient Ablation of Genes in Human Hematopoietic Stem and Effector Cells using CRISPR/Cas9(Elsevier BV, 2014) Mandal, Pankaj; Ferreira, Leonardo Manuel Ramos; Collins, Ryan; Meissner, Torsten; Boutwell, C; Friesen, Max; Vrbanac, Vladimir; Garrison, Brian Scott; Stortchevoi, Alexei; Bryder, David; Musunuru, Kiran; Brand, Harrison; Tager, Andrew Martin; Allen, Todd; Talkowski, Michael; Rossi, Derrick; Cowan, ChadGenome editing via CRISPR/Cas9 has rapidly become the tool of choice by virtue of its efficacy and ease of use. However, CRISPR/Cas9-mediated genome editing in clinically relevant human somatic cells remains untested. Here, we report CRISPR/Cas9 targeting of two clinically relevant genes, B2M and CCR5, in primary human CD4+ T cells and CD34+ hematopoietic stem and progenitor cells (HSPCs). Use of single RNA guides led to highly efficient mutagenesis in HSPCs but not in T cells. A dual guide approach improved gene deletion efficacy in both cell types. HSPCs that had undergone genome editing with CRISPR/Cas9 retained multilineage potential. We examined predicted on- and off-target mutations via target capture sequencing in HSPCs and observed low levels of off-target mutagenesis at only one site. These results demonstrate that CRISPR/Cas9 can efficiently ablate genes in HSPCs with minimal off-target mutagenesis, which could have broad applicability for hematopoietic cell-based therapy.Publication Early type I Interferon response induces upregulation of human β-defensin 1 during acute HIV-1 infection(Public Library of Science, 2017) Corleis, Björn; Lisanti, Antonella C.; Körner, Christian; Schiff, Abby; Rosenberg, Eric; Allen, Todd; Altfeld, Marcus; Kwon, DouglasHIV-1 is able to evade innate antiviral responses during acute infection to establish a chronic systemic infection which, in the absence of antiretroviral therapy (ART), typically progresses to severe immunodeficiency. Understanding these early innate immune responses against HIV-1 and their mechanisms of failure is relevant to the development of interventions to better prevent HIV-1 transmission. Human beta defensins (HBDs) are antibacterial peptides but have recently also been associated with control of viral replication. HBD1 and 2 are expressed in PBMCs as well as intestinal tissue, but their expression in vivo during HIV-1 infection has not been characterized. We demonstrate that during acute HIV-1 infection, HBD1 but not HBD2 is highly upregulated in circulating monocytes but returns to baseline levels during chronic infection. HBD1 expression in monocytes can be induced by HIV-1 in vitro, although direct infection may not entirely account for the increase in HBD1 during acute infection. We provide evidence that HIV-1 triggers antiviral IFN-α responses, which act as a potent inducer of HBD1. Our results show the first characterization of induction of an HBD during acute and chronic viral infection in humans. HBD1 has been reported to have low activity against HIV-1 compared to other defensins, suggesting that in vivo induced defensins may not significantly contribute to the robust early antiviral response against HIV-1. These data provide important insight into the in vivo kinetics of HBD expression, the mechanism of HBD1 induction by HIV-1, and the role of HBDs in the early innate response to HIV-1 during acute infection.Publication Highly Sensitive and Specific Detection of Rare Variants in Mixed Viral Populations from Massively Parallel Sequence Data(Public Library of Science, 2012) Macalalad, Alexander R.; Zody, M; Charlebois, Patrick; Lennon, Niall J.; Newman, Ruchi M.; Malboeuf, Christine M.; Ryan, Elizabeth Marie; Boutwell, C; Power, Karen A.; Brackney, Doug E.; Pesko, Kendra N.; Levin, Joshua Z.; Ebel, Gregory D.; Allen, Todd; Birren, Bruce W.; Henn, Matthew R.Viruses diversify over time within hosts, often undercutting the effectiveness of host defenses and therapeutic interventions. To design successful vaccines and therapeutics, it is critical to better understand viral diversification, including comprehensively characterizing the genetic variants in viral intra-host populations and modeling changes from transmission through the course of infection. Massively parallel sequencing technologies can overcome the cost constraints of older sequencing methods and obtain the high sequence coverage needed to detect rare genetic variants (<1%) within an infected host, and to assay variants without prior knowledge. Critical to interpreting deep sequence data sets is the ability to distinguish biological variants from process errors with high sensitivity and specificity. To address this challenge, we describe V-Phaser, an algorithm able to recognize rare biological variants in mixed populations. V-Phaser uses covariation (i.e. phasing) between observed variants to increase sensitivity and an expectation maximization algorithm that iteratively recalibrates base quality scores to increase specificity. Overall, V-Phaser achieved >97% sensitivity and >97% specificity on control read sets. On data derived from a patient after four years of HIV-1 infection, V-Phaser detected 2,015 variants across the ∼10 kb genome, including 603 rare variants (<1% frequency) detected only using phase information. V-Phaser identified variants at frequencies down to 0.2%, comparable to the detection threshold of allele-specific PCR, a method that requires prior knowledge of the variants. The high sensitivity and specificity of V-Phaser enables identifying and tracking changes in low frequency variants in mixed populations such as RNA viruses.Publication Whole Genome Deep Sequencing of HIV-1 Reveals the Impact of Early Minor Variants Upon Immune Recognition During Acute Infection(Public Library of Science, 2012) Henn, Matthew R.; Charlebois, Patrick; Lennon, Niall J.; Power, Karen A.; Macalalad, Alexander R.; Berlin, Aaron M.; Malboeuf, Christine M.; Gnerre, Sante; Erlich, Rachel L.; Green, Lisa M.; Berical, Andrew; Wang, Yaoyu; Newman, Ruchi; Axten, Karen L.; Gladden, Adrianne D.; Battis, Laura; Kemper, Michael; Zeng, Qiandong; Shea, Terrance P.; Gujja, Sharvari; Zedlack, Carmen; Gasser, Olivier; Brander, Christian; Günthard, Huldrych F.; Brumme, Zabrina L.; Brumme, Chanson J.; Bazner, Suzane; Rychert, Jenna; Tinsley, Jake P.; Levin, Joshua Z.; Jessen, Heiko; Birren, Bruce W.; Boutwell, C; Ryan, Elizabeth M.; Zody, M; Casali, Monica; Streeck, Hendrik; Bloom, Allyson; Dudek, Timothy E; Tully, Damien C; Hess, Christoph; Mayer, Kenneth; Rosenberg, Eric; Pereyra, F; Young, Sarah K.; Altfeld, Marcus; Walker, Bruce; Allen, ToddDeep sequencing technologies have the potential to transform the study of highly variable viral pathogens by providing a rapid and cost-effective approach to sensitively characterize rapidly evolving viral quasispecies. Here, we report on a high-throughput whole HIV-1 genome deep sequencing platform that combines 454 pyrosequencing with novel assembly and variant detection algorithms. In one subject we combined these genetic data with detailed immunological analyses to comprehensively evaluate viral evolution and immune escape during the acute phase of HIV-1 infection. The majority of early, low frequency mutations represented viral adaptation to host CD8+ T cell responses, evidence of strong immune selection pressure occurring during the early decline from peak viremia. CD8+ T cell responses capable of recognizing these low frequency escape variants coincided with the selection and evolution of more effective secondary HLA-anchor escape mutations. Frequent, and in some cases rapid, reversion of transmitted mutations was also observed across the viral genome. When located within restricted CD8 epitopes these low frequency reverting mutations were sufficient to prime de novo responses to these epitopes, again illustrating the capacity of the immune response to recognize and respond to low frequency variants. More importantly, rapid viral escape from the most immunodominant CD8+ T cell responses coincided with plateauing of the initial viral load decline in this subject, suggestive of a potential link between maintenance of effective, dominant CD8 responses and the degree of early viremia reduction. We conclude that the early control of HIV-1 replication by immunodominant CD8+ T cell responses may be substantially influenced by rapid, low frequency viral adaptations not detected by conventional sequencing approaches, which warrants further investigation. These data support the critical need for vaccine-induced CD8+ T cell responses to target more highly constrained regions of the virus in order to ensure the maintenance of immunodominant CD8 responses and the sustained decline of early viremia.Publication Broadly directed virus-specific CD4+ T cell responses are primed during acute hepatitis C infection, but rapidly disappear from human blood with viral persistence(The Rockefeller University Press, 2012) Schulze zur Wiesch, Julian; Ciuffreda, Donatella; Lewis-Ximenez, Lia; Kasprowicz, Victoria Olivia; Nolan, Brian E.; Streeck, Hendrik; Aneja, Jasneet; Reyor, Laura L.; Allen, Todd; Lohse, Ansgar W.; McGovern, Barbara; Chung, Raymond; Kwok, William W.; Kim, Arthur; Lauer, GeorgVigorous proliferative CD4+ T cell responses are the hallmark of spontaneous clearance of acute hepatitis C virus (HCV) infection, whereas comparable responses are absent in chronically evolving infection. Here, we comprehensively characterized the breadth, specificity, and quality of the HCV-specific CD4+ T cell response in 31 patients with acute HCV infection and varying clinical outcomes. We analyzed in vitro T cell expansion in the presence of interleukin-2, and ex vivo staining with HCV peptide-loaded MHC class II tetramers. Surprisingly, broadly directed HCV-specific CD4+ T cell responses were universally detectable at early stages of infection, regardless of the clinical outcome. However, persistent viremia was associated with early proliferative defects of the HCV-specific CD4+ T cells, followed by rapid deletion of the HCV-specific response. Only early initiation of antiviral therapy was able to preserve CD4+ T cell responses in acute, chronically evolving infection. Our results challenge the paradigm that HCV persistence is the result of a failure to prime HCV-specific CD4+ T cells. Instead, broadly directed HCV-specific CD4+ T cell responses are usually generated, but rapid exhaustion and deletion of these cells occurs in the majority of patients. The data further suggest a short window of opportunity to prevent the loss of CD4+ T cell responses through antiviral therapy.Publication The Humanized BLT Mouse to Study HIV Transmission(BioMed Central, 2012) Deruaz, Maud; Murooka, Thomas; Dudek, Timothy E; Vrbanac, Vladimir; Tivet, T; Bankert, KC; Allen, Todd; Tager, Andrew Martin; Luster, AndrewPublication Immune-Driven Recombination and Loss of Control after HIV Superinfection(The Rockefeller University Press, 2008) Streeck, Hendrik; Li, Bin; Poon, Art F. Y.; Schneidewind, Anne; Gladden, Adrianne D.; Power, Karen A.; Daskalakis, Demetre; Bazner, Suzane; Zuniga, Rosario; Brander, Christian; Rosenberg, Eric; Frost, Simon D. W.; Altfeld, Marcus; Allen, ToddAfter acute HIV infection, CD8^{+} T cells are able to control viral replication to a set point. This control is often lost after superinfection, although the mechanism behind this remains unclear. In this study, we illustrate in an HLA-B27^{+} subject that loss of viral control after HIV superinfection coincides with rapid recombination events within two narrow regions of Gag and Env. Screening for CD8^{+} T cell responses revealed that each of these recombination sites (∼50 aa) encompassed distinct regions containing two immunodominant CD8 epitopes (B27-KK10 in Gag and Cw1-CL9 in Env). Viral escape and the subsequent development of variant-specific de novo CD8^{+} T cell responses against both epitopes were illustrative of the significant immune selection pressures exerted by both responses. Comprehensive analysis of the kinetics of CD8 responses and viral evolution indicated that the recombination events quickly facilitated viral escape from both dominant WT- and variant-specific responses. These data suggest that the ability of a superinfecting strain of HIV to overcome preexisting immune control may be related to its ability to rapidly recombine in critical regions under immune selection pressure. These data also support a role for cellular immune pressures in driving the selection of new recombinant forms of HIV.