Person: Streeck, Hendrik
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Streeck
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Hendrik
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Streeck, Hendrik
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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 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.Publication OA031-04. Impairment of HIV-1-specific CD8+ T cell function by soluble epithelial adhesion molecules(BioMed Central, 2009) Trocha, K; Chevalier, M; Caron, T; Pyo, A; Toth, I; Rodig, SJ; Streeck, Hendrik; Kwon, Douglas; Jolin, Julie; Law, K; Kaufmann, Daniel E.; Walker, Bruce; Altfeld, MarcusPublication Immunodominant HIV-1 Cd4+ T Cell Epitopes in Chronic Untreated Clade C HIV-1 Infection(Public Library of Science, 2009) Ramduth, Danni; Day, Cheryl L.; Thobakgale, Christina F.; Mkhwanazi, Nompumelelo P.; de Pierres, Chantal; Reddy, Sharon; van der Stok, Mary; Mncube, Zenele; Nair, Kriebashne; Moodley, Eshia S.; Coovadia, Hoosen M.; Kiepiela, Photini; Kaufmann, Daniel E.; Streeck, Hendrik; Goulder, Philip J.; Walker, BruceBackground: A dominance of Gag-specific CD8+ T cell responses is significantly associated with a lower viral load in individuals with chronic, untreated clade C human immunodeficiency virus type 1 (HIV-1) infection. This association has not been investigated in terms of Gag-specific CD4+ T cell responses, nor have clade C HIV-1–specific CD4+ T cell epitopes, likely a vital component of an effective global HIV-1 vaccine, been identified. Methodology/Principal Findings: Intracellular cytokine staining was conducted on 373 subjects with chronic, untreated clade C infection to assess interferon-gamma (IFN-γ) responses by CD4+ T cells to pooled Gag peptides and to determine their association with viral load and CD4 count. Gag-specific IFN-γ–producing CD4+ T cell responses were detected in 261/373 (70%) subjects, with the Gag responders having a significantly lower viral load and higher CD4 count than those with no detectable Gag response (p<0.0001 for both parameters). To identify individual peptides targeted by HIV-1–specific CD4+ T cells, separate ELISPOT screening was conducted on CD8-depleted PBMCs from 32 chronically infected untreated subjects, using pools of overlapping peptides that spanned the entire HIV-1 clade C consensus sequence, and reconfirmed by flow cytometry to be CD4+ mediated. The ELISPOT screening identified 33 CD4+ peptides targeted by 18/32 patients (56%), with 27 of the 33 peptides located in the Gag region. Although the breadth of the CD4+ responses correlated inversely with viral load (p = 0.015), the magnitude of the response was not significantly associated with viral load. Conclusions/Significance: These data indicate that in chronic untreated clade C HIV-1 infection, IFN-γ–secreting Gag-specific CD4+ T cell responses are immunodominant, directed at multiple distinct epitopes, and associated with viral control.Publication P09-20 LB. Ultra-Deep Sequencing of Full-Length HIV-1 Genomes Identifies Rapid Viral Evolution During Acute Infection(BioMed Central, 2009) Henn, MR; Lennon, N; Malboeuf, C; Charlebois, P; Philips, L; Berical, A; Erlich, R; Kemper, M; Axten, K; Brumme, Z; Brumme, C; Jessen, H; Nusbaum, C; Birren, B; Allen, TM; Boutwell, C; Power, K; Gladden, Andrew B; Levin, Jonathan; Casali, Monica; Berlin, Adam; Anderson, S; Streeck, Hendrik; Ryan, Edward; Wang, Y; Green, L; Russ, Christiana; Rosenberg, Eric; Altfeld, Marcus; Walker, BrucePublication P16-31. Skewed HIV-1-Specific CD4+ Th2 Helper Cell Contribution in Progressive HIV-1 Infection(BioMed Central, 2009) Chevalier, M; Pyo, A; Jolin, J. S.; Addo, Marylyn Martina; Kwon, DS; Toth, I; Walker, Bruce; Streeck, HendrikPublication P16-18. Regulatory T Cell Frequencies Correlate With T Cell Activation in Chronic HIV-1 Infection(BioMed Central, 2009) Pyo, A; Trocha, A; Toth, I; Addo, MM; Angin, Mathieu; Streeck, Hendrik; Pereyra, F; Walker, Bruce; Altfeld, Marcus; Alter, G; Kwon, D; Wen, FPublication Antigen Load and Viral Sequence Diversification Determine the Functional Profile of HIV-1–Specific CD8+ T Cells(Public Library of Science, 2008) Brumme, Zabrina L; Anastario, Michael; Cohen, Kristin W; Jolin, Jonathan S; Brumme, Chanson J; Streeck, Hendrik; Meier, Angela; Rosenberg, Eric; Alter, Galit; Allen, Todd; Walker, Bruce; Altfeld, MarcusBackground: Virus-specific CD8+ T lymphocytes play a key role in the initial reduction of peak viremia during acute viral infections, but display signs of increasing dysfunction and exhaustion under conditions of chronic antigen persistence. It has been suggested that virus-specific CD8+ T cells with a “polyfunctional” profile, defined by the capacity to secrete multiple cytokines or chemokines, are most competent in controlling viral replication in chronic HIV-1 infection. We used HIV-1 infection as a model of chronic persistent viral infection to investigate the process of exhaustion and dysfunction of virus-specific CD8+ T cell responses on the single-epitope level over time, starting in primary HIV-1 infection. Methods and Findings: We longitudinally analyzed the polyfunctional epitope-specific CD8+ T cell responses of 18 patients during primary HIV-1 infection before and after therapy initiation or sequence variation in the targeted epitope. Epitope-specific CD8+ T cells responded with multiple effector functions to antigenic stimulation during primary HIV-1 infection, but lost their polyfunctional capacity in response to antigen and up-regulated programmed death 1 (PD-1) expression with persistent viremic infection. This exhausted phenotype significantly decreased upon removal of stimulation by antigen, either in response to antiretroviral therapy or by reduction of epitope-specific antigen load in the presence of ongoing viral replication, as a consequence of in vivo selection of cytotoxic T lymphocyte escape mutations in the respective epitopes. Monofunctionality increased in CD8+ T cell responses directed against conserved epitopes from 49% (95% confidence interval 27%–72%) to 76% (56%–95%) (standard deviation [SD] of the effect size 0.71), while monofunctionality remained stable or slightly decreased for responses directed against escaped epitopes from 61% (47%–75%) to 56% (42%–70%) (SD of the effect size 0.18) (p < 0.05). Conclusion: These data suggest that persistence of antigen can be the cause, rather than the consequence, of the functional impairment of virus-specific T cell responses observed during chronic HIV-1 infection, and underscore the importance of evaluating autologous viral sequences in studies aimed at investigating the relationship between virus-specific immunity and associated pathogenesis.Publication HLA Alleles Associated with Delayed Progression to AIDS Contribute Strongly to the Initial CD8+ T Cell Response against HIV-1(Public Library of Science, 2006) Kalife, Elizabeth T; Qi, Ying; Johnston, Mary N; Burgett, Nicole; Swartz, Martha E; Yang, Amy; Rockstroh, Juergen K; Jessen, Heiko; Carrington, Mary; Altfeld, Marcus; Streeck, Hendrik; Lichterfeld, Mathias; Alter, Galit; Yu, Xu; Meier, Angela; Allen, Todd; Rosenberg, Eric; Walker, BruceBackground: Very little is known about the immunodominance patterns of HIV-1-specific T cell responses during primary HIV-1 infection and the reasons for human lymphocyte antigen (HLA) modulation of disease progression. Methods and Findings: In a cohort of 104 individuals with primary HIV-1 infection, we demonstrate that a subset of CD8+ T cell epitopes within HIV-1 are consistently targeted early after infection, while other epitopes subsequently targeted through the same HLA class I alleles are rarely recognized. Certain HLA alleles consistently contributed more than others to the total virus-specific CD8+ T cell response during primary infection, and also reduced the absolute magnitude of responses restricted by other alleles if coexpressed in the same individual, consistent with immunodomination. Furthermore, individual HLA class I alleles that have been associated with slower HIV-1 disease progression contributed strongly to the total HIV-1-specific CD8+ T cell response during primary infection. Conclusions: These data demonstrate consistent immunodominance patterns of HIV-1-specific CD8+ T cell responses during primary infection and provide a mechanistic explanation for the protective effect of specific HLA class I alleles on HIV-1 disease progression.