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ABSTRACT: Emerging influenza viruses pose a serious risk to global human health. Recent studies in ferrets, macaques and humans suggest that seasonal H1N1 (sH1N1) infection provides some cross-protection against 2009 pandemic influenza viruses (H1N1pdm) but the correlates of cross-protection are poorly understood. Here we show that seasonal infection of influenza-naive Indian rhesus macaques (Macaca mulatta) with A/Kawasaki/173/2001 (K173; sH1N1) virus induces antibodies capable of binding the haemagglutinin (HA) of both the homologous seasonal virus and the antigenically divergent A/California/04/2009 (CA/04; H1N1pdm) strain, in the absence of detectable H1N1pdm-specific neutralizing antibodies. These influenza-specific antibodies activated macaque NK cells to express both CD107a and IFN-γ in the presence of HA proteins from either sH1N1 or H1N1pdm viruses. Although, influenza-specific ADCC mediated NK cell activation diminished in titre over time following sH1N1 infection, they rapidly expanded within 7 days following H1N1pdm exposure. Further, we found that influenza-specific ADCC was present in broncho-alveolar lavage fluid and able to activate lung NK cells. We conclude that infection with a seasonal influenza virus can induce antibodies that mediate ADCC capable of recognizing divergent influenza virus strains. Cross-reactive ADCC may provide a mechanism to reduce the severity of divergent influenza virus infections.
Journal of Virology 03/2013; · 5.40 Impact Factor
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Tokiko Watanabe,
Masaki Imai,
Shinji Watanabe,
Kyoko Shinya,
Masato Hatta,
Chengjun Li,
Gabriele Neumann,
Makoto Ozawa,
Anthony Hanson,
Gongxun Zhong, [......],
Daniel Schenkman,
Kevin Brunner,
Saverio V Capuano, Jason T Weinfurter,
Anette Kilander,
Susanne G Dudman,
M Suresh,
Olav Hungnes,
Thomas C Friedrich,
Yoshihiro Kawaoka
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ABSTRACT: The first influenza pandemic of the 21st century was caused by novel H1N1 viruses that emerged in early 2009. Molecular evolutionary analyses of the 2009 pandemic influenza A H1N1 [A(H1N1)pdm09] virus revealed two major clusters, cluster I and cluster II. Although the pathogenicity of viruses belonging to cluster I, which became extinct by the end of 2009, has been examined in a nonhuman primate model, the pathogenic potential of viruses belonging to cluster II, which has spread more widely in the world, has not been studied in this animal model. Here, we characterized two Norwegian isolates belonging to cluster II, namely, A/Norway/3568/2009 (Norway3568) and A/Norway/3487-2/2009 (Norway3487), which caused distinct clinical symptoms, despite their genetic similarity. We observed more efficient replication in cultured cells and delayed virus clearance from ferret respiratory organs for Norway3487 virus, which was isolated from a severe case, compared with the efficiency of replication and time of clearance of Norway3568 virus, which was isolated from a mild case. Moreover, Norway3487 virus to some extent caused more severe lung damage in nonhuman primates than did Norway3568 virus. Our data suggest that the distinct replicative and pathogenic potentials of these two viruses may result from differences in their biological properties (e.g., the receptor-binding specificity of hemagglutinin and viral polymerase activity).
Journal of Virology 06/2012; 86(17):9361-8. · 5.40 Impact Factor
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Melisa L Budde,
Justin M Greene,
Emily N Chin,
Adam J Ericsen,
Matthew Scarlotta,
Brian T Cain,
Ngoc H Pham,
Ericka A Becker,
Max Harris, Jason T Weinfurter,
Shelby L O'Connor,
Michael Piatak,
Jeffrey D Lifson,
Emma Gostick,
David A Price,
Thomas C Friedrich,
David H O'Connor
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ABSTRACT: Specific major histocompatibility complex (MHC) class I alleles are associated with an increased frequency of spontaneous control of human and simian immunodeficiency viruses (HIV and SIV). The mechanism of control is thought to involve MHC class I-restricted CD8(+) T cells, but it is not clear whether particular CD8(+) T cell responses or a broad repertoire of epitope-specific CD8(+) T cell populations (termed T cell breadth) are principally responsible for mediating immunologic control. To test the hypothesis that heterozygous macaques control SIV replication as a function of superior T cell breadth, we infected MHC-homozygous and MHC-heterozygous cynomolgus macaques with the pathogenic virus SIVmac239. As measured by a gamma interferon enzyme-linked immunosorbent spot assay (IFN-γ ELISPOT) using blood, T cell breadth did not differ significantly between homozygotes and heterozygotes. Surprisingly, macaques that controlled SIV replication, regardless of their MHC zygosity, shared durable T cell responses against similar regions of Nef. While the limited genetic variability in these animals prevents us from making generalizations about the importance of Nef-specific T cell responses in controlling HIV, these results suggest that the T cell-mediated control of virus replication that we observed is more likely the consequence of targeting specificity rather than T cell breadth.
Journal of Virology 05/2012; 86(14):7596-604. · 5.40 Impact Factor
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Shelby L O'Connor,
Ericka A Becker, Jason T Weinfurter,
Emily N Chin,
Melisa L Budde,
Emma Gostick,
Michael Correll,
Michael Gleicher,
Austin L Hughes,
David A Price,
Thomas C Friedrich,
David H O'Connor
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ABSTRACT: CD8+ T cell responses rapidly select viral variants during acute human immunodeficiency virus (HIV)/simian immunodeficiency virus (SIV) infection. We used pyrosequencing to examine variation within three SIV-derived epitopes (Gag₃₈₆₋₃₉₄GW9, Nef₁₀₃₋₁₁₁RM9, and Rev₅₉₋₆₈SP10) targeted by immunodominant CD8+ T cell responses in acutely infected Mauritian cynomolgus macaques. In animals recognizing all three epitopes, variation within Rev₅₉₋₆₈SP10 was associated with delayed accumulation of variants in Gag₃₈₆₋₃₉₄GW9 but had no effect on variation within Nef₁₀₃₋₁₁₁RM9. This demonstrates that the entire T cell repertoire, rather than a single T cell population, influences the timing of immune escape, thereby providing the first example of conditional CD8+ T cell escape in HIV/SIV infection.
Journal of Virology 01/2012; 86(1):605-9. · 5.40 Impact Factor
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ABSTRACT: In mouse models of influenza, T cells can confer broad protection against multiple viral subtypes when antibodies raised against a single subtype fail to do so. However, the role of T cells in protecting humans against influenza remains unclear. Here we employ a translational nonhuman primate model to show that cross-reactive T cell responses play an important role in early clearance of infection with 2009 pandemic H1N1 influenza virus (H1N1pdm). To "prime" cellular immunity, we first infected 5 rhesus macaques with a seasonal human H1N1 isolate. These animals made detectable cellular and antibody responses against the seasonal H1N1 isolate but had no neutralizing antibodies against H1N1pdm. Four months later, we challenged the 5 "primed" animals and 7 naive controls with H1N1pdm. In naive animals, CD8+ T cells with an activated phenotype (Ki-67+ CD38+) appeared in blood and lung 5-7 days post inoculation (p.i.) with H1N1pdm and reached peak magnitude 7-10 days p.i. In contrast, activated T cells were recruited to the lung as early as 2 days p.i. in "primed" animals, and reached peak frequencies in blood and lung 4-7 days p.i. Interferon (IFN)-γ Elispot and intracellular cytokine staining assays showed that the virus-specific response peaked earlier and reached a higher magnitude in "primed" animals than in naive animals. This response involved both CD4+ and CD8+ T cells. Strikingly, "primed" animals cleared H1N1pdm infection significantly earlier from the upper and lower respiratory tract than the naive animals did, and before the appearance of H1N1pdm-specific neutralizing antibodies. Together, our results suggest that cross-reactive T cell responses can mediate early clearance of an antigenically novel influenza virus in primates. Vaccines capable of inducing such cross-reactive T cells may help protect humans against severe disease caused by newly emerging pandemic influenza viruses.
PLoS Pathogens 11/2011; 7(11):e1002381. · 9.13 Impact Factor
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Tokiko Watanabe,
Kyoko Shinya,
Shinji Watanabe,
Masaki Imai,
Masato Hatta,
Chengjun Li,
Ben F Wolter,
Gabriele Neumann,
Anthony Hanson,
Makoto Ozawa, [......],
Akiko Makino,
Emily A Travanty,
Jieru Wang,
Anette Kilander,
Susanne G Dudman,
M Suresh,
Robert J Mason,
Olav Hungnes,
Thomas C Friedrich,
Yoshihiro Kawaoka
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ABSTRACT: The first influenza pandemic of the 21st century was caused by novel H1N1 viruses that emerged in early 2009. An Asp-to-Gly change at position 222 of the receptor-binding protein hemagglutinin (HA) correlates with more-severe infections in humans. The amino acid at position 222 of HA contributes to receptor-binding specificity with Asp (typically found in human influenza viruses) and Gly (typically found in avian and classic H1N1 swine influenza viruses), conferring binding to human- and avian-type receptors, respectively. Here, we asked whether binding to avian-type receptors enhances influenza virus pathogenicity. We tested two 2009 pandemic H1N1 viruses possessing HA-222G (isolated from severe cases) and two viruses that possessed HA-222D. In glycan arrays, viruses possessing HA-222D preferentially bound to human-type receptors, while those encoding HA-222G bound to both avian- and human-type receptors. This difference in receptor binding correlated with efficient infection of viruses possessing HA-222G, compared to those possessing HA-222D, in human lung tissue, including alveolar type II pneumocytes, which express avian-type receptors. In a nonhuman primate model, infection with one of the viruses possessing HA-222G caused lung damage more severe than did infection with a virus encoding HA-222D, although these pathological differences were not observed for the other virus pair with either HA-222G or HA-222D. These data demonstrate that the acquisition of avian-type receptor-binding specificity may result in more-efficient infection of human alveolar type II pneumocytes and thus more-severe lung damage. Collectively, these findings suggest a new mechanism by which influenza viruses may become more pathogenic in mammals, including humans.
Journal of Virology 09/2011; 85(24):13195-203. · 5.40 Impact Factor
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Jason T Weinfurter,
Gemma E May,
Taeko Soma,
Ann J Hessell,
Enrique J León,
Caitlin E Macnair,
Shari M Piaskowski,
Kim Weisgrau,
Jessica Furlott,
Nicholas J Maness,
Jason Reed,
Nancy A Wilson,
Eva G Rakasz,
Dennis R Burton,
Thomas C Friedrich
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ABSTRACT: Human immunodeficiency virus (HIV)-positive individuals can be superinfected with different virus strains. Individuals who control an initial HIV infection are therefore still at risk for subsequent infection with divergent viruses, but the barriers to such superinfection remain unclear. Here we tested long-term nonprogressors' (LTNPs') susceptibility to superinfection using Indian rhesus macaques that express the major histocompatibility complex class I (MHC-I) allele Mamu-B 17, which is associated with control of the pathogenic AIDS virus SIVmac239. The Mamu-B 17-restricted CD8(+) T cell repertoire is focused almost entirely on 5 epitopes. We engineered a series of SIVmac239 variants bearing mutations in 3, 4, or all 5 of these epitopes and used them to serially challenge 2 Mamu-B 17-positive LTNPs. None of the escape variants caused breakthrough replication in LTNPs, although they readily infected Mamu-B 17-negative naive macaques. In vitro competing coculture assays and examination of viral evolution in hosts lacking Mamu-B 17 suggested that the mutant viruses had negligible defects in replicative fitness. Both LTNPs maintained robust immune responses, including simian immunodeficiency virus (SIV)-specific CD8(+) and CD4(+) T cells and neutralizing antibodies. Our results suggest that escape mutations in epitopes bound by "protective" MHC-I molecules may not be sufficient to establish superinfection in LTNPs.
Journal of Virology 10/2010; 85(1):530-41. · 5.40 Impact Factor
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Laura E Valentine,
John T Loffredo,
Alex T Bean,
Enrique J León,
Caitlin E MacNair,
Dominic R Beal,
Shari M Piaskowski,
Yann C Klimentidis,
Simon M Lank,
Roger W Wiseman, Jason T Weinfurter,
Gemma E May,
Eva G Rakasz,
Nancy A Wilson,
Thomas C Friedrich,
David H O'Connor,
David B Allison,
David I Watkins
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ABSTRACT: An understanding of the mechanism(s) by which some individuals spontaneously control human immunodeficiency virus (HIV)/simian immunodeficiency virus replication may aid vaccine design. Approximately 50% of Indian rhesus macaques that express the major histocompatibility complex (MHC) class I allele Mamu-B*08 become elite controllers after infection with simian immunodeficiency virus SIVmac239. Mamu-B*08 has a binding motif that is very similar to that of HLA-B27, a human MHC class I allele associated with the elite control of HIV, suggesting that SIVmac239-infected Mamu-B*08-positive (Mamu-B*08+) animals may be a good model for the elite control of HIV. The association with MHC class I alleles implicates CD8+ T cells and/or natural killer cells in the control of viral replication. We therefore introduced point mutations into eight Mamu-B*08-restricted CD8+ T-cell epitopes to investigate the contribution of epitope-specific CD8+ T-cell responses to the development of the control of viral replication. Ten Mamu-B*08+ macaques were infected with this mutant virus, 8X-SIVmac239. We compared immune responses and viral loads of these animals to those of wild-type SIVmac239-infected Mamu-B*08+ macaques. The five most immunodominant Mamu-B*08-restricted CD8+ T-cell responses were barely detectable in 8X-SIVmac239-infected animals. By 48 weeks postinfection, 2 of 10 8X-SIVmac239-infected Mamu-B*08+ animals controlled viral replication to <20,000 viral RNA (vRNA) copy equivalents (eq)/ml plasma, while 10 of 15 wild-type-infected Mamu-B*08+ animals had viral loads of <20,000 vRNA copy eq/ml (P = 0.04). Our results suggest that these epitope-specific CD8+ T-cell responses may play a role in establishing the control of viral replication in Mamu-B*08+ macaques.
Journal of Virology 09/2009; 83(22):11514-27. · 5.40 Impact Factor
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Matthew R Reynolds,
Andrea M Weiler,
Kim L Weisgrau,
Shari M Piaskowski,
Jessica R Furlott, Jason T Weinfurter,
Masahiko Kaizu,
Taeko Soma,
Enrique J León,
Caitlin MacNair, [......],
David A Price,
Thomas C Friedrich,
Eva G Rakasz,
Nancy A Wilson,
Adrian B McDermott,
Rosanne Boyle,
David B Allison,
Dennis R Burton,
Wayne C Koff,
David I Watkins
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ABSTRACT: An effective AIDS vaccine will need to protect against globally diverse isolates of HIV. To address this issue in macaques, we administered a live-attenuated simian immunodeficiency virus (SIV) vaccine and challenged with a highly pathogenic heterologous isolate. Vaccinees reduced viral replication by approximately 2 logs between weeks 2-32 (P < or = 0.049) postchallenge. Remarkably, vaccinees expressing MHC-I (MHC class I) alleles previously associated with viral control completely suppressed acute phase replication of the challenge virus, implicating CD8(+) T cells in this control. Furthermore, transient depletion of peripheral CD8(+) lymphocytes in four vaccinees during the chronic phase resulted in an increase in virus replication. In two of these animals, the recrudescent virus population contained only the vaccine strain and not the challenge virus. Alarmingly, however, we found evidence of recombinant viruses emerging in some of the vaccinated animals. This finding argues strongly against an attenuated virus vaccine as a solution to the AIDS epidemic. On a more positive note, our results suggest that MHC-I-restricted CD8(+) T cells contribute to the protection induced by the live-attenuated SIV vaccine and demonstrate that vaccine-induced CD8(+) T cell responses can control replication of heterologous challenge viruses.
Journal of Experimental Medicine 10/2008; 205(11):2537-50. · 13.85 Impact Factor
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David H O'Connor,
Bianca R Mothe, Jason T Weinfurter,
Sarah Fuenger,
William M Rehrauer,
Peicheng Jing,
Richard R Rudersdorf,
Max E Liebl,
Kendall Krebs,
Joshua Vasquez, [......],
Chenxi Wang,
G G Doxiadis,
David C Montefiori,
Austin Hughes,
Dennis R Burton,
David B Allison,
Steven M Wolinsky,
Ronald Bontrop,
Louis J Picker,
David I Watkins
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ABSTRACT: Certain major histocompatibility complex class I (MHC-I) alleles are associated with delayed disease progression in individuals infected with human immunodeficiency virus (HIV) and in macaques infected with simian immunodeficiency virus (SIV). However, little is known about the influence of these MHC alleles on acute-phase cellular immune responses. Here we follow 51 animals infected with SIV(mac)239 and demonstrate a dramatic association between Mamu-A*01 and -B*17 expression and slowed disease progression. We show that the dominant acute-phase cytotoxic T lymphocyte (CTL) responses in animals expressing these alleles are largely directed against two epitopes restricted by Mamu-A*01 and one epitope restricted by Mamu-B*17. One Mamu-A*01-restricted response (Tat(28-35)SL8) and the Mamu-B*17-restricted response (Nef(165-173)IW9) typically select for viral escape variants in early SIV(mac)239 infection. Interestingly, animals expressing Mamu-A*1 and -B*17 have less variation in the Tat(28-35)SL8 epitope during chronic infection than animals that express only Mamu-A*01. Our results show that MHC-I alleles that are associated with slow progression to AIDS bind epitopes recognized by dominant CTL responses during acute infection and underscore the importance of understanding CTL responses during primary HIV infection.
Journal of Virology 09/2003; 77(16):9029-40. · 5.40 Impact Factor
