scholarly journals Protective Role of Cytotoxic T Lymphocytes in Filovirus Hemorrhagic Fever

2011 ◽  
Vol 2011 ◽  
pp. 1-13 ◽  
Author(s):  
Kelly Lyn Warfield ◽  
Gene Garrard Olinger
Keyword(s):  
Animal Models ◽  
Ebola Virus ◽  
Cytotoxic T Lymphocyte ◽  
Low Frequency ◽  
Neutralizing Antibody ◽  
Hemorrhagic Fever ◽  
Protective Role ◽  
Emerging Viruses ◽  
Lethal Challenge ◽  
Ctl Responses

Infection with many emerging viruses, such as the hemorrhagic fever disease caused by the filoviruses, Marburg (MARV), and Ebola virus (EBOV), leaves the host with a short timeframe in which to mouse a protective immune response. In lethal cases, uncontrolled viral replication and virus-induced immune dysregulation are too severe to overcome, and mortality is generally associated with a lack of notable immune responses. Vaccination studies in animals have demonstrated an association of IgG and neutralizing antibody responses against the protective glycoprotein antigen with survival from lethal challenge. More recently, studies in animal models of filovirus hemorrhagic fever have established that induction of a strong filovirus-specific cytotoxic T lymphocyte (CTL) response can facilitate complete viral clearance. In this review, we describe assays used to discover CTL responses after vaccination or live filovirus infection in both animal models and human clinical trials. Unfortunately, little data regarding CTL responses have been collected from infected human survivors, primarily due to the low frequency of disease and the inability to perform these studies in the field. Advancements in assays and technologies may allow these studies to occur during future outbreaks.

scholarly journals Patterns of Immunodominance in HIV-1–specific Cytotoxic T Lymphocyte Responses in Two Human Histocompatibility Leukocyte Antigens (HLA)-identical Siblings with HLA-A*0201 Are Influenced by Epitope Mutation

1997 ◽  
Vol 185 (8) ◽  
pp. 1423-1433 ◽  
Author(s):  
P.J.R. Goulder ◽  
A.K. Sewell ◽  
D.G. Lalloo ◽  
D.A. Price ◽  
J.A. Whelan ◽  
...  
Keyword(s):  
Cytotoxic T Lymphocyte ◽  
Low Frequency ◽  
State Level ◽  
Hla Class I ◽  
Leukocyte Antigens ◽  
Immunodeficiency Virus ◽  
Lymphocyte Responses ◽  
Epitope Selection ◽  
Immunodominant Epitopes ◽  
Ctl Responses

Primary human immunodeficiency virus (HIV) infection is controlled principally by HIV-specific cytotoxic T lymphocytes (CTL) to a steady-state level of virus load, which strongly influences the ultimate rate of progression to disease. Epitope selection by CTL may be an important determinant of the degree of immune control over the virus. This report describes the CTL responses of two HLA-identical hemophiliac brothers who were exposed to identical batches of Factor VIII and became seropositive within 10 wk of one another. Both have HLA-A*0201. The CTL responses of the two siblings were very dissimilar, one donor making strong responses to two epitopes within p17 Gag (HLA-A*0201–restricted SLYNTVATL and HLA-A3–restricted RLRPGGKKK). The sibling responded to neither epitope, but made strong responses to two epitopes presented by HLA-B7. This was not the result of differences in presentation of the epitopes. However, mutations in both immunodominant epitopes of the p17 Gag responder were seen in proviral sequences of the nonresponder. We then documented the CTL responses to two HLA-A*0201–restricted epitopes, in Gag (SLYNTVATL) and Pol (ILKEPVHGV) in 22 other HIV-infected donors with HLA-A*0201. The majority (71%) generated responses to the Gag epitope. In the 29% of donors failing to respond to the Gag epitope in standard assays, there was evidence of low frequency memory CTL responses using peptide stimulation of PBMC, and most of these donors also showed mutations in or around the Gag epitope. We concluded that HLA class I genotype determines epitope selection initially but that mutation in immunodominant epitopes can profoundly alter the pattern of CTL response.

scholarly journals Nosocomial Transmission of Emerging Viruses via Aerosol-Generating Medical Procedures

Viruses ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 940 ◽  
Author(s):  
Seth D. Judson ◽  
Vincent J. Munster
Keyword(s):  
Health Care ◽  
Ebola Virus ◽  
Viral Infections ◽  
Nipah Virus ◽  
Hemorrhagic Fever ◽  
Nosocomial Transmission ◽  
Medical Procedures ◽  
Emerging Viruses ◽  
Pathogenic Viruses ◽  
Infection Control Guidelines

Recent nosocomial transmission events of emerging and re-emerging viruses, including Ebola virus, Middle East respiratory syndrome coronavirus, Nipah virus, and Crimean–Congo hemorrhagic fever orthonairovirus, have highlighted the risk of nosocomial transmission of emerging viruses in health-care settings. In particular, concerns and precautions have increased regarding the use of aerosol-generating medical procedures when treating patients with such viral infections. In spite of increasing associations between aerosol-generating medical procedures and the nosocomial transmission of viruses, we still have a poor understanding of the risks of specific procedures and viruses. In order to identify which aerosol-generating medical procedures and emerging viruses pose a high risk to health-care workers, we explore the mechanisms of aerosol-generating medical procedures, as well as the transmission pathways and characteristics of highly pathogenic viruses associated with nosocomial transmission. We then propose how research, both in clinical and experimental settings, could advance current infection control guidelines.

scholarly journals The Anamnestic Neutralizing Antibody Response Is Critical for Protection of Mice from Challenge following Vaccination with a Plasmid Encoding the Japanese Encephalitis Virus Premembrane and Envelope Genes

1999 ◽  
Vol 73 (7) ◽  
pp. 5527-5534 ◽  
Author(s):  
Eiji Konishi ◽  
Masaoki Yamaoka ◽  
Khin-Sane-Win ◽  
Ichiro Kurane ◽  
Kazuo Takada ◽  
...  
Keyword(s):  
Japanese Encephalitis ◽  
Neutralizing Antibodies ◽  
Cytotoxic T Lymphocyte ◽  
Neutralizing Antibody ◽  
Immunoglobulin M ◽  
Antibody Activity ◽  
Lethal Challenge ◽  
Challenge Virus ◽  
Coding Regions

ABSTRACT For Japanese encephalitis (JE), we previously reported that recombinant vaccine-induced protection from disease does not prevent challenge virus replication in mice. Moreover, DNA vaccines for JE can provide protection from high challenge doses in the absence of detectable prechallenge neutralizing antibodies. In the present study, we evaluated the role of postchallenge immune responses in determining the outcome of JE virus infection, using mice immunized with a plasmid, pcDNA3JEME, encoding the JE virus premembrane (prM) and envelope (E) coding regions. In the first experiment, 10 mice were vaccinated once (five animals) or twice (remainder) with 100 μg of pcDNA3JEME. All of these mice showed low (6 of 10) or undetectable (4 of 10) levels of neutralizing antibodies. Interestingly, eight of these animals showed a rapid rise in neutralizing antibody following challenge with 10,000 50% lethal doses of JE virus and survived for 21 days, whereas only one of the two remaining animals survived. No unimmunized animals exhibited a rise of neutralizing antibody or survived challenge. Levels of JE virus-specific immunoglobulin M class antibodies were elevated following challenge in half of the unimmunized mice and in the single pcDNA3JEME-immunized mouse that died. In the second experiment, JE virus-specific primary cytotoxic T-lymphocyte (CTL) activity was detected in BALB/c mice immunized once with 100 μg of pcDNA3JEME 4 days after challenge, indicating a strong postchallenge recall of CTLs. In the third experiment, evaluation of induction of CTLs and antibody activity by plasmids containing portions of the prM/E cassette demonstrated that induction of CTL responses alone were not sufficient to prevent death. Finally, we showed that antibody obtained from pcDNA3JEME-immunized mice 4 days following challenge could partially protect recipient mice from lethal challenge. Taken together, these results indicate that neutralizing antibody produced following challenge provides the critical protective component in pcDNA3JEME-vaccinated mice.

scholarly journals Long-Term Control of Simian Immunodeficiency Virus Replication with Central Memory CD4+ T-Cell Preservation after Nonsterile Protection by a Cytotoxic T-Lymphocyte-Based Vaccine

2007 ◽  
Vol 81 (10) ◽  
pp. 5202-5211 ◽  
Author(s):  
Miki Kawada ◽  
Tetsuo Tsukamoto ◽  
Hiroyuki Yamamoto ◽  
Akiko Takeda ◽  
Hiroko Igarashi ◽  
...  
Keyword(s):  
Simian Immunodeficiency Virus ◽  
T Lymphocyte ◽  
Cytotoxic T Lymphocyte ◽  
Chronic Phase ◽  
Neutralizing Antibody ◽  
Viral Control ◽  
Specific Ctls ◽  
Immunodeficiency Virus ◽  
Ctl Responses

ABSTRACT Induction of virus-specific CD8+ cytotoxic T-lymphocyte (CTL) responses is a promising strategy for AIDS vaccine development. However, it has remained unclear if or how long-term viral containment and disease control are attainable by CTL-based nonsterile protection. Here, we present three rhesus macaques that successfully maintained Env-independent vaccine-based control of simian immunodeficiency virus (SIV) mac239 replication without disease progression for more than 3 years. SIV-specific neutralizing antibody induction was inefficient in these controllers. Vaccine-induced Gag-specific CTLs were crucial for the chronic as well as the primary viral control in one of them, whereas those Gag-specific CTL responses became undetectable and CTLs specific for SIV antigens other than Gag, instead, became predominant in the chronic phase in the other two controllers. A transient CD8+ cell depletion experiment 3 years postinfection resulted in transient reappearance of plasma viremia in these two animals, suggesting involvement of the SIV non-Gag-specific CTLs in the chronic SIV control. This sustained, neutralizing antibody-independent viral control was accompanied with preservation of central memory CD4+ T cells in the chronic phase. Our results suggest that prophylactic CTL vaccine-based nonsterile protection can result in long-term viral containment by adapted CTL responses for AIDS prevention.

scholarly journals Kinetic Analysis of the Specific Host Response to a Murine Gammaherpesvirus

1998 ◽  
Vol 72 (2) ◽  
pp. 943-949 ◽  
Author(s):  
Philip G. Stevenson ◽  
Peter C. Doherty
Keyword(s):  
Lymph Nodes ◽  
Cell Activation ◽  
Cytotoxic T Lymphocyte ◽  
Low Frequency ◽  
Neutralizing Antibody ◽  
Total Serum ◽  
Enzyme Linked Immunosorbent Assay ◽  
B Cell Activation ◽  
Murine Gammaherpesvirus ◽  
Gammaherpesvirus 68

ABSTRACT Respiratory infection of BALB/c mice with the murine gammaherpesvirus 68 (MHV-68) induces the clonal expansion of virus-specific cytotoxic T-lymphocyte (CTL) precursors (CTLp) in the regional, mediastinal lymph nodes (MLN). Some of these CTLps differentiate to become fully functional CTL effectors, which can be detected in both the lymphoid tissue and in the site of pathology in the lung. Though the lymph nodes and spleen harbor substantial populations of latently infected B cells for life, the level of virus-specific CTL activity decreases rapidly in all sites. The CD8+ CTLp numbers fall to background levels in the MLN within several months of the termination of the productive phase of MHV-68 infection in the respiratory epithelium but are maintained at relatively low frequency in the spleen. The continued presence of a gamma interferon-producing, MHV-68-specific CD4+ set can also be demonstrated in cultured spleen cells. The virus-specific immunoglobulin G (IgG) response is slow to develop, with serum neutralizing antibody and enzyme-linked immunosorbent assay titers continuing to rise for several months. The level of total serum IgG increases dramatically within 2 weeks of infection, probably as a consequence of polyclonal B-cell activation, and remains high. The immune response profile is clearly influenced by the persistence of this DNA virus.

scholarly journals DNA Immunization with Minigenes: Low Frequency of Memory Cytotoxic T Lymphocytes and Inefficient Antiviral Protection Are Rectified by Ubiquitination

1998 ◽  
Vol 72 (6) ◽  
pp. 5174-5181 ◽  
Author(s):  
Fernando Rodriguez ◽  
Ling Ling An ◽  
Stephanie Harkins ◽  
Jie Zhang ◽  
Masayuki Yokoyama ◽  
...  
Keyword(s):  
Cytotoxic T Lymphocyte ◽  
Low Frequency ◽  
Cellular Protein ◽  
Lytic Activity ◽  
Dna Immunization ◽  
Virus Challenge ◽  
Effector Functions ◽  
Precursor Frequency ◽  
Memory Cytotoxic T Lymphocytes ◽  
Ctl Responses

ABSTRACT Our previous studies have shown that isolated cytotoxic T lymphocyte (CTL), B-cell, and T-helper epitopes, for which we coined the term minigenes, can be effective vaccines; when expressed from recombinant vaccinia viruses, these short immunogenic sequences confer protection against a variety of viruses and bacteria. In addition, we have previously demonstrated the utility of DNA immunization using plasmids encoding full-length viral proteins. Here we combine the two approaches and evaluate the effectiveness of minigenes in DNA immunization. We find that DNA immunization with isolated minigenes primes virus-specific memory CTL responses which, 4 days following virus challenge, appear similar in magnitude to those induced by vaccines known to be protective. Surprisingly, this vigorous CTL response fails to confer protection against a normally lethal virus challenge, although the CTL appear fully functional because, along with their high lytic activity, they are similar in affinity and cytokine secretion to CTL induced by virus infection. However this DNA immunization with isolated minigenes results in a low CTL precursor frequency; only 1 in ∼40,000 T cells is epitope specific. In contrast, a plasmid encoding the same minigene sequences covalently attached to the cellular protein ubiquitin induces protective immunity and a sixfold-higher frequency of CTL precursors. Thus, we show that the most commonly employed criterion to evaluate CTL responses—the presence of lytic activity following secondary stimulation—does not invariably correlate with protection; instead, the better correlate of protection is the CTL precursor frequency. Recent observations indicate that certain effector functions are active in memory CTL and do not require prolonged stimulation. We suggest that these early effector functions of CTL, immediately following infection, are critical in controlling virus dissemination and in determining the outcome of the infection. Finally, we show that improved performance of the ubiquitinated minigenes most probably requires polyubiquitination of the fusion protein, suggesting that the enhancement results from more effective delivery of the minigene to the proteasome.

scholarly journals Favipiravir Pharmacokinetics in Nonhuman Primates and Insights for Future Efficacy Studies of Hemorrhagic Fever Viruses

2016 ◽  
Vol 61 (1) ◽  
Author(s):  
Vincent Madelain ◽  
Jérémie Guedj ◽  
France Mentré ◽  
Thi Huyen Tram Nguyen ◽  
Frédéric Jacquot ◽  
...  
Keyword(s):  
Animal Models ◽  
Nonhuman Primates ◽  
Ebola Virus ◽  
Plasma Concentrations ◽  
Elimination Rate ◽  
Hemorrhagic Fever ◽  
Large Animal ◽  
Dosing Regimens ◽  
Over Time ◽  
Efficacy Studies

ABSTRACT Favipiravir is an RNA polymerase inhibitor that showed strong antiviral efficacy in vitro and in small-animal models of several viruses responsible for hemorrhagic fever (HF), including Ebola virus. The aim of this work was to characterize the complex pharmacokinetics of favipiravir in nonhuman primates (NHPs) in order to guide future efficacy studies of favipiravir in large-animal models. Four different studies were conducted in 30 uninfected cynomolgus macaques of Chinese (n = 17) or Mauritian (n = 13) origin treated with intravenous favipiravir for 7 to 14 days with maintenance doses of 60 to 180 mg/kg of body weight twice a day (BID). A pharmacokinetic model was developed to predict the plasma concentrations obtained with different dosing regimens, and the model predictions were compared to the 50% effective concentration (EC50) of favipiravir against several viruses. Favipiravir pharmacokinetics were described by a model accounting for concentration-dependent aldehyde oxidase inhibition. The enzyme-dependent elimination rate increased over time and was higher in NHPs of Mauritian origin than in those of Chinese origin. Maintenance doses of 100 and 120 mg/kg BID in Chinese and Mauritian NHPs, respectively, are predicted to achieve median trough plasma free concentrations above the EC50 for Lassa and Marburg viruses until day 7. For Ebola virus, higher doses are required. After day 7, a 20% dose increase is needed to compensate for the increase in drug clearance over time. These results will help rationalize the choice of dosing regimens in future studies evaluating the antiviral effect of favipiravir in NHPs and support its development against a variety of HF viruses.

scholarly journals Ebola Virus Can Be Effectively Neutralized by Antibody Produced in Natural Human Infection

1999 ◽  
Vol 73 (7) ◽  
pp. 6024-6030 ◽  
Author(s):  
Toshiaki Maruyama ◽  
Luis L. Rodriguez ◽  
Peter B. Jahrling ◽  
Anthony Sanchez ◽  
Ali S. Khan ◽  
...  
Keyword(s):  
Envelope Glycoprotein ◽  
Neutralizing Antibodies ◽  
Ebola Virus ◽  
Democratic Republic Of Congo ◽  
Low Frequency ◽  
Vaccine Design ◽  
Neutralizing Antibody ◽  
Human Infection ◽  
Fab Fragment ◽  
Phage Display Libraries

ABSTRACT The activity of antibodies against filoviruses is poorly understood but has important consequences for vaccine design and passive prophylaxis. To investigate this activity, a panel of recombinant human monoclonal antibodies to Ebola virus antigens was isolated from phage display libraries constructed from RNA from donors who recovered from infection in the 1995 Ebola virus outbreak in Kikwit, Democratic Republic of Congo. Antibodies reactive with nucleoprotein (NP), envelope glycoprotein (GP), and secreted envelope glycoprotein (sGP) were characterized by immunofluorescence and radioimmunoprecipitation assays. Four antibodies reacting strongly with sGP and weakly with GP and two antibodies reacting with NP were not neutralizing. An antibody specific for GP neutralized Ebola virus to 50% at 0.4 μg/ml as the recombinant Fab fragment and to 50% at 0.3 μg/ml (90% at 2.6 μg/ml) as the corresponding whole immunoglobulin G1 molecule. The studies indicate that neutralizing antibodies are produced in infection by Ebola virus although probably at a relatively low frequency. The neutralizing antibody may be useful in vaccine design and as a prophylactic agent against Ebola virus infection.

scholarly journals Single-Injection Vaccine Protects Nonhuman Primates against Infection with Marburg Virus and Three Species of Ebola Virus

2009 ◽  
Vol 83 (14) ◽  
pp. 7296-7304 ◽  
Author(s):  
Thomas W. Geisbert ◽  
Joan B. Geisbert ◽  
Anders Leung ◽  
Kathleen M. Daddario-DiCaprio ◽  
Lisa E. Hensley ◽  
...  
Keyword(s):  
Nonhuman Primates ◽  
Ebola Virus ◽  
Single Injection ◽  
Hemorrhagic Fever ◽  
Marburg Virus ◽  
Lethal Challenge ◽  
Glycoprotein G ◽  
Unvaccinated Control ◽  
Zaire Ebolavirus ◽  
Vesicular Stomatitis

ABSTRACT The filoviruses Marburg virus and Ebola virus cause severe hemorrhagic fever with high mortality in humans and nonhuman primates. Among the most promising filovirus vaccines under development is a system based on recombinant vesicular stomatitis virus (VSV) that expresses a single filovirus glycoprotein (GP) in place of the VSV glycoprotein (G). Here, we performed a proof-of-concept study in order to determine the potential of having one single-injection vaccine capable of protecting nonhuman primates against Sudan ebolavirus (SEBOV), Zaire ebolavirus (ZEBOV), Cote d'Ivoire ebolavirus (CIEBOV), and Marburgvirus (MARV). In this study, 11 cynomolgus monkeys were vaccinated with a blended vaccine consisting of equal parts of the vaccine vectors VSVΔG/SEBOVGP, VSVΔG/ZEBOVGP, and VSVΔG/MARVGP. Four weeks later, three of these animals were challenged with MARV, three with CIEBOV, three with ZEBOV, and two with SEBOV. Three control animals were vaccinated with VSV vectors encoding a nonfilovirus GP and challenged with SEBOV, ZEBOV, and MARV, respectively, and five unvaccinated control animals were challenged with CIEBOV. Importantly, none of the macaques vaccinated with the blended vaccine succumbed to a filovirus challenge. As expected, an experimental control animal vaccinated with VSVΔG/ZEBOVGP and challenged with SEBOV succumbed, as did the positive controls challenged with SEBOV, ZEBOV, and MARV, respectively. All five control animals challenged with CIEBOV became severely ill, and three of the animals succumbed on days 12, 12, and 14, respectively. The two animals that survived CIEBOV infection were protected from subsequent challenge with either SEBOV or ZEBOV, suggesting that immunity to CIEBOV may be protective against other species of Ebola virus. In conclusion, we developed an immunization scheme based on a single-injection vaccine that protects nonhuman primates against lethal challenge with representative strains of all human pathogenic filovirus species.

scholarly journals Adenovirus Vectors Expressing Hantavirus Proteins Protect Hamsters against Lethal Challenge with Andes Virus

2009 ◽  
Vol 83 (14) ◽  
pp. 7285-7295 ◽  
Author(s):  
David Safronetz ◽  
Nagendra R. Hegde ◽  
Hideki Ebihara ◽  
Michael Denton ◽  
Gary P. Kobinger ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Cytotoxic T Lymphocyte ◽  
Clinical Signs ◽  
Hemorrhagic Fever ◽  
Lethal Challenge ◽  
Robust Immune Response ◽  
Reverse Transcription Pcr ◽  
Andes Virus ◽  
Lymphocyte Responses ◽  
Hantavirus Proteins

ABSTRACT Hantaviruses infect humans following aerosolization from rodent feces and urine, producing hemorrhagic fever with renal syndrome and hantavirus pulmonary syndrome. Due to the high rates of mortality and lack of therapies, vaccines are urgently needed. Nonreplicating adenovirus (Ad) vectors that express Andes hantavirus (ANDV) nucleocapsid protein (AdN) or glycoproteins (AdGN and AdGC) were constructed. Ad vectors were tested for their ability to protect Syrian hamsters from a lethal ANDV infection that mimics the pulmonary disease seen in humans. When administered once, all three Ad vectors, individually or in combination, elicited a robust immune response that protected hamsters. No vaccinated animal died, and there were no obvious clinical signs of disease. Further, hantavirus RNA was not detected by sensitive reverse transcription-PCR in tissues and blood of hamsters immunized with both AdGN and AdGC. Cellular immunity appeared to be important for protection because the AdN vector completely protected animals. All three Ad vectors produced strong cytotoxic T-lymphocyte responses directed to hantavirus proteins in mice. Moreover, hamsters vaccinated with AdN, AdGN, or AdGC produced no detectable neutralizing antibodies yet were protected. These Ad vectors represent the first vaccines that prevent lethal hantavirus disease and, in some instances (AdGN and AdGC), provide sterile immunity. These observations set the stage for a more detailed characterization of the types of immunity required to protect humans from hantavirus infections.

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