scholarly journals Humanization of Murine Neutralizing Antibodies against Human Herpesvirus 6B

2019 ◽  
Vol 93 (10) ◽  
Author(s):  
Bochao Wang ◽  
Mitsuhiro Nishimura ◽  
Yuji Maekawa ◽  
Toshiya Kotari ◽  
Toshiomi Okuno ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Primary Infection ◽  
Antiviral Treatment ◽  
Antiviral Agents ◽  
Human Herpesvirus ◽  
Febrile Seizures ◽  
Human Immune System ◽  
Hematopoietic Stem ◽  
Glycoprotein Complex ◽  
Humanized Antibodies

ABSTRACTExanthem subitum is a common childhood illness caused by primary infection with human herpesvirus 6B (HHV-6B). It is occasionally complicated by febrile seizures and even encephalitis. HHV-6B reactivation also causes encephalitis, especially after allogeneic hematopoietic stem cell transplantation. However, no adequate antiviral treatment for HHV-6B has yet been established. Mouse-derived monoclonal antibodies (MAbs) against the HHV-6B envelope glycoprotein complex gH/gL/gQ1/gQ2 have been shown to neutralize the viral infection. These antibodies have the potential to become antiviral agents against HHV-6B despite their inherent immunogenicity to the human immune system. Humanization of MAbs derived from other species is one of the proven solutions to such a dilemma. In this study, we constructed chimeric forms of two neutralizing MAbs against HHV-6B to make humanized antibodies. Both showed neutralizing activities equivalent to those of their original forms. This is the first report of humanized antibodies against HHV-6B and provides a basis for the further development of HHV-6B-specific antivirals.IMPORTANCEHuman herpesvirus 6B (HHV-6B) establishes lifelong latent infection in most individuals after the primary infection. Encephalitis is the most severe complication caused by both the primary infection and the reactivation of HHV-6B and is the cause of considerable mortality in patients, without any established treatments to date. The humanization of the murine neutralizing antibodies described in this research provided a feasible way to reduce the inherent immunogenicity of the antibodies without changing their neutralizing activities. These newly designed chimeric antibodies against HHV-6B have the potential to be candidates for antivirals for future use.

scholarly journals Long-term Outcomes of Patients With Human Herpesvirus 6 Encephalitis

2019 ◽  
Vol 6 (7) ◽  
Author(s):  
Madiha Fida ◽  
Ahmed M Hamdi ◽  
Alexandra Bryson ◽  
Raymund R Razonable ◽  
Omar Abu Saleh
Keyword(s):  
Stem Cell ◽  
Antiviral Treatment ◽  
Human Herpesvirus ◽  
Hematologic Malignancies ◽  
Hippocampal Atrophy ◽  
Human Herpesvirus 6 ◽  
Long Term Outcomes ◽  
Hematopoietic Stem ◽  
Human Herpesviruses

Abstract Human herpesviruses 6 (HHV-6) A and B cause encephalitis in patients with hematologic malignancies, especially those undergoing allogeneic hematopoietic stem cell transplantation. In this cohort of 10 patients, persistent neurologic deficits associated with moderate to severe bilateral hippocampal atrophy were characteristic long-term findings, despite prolonged antiviral treatment.

Human herpesvirus 6 encephalitis in a patient treated with everolimus for renal cell carcinoma

2020 ◽  
Vol 26 (8) ◽  
pp. 2052-2057
Author(s):  
Stefania Kokkali ◽  
Isabelle Oddou ◽  
Justine Gantzer ◽  
Aikaterini Fitsiori
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Antiviral Treatment ◽  
Brain Magnetic Resonance Imaging ◽  
Human Herpesvirus ◽  
Cell Transplant ◽  
Human Herpesvirus 6 ◽  
Hematopoietic Stem ◽  
Herpesvirus 6

Introduction Everolimus is a mammalian target of rapamycin inhibitor and is approved as second-line treatment or beyond for renal cell carcinoma. We report a case of a 75-year-old male treated with everolimus for metastatic renal cell carcinoma, after sunitinib treatment, who was diagnosed with human herpesvirus 6 encephalitis. Case report After 39 months of everolimus, 10 mg per day, our patient was admitted with fever, consciousness disorders and a partial epileptic crisis. Laboratory tests revealed lymphopenia (170 lymphocytes/mm3), and polymerase chain reaction in cerebrospinal fluid was positive for human herpesvirus 6. Brain magnetic resonance imaging study demonstrated hippocampal abnormality and a pontine lesion. Management and outcome The patient stopped everolimus treatment indefinitely. He received ganciclovir initially intravenously, with a rapid clinical improvement, as well as polyvalent immunoglobulins were given to correct hypogammaglobulinemia. Two months later, antiviral therapy was switched to oral ganciclovir, which was never stopped. A new lumbar puncture was performed one month after the initiation of antiviral treatment, which did not reveal human herpesvirus 6 DNA anymore. Discussion Human herpesvirus 6 encephalitis is more common in hematopoietic stem cell transplant recipients and HIV patients. This is the first case probably associated to everolimus treatment. In contrast to most patients diagnosed with this infection, who either die or develop neurologic sequelae, our patient almost fully recovered two months later.

Diverse and insidious human herpesvirus 6A/B: how to find and neutralize it?

2020 ◽  
Vol 18 (3) ◽  
pp. 190-196
Author(s):  
N.O. Mishakina ◽  
◽  
O.A. Rychkova ◽  
L.V. Khanipova ◽  
D.V. Usenko ◽  
...  
Keyword(s):  
Primary Infection ◽  
Latent Infection ◽  
Human Herpesvirus ◽  
Human Immune System ◽  
Human Herpes Virus ◽  
Human Herpes Virus 6 ◽  
Long Time ◽  
Human Immune ◽  
Convulsive Seizures ◽  
Immune Neutropenia

Herpesvirus infections are one of the most common groups of human infectious diseases. Having unique mechanisms of interaction with the human immune system, they can persist in the organism for a long time and can be reactivated by immunosuppressive factors. Human herpesvirus 6A/B (HHV-6A/B) is one of the most common but still insufficiently studied viruses affecting children. There are several variants of HHV-6 infection, including acute primary infection (primarily in young children, manifesting itself with sudden exanthema and febrile convulsive seizures), latent primary infection (manifesting itself with non-immune neutropenia), reactivation of latent infection (in children of pre-school and school age, primarily developing as respiratory infection and infectious mononucleosis), and chromosomally integrated form. This article discusses the issues of epidemiology, clinical mani-festations, diagnosis, and treatment of HHV-6A/B infection in children. Key words: herpesvirus infection, human herpes virus 6, children, diagnosis, treatment

scholarly journals Endogenously Produced SARS-CoV-2 Specific IgG Antibodies May Have a Limited Impact on Clearing Nasal Shedding of Virus during Primary Infection in Humans

Viruses ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 516
Author(s):  
Shuyi Yang ◽  
Keith R. Jerome ◽  
Alexander L. Greninger ◽  
Joshua T. Schiffer ◽  
Ashish Goyal
Keyword(s):  
Production Rate ◽  
Neutralizing Antibodies ◽  
Primary Infection ◽  
Natural Infection ◽  
Viral Clearance ◽  
Clinical Severity ◽  
Igg Antibodies ◽  
Igm Antibodies ◽  
Specific Igg ◽  
Specific Igg Antibodies

While SARS-CoV-2 specific neutralizing antibodies have been developed for therapeutic purposes, the specific viral triggers that drive the generation of SARS-CoV-2 specific IgG and IgM antibodies remain only partially characterized. Moreover, it is unknown whether endogenously derived antibodies drive viral clearance that might result in mitigation of clinical severity during natural infection. We developed a series of non-linear mathematical models to investigate whether SARS-CoV-2 viral and antibody kinetics are coupled or governed by separate processes. Patients with severe disease had a higher production rate of IgG but not IgM antibodies. Maximal levels of both isotypes were governed by their production rate rather than different saturation levels between people. Our results suggest that an exponential surge in IgG levels occurs approximately 5–10 days after symptom onset with no requirement for continual antigenic stimulation. SARS-CoV-2 specific IgG antibodies appear to have limited to no effect on viral dynamics but may enhance viral clearance late during primary infection resulting from the binding effect of antibody to virus, rather than neutralization. In conclusion, SARS-CoV-2 specific IgG antibodies may play only a limited role in clearing infection from the nasal passages despite providing long-term immunity against infection following vaccination or prior infection.

scholarly journals Neutralizing Antibody Therapeutics for COVID-19

Viruses ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 628
Author(s):  
Aeron C. Hurt ◽  
Adam K. Wheatley
Keyword(s):  
High Risk ◽  
Neutralizing Antibodies ◽  
Controlled Trial ◽  
Antiviral Treatment ◽  
Severe Disease ◽  
Neutralizing Antibody ◽  
Supplemental Oxygen ◽  
European Medicines Agency ◽  
Global Public Health ◽  
Public Health Burden

The emergence of SARS-CoV-2 and subsequent COVID-19 pandemic has resulted in a significant global public health burden, leading to an urgent need for effective therapeutic strategies. In this article, we review the role of SARS-CoV-2 neutralizing antibodies (nAbs) in the clinical management of COVID-19 and provide an overview of recent randomized controlled trial data evaluating nAbs in the ambulatory, hospitalized and prophylaxis settings. Two nAb cocktails (casirivimab/imdevimab and bamlanivimab/etesevimab) and one nAb monotherapy (bamlanivimab) have been granted Emergency Use Authorization by the US Food and Drug Administration for the treatment of ambulatory patients who have a high risk of progressing to severe disease, and the European Medicines Agency has similarly recommended both cocktails and bamlanivimab monotherapy for use in COVID-19 patients who do not require supplemental oxygen and who are at high risk of progressing to severe COVID-19. Efficacy of nAbs in hospitalized patients with COVID-19 has been varied, potentially highlighting the challenges of antiviral treatment in patients who have already progressed to severe disease. However, early data suggest a promising prophylactic role for nAbs in providing effective COVID-19 protection. We also review the risk of treatment-emergent antiviral resistant “escape” mutants and strategies to minimize their occurrence, discuss the susceptibility of newly emerging SARS-COV-2 variants to nAbs, as well as explore administration challenges and ways to improve patient access.

scholarly journals Amino Acids 1055 to 1192 in the S2 Region of Severe Acute Respiratory Syndrome Coronavirus S Protein Induce Neutralizing Antibodies: Implications for the Development of Vaccines and Antiviral Agents

2005 ◽  
Vol 79 (6) ◽  
pp. 3289-3296 ◽  
Author(s):  
Choong-Tat Keng ◽  
Aihua Zhang ◽  
Shuo Shen ◽  
Kuo-Ming Lip ◽  
Burtram C. Fielding ◽  
...  
Keyword(s):  
Amino Acids ◽  
Severe Acute Respiratory Syndrome ◽  
Viral Entry ◽  
Neutralizing Antibodies ◽  
Antiviral Agents ◽  
Host Cells ◽  
Heptad Repeat ◽  
Antigenic Determinants ◽  
Amino Acid Residues ◽  
S Protein

ABSTRACT The spike (S) protein of the severe acute respiratory syndrome coronavirus (SARS-CoV) interacts with cellular receptors to mediate membrane fusion, allowing viral entry into host cells; hence it is recognized as the primary target of neutralizing antibodies, and therefore knowledge of antigenic determinants that can elicit neutralizing antibodies could be beneficial for the development of a protective vaccine. Here, we expressed five different fragments of S, covering the entire ectodomain (amino acids 48 to 1192), as glutathione S-transferase fusion proteins in Escherichia coli and used the purified proteins to raise antibodies in rabbits. By Western blot analysis and immunoprecipitation experiments, we showed that all the antibodies are specific and highly sensitive to both the native and denatured forms of the full-length S protein expressed in virus-infected cells and transfected cells, respectively. Indirect immunofluorescence performed on fixed but unpermeabilized cells showed that these antibodies can recognize the mature form of S on the cell surface. All the antibodies were also able to detect the maturation of the 200-kDa form of S to the 210-kDa form by pulse-chase experiments. When the antibodies were tested for their ability to inhibit SARS-CoV propagation in Vero E6 culture, it was found that the anti-SΔ10 antibody, which was targeted to amino acid residues 1029 to 1192 of S, which include heptad repeat 2, has strong neutralizing activities, suggesting that this region of S carries neutralizing epitopes and is very important for virus entry into cells.

scholarly journals Real-Time PCR as a Versatile Tool for Investigating the Susceptibility of Human Herpesvirus 6 to Antiviral Agents

2003 ◽  
Vol 47 (9) ◽  
pp. 3021-3024 ◽  
Author(s):  
Muriel Macé ◽  
Chaysavanh Manichanh ◽  
Pascale Bonnafous ◽  
Stéphanie Précigout ◽  
David Boutolleau ◽  
...  
Keyword(s):  
Real Time ◽  
Real Time Pcr ◽  
Antiviral Agents ◽  
Antiviral Drug ◽  
Human Herpesvirus ◽  
Drug Susceptibility ◽  
Human Herpesvirus 6 ◽  
Versatile Tool ◽  
Herpesvirus 6

ABSTRACT A quantitative real-time PCR assay was developed for the determination of antiviral drug susceptibility and growth kinetics of human herpesvirus 6. The susceptibility and fitness of a sensitive strain, HST, and its ganciclovir-resistant derivative, GCVR1, were then characterized, leading us to conclude that the mutations of this latter virus did not alter its fitness significantly.

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