The COMPLEXity in herpesvirus entry

Sathiyamoorthy, Karthik; Chen, Jia; Longnecker, Richard; Jardetzky, Theodore S.

doi:10.1016/j.coviro.2017.04.006

Cited by 79 publications

(70 citation statements)

References 46 publications

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“…The glycoprotein complex based on the conserved glycoprotein H (gH)-gL is known as the viral ligand. It binds to its cell receptor and then mediates membrane fusion between the viral envelope and cell membranes by cooperating with the fusion protein gB (13). In our recent research, we identified the gH/gL/gQ1/gQ2 complex as the ligand for a cellular receptor of HHV-6B, human CD134, which we had identified previously (14)(15)(16).…”

mentioning

confidence: 99%

Humanization of Murine Neutralizing Antibodies against Human Herpesvirus 6B

Wang

Nishimura

Maekawa

et al. 2019

J Virol

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Exanthem 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. IMPORTANCE Human 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. a IC 50 , half-maximal inhibitory concentration. FIG 7 Model of the possible mechanisms of neutralization by MAbs KH-1 and OHV-3. For HHV-6B entry, the gH/gL/gQ1/gQ2 glycoprotein complex, especially gQ1, binds directly to the cell receptor CD134. (A) KH-1, which interacts with gQ1, could directly inhibit receptor binding. (B) The interaction of gH with OHV-3 could affect gH function (fusion or association with gB) and thus inhibit viral entry. Humanization of Neutralizing MAbs against HHV-6B Journal of Virology May 2019 Volume 93 Issue 10 e02270-18 jvi.asm.org 7proteins by MAbs may affect their functions for entry. Further studies are required to answer these questions. MATERIALS AND METHODS Cells and viruses.Human embryonic kidney (HEK) 293T cells were cultured at 37°C under 5% CO 2 in Dulbecco's modified Eagle medium (DMEM) containing 8% fetal bovine serum, 4 mM L-glutamine, and 20 g/ml gentamicin. Serum-free CD 293 medium (Thermo Fisher Scientific) supplemented with 4 mM L-glutamine and 20 g/ml gentamicin was used after transfections. The human T-cell line MT4 was cultured in RPMI 1640 medium with 8% fetal bovine serum containing 20 g/ml gentamicin. HHV-6B strain HST was prepared as described previously (15). For virus propagation, umbilical cord blood m...

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confidence: 99%

Humanization of Murine Neutralizing Antibodies against Human Herpesvirus 6B

Wang

Nishimura

Maekawa

et al. 2019

J Virol

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“…Human CMV (HCMV) is prevalent in 60-100% of a given population [43]. Infection is established within salivary gland epithelial cells [45], and disseminates throughout the host during latency [46]. Infection is established within salivary gland epithelial cells [45], and disseminates throughout the host during latency [46].…”

Section: Herpesvirus Infectionmentioning

confidence: 99%

“…HCMV manifests a lifelong latent infection, with subclinical presentation and immune control in immunocompetent individuals [1,44]. Infection is established within salivary gland epithelial cells [45], and disseminates throughout the host during latency [46].…”

Section: Herpesvirus Infectionmentioning

confidence: 99%

HLA-E: exploiting pathogen-host interactions for vaccine development

Sharpe

Bowyer

Brackenridge

et al. 2019

Clinical and Experimental Immunology

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Summary Viruses, when used as vectors for vaccine antigen delivery, can induce strong cellular and humoral responses against target epitopes. Recent work by Hansen et al. describes the use of a cytomegalovirus‐vectored vaccine, which is able to generate a stable effector‐memory T cell population at the sites of vaccination in rhesus macaques. This vaccine, targeted towards multiple epitopes in simian immunodeficiency virus (SIV), did not induce classical CD8+ T cells. However, non‐canonical CD8+ T cell induction occurred via major histocompatibility complex (MHC) class II and MHC‐E. The MHC‐E‐restricted T cells could recognize broad epitopes across the SIV peptides, and conferred protection against viral challenge to 55% of vaccinated macaques. The human homologue, human leucocyte antigen (HLA)‐E, is now being targeted as a new avenue for vaccine development. In humans, HLA‐E is an unusually oligomorphic class Ib MHC molecule, in comparison to highly polymorphic MHC class Ia. Whereas MHC class Ia presents peptides derived from pathogens to T cells, HLA‐E classically binds defined leader peptides from class Ia MHC peptides and down‐regulates NK cell cytolytic activity when presented on the cell surface. HLA‐E can also restrict non‐canonical CD8+ T cells during natural infection with various pathogens, although the extent to which they are involved in pathogen control is mostly unknown. In this review, an overview is provided of HLA‐E and its ability to interact with NK cells and non‐canonical T cells. Also discussed are the unforeseen beneficial effects of vaccination, including trained immunity of NK cells from bacille Calmette–Guérin (BCG) vaccination, and the broad restriction of non‐canonical CD8+ T cells by cytomegalovirus (CMV)‐vectored vaccines in pre‐clinical trials.

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“…change that initiates membrane fusion [209,210]. Additional viral proteins can interact with gH/gL to form different receptor-binding complexes in each HHV [211]. In fact, in betaherpesviruses, gH/gL dimers are efficiently exposed on the virion envelope only when in complex with other viral proteins [212][213][214].…”

Section: Glmentioning

confidence: 99%

Chemokines encoded by herpesviruses

Pontejo

Murphy

2017

Journal of Leukocyte Biology

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Viruses use diverse strategies to elude the immune system, including copying and repurposing host cytokine and cytokine receptor genes. For herpesviruses, the chemokine system of chemotactic cytokines and receptors is a common source of copied genes. Here, we review the current state of knowledge about herpesvirus-encoded chemokines and discuss their possible roles in viral pathogenesis, as well as their clinical potential as novel anti-inflammatory agents or targets for new antiviral strategies.

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The COMPLEXity in herpesvirus entry

Cited by 79 publications

References 46 publications

Humanization of Murine Neutralizing Antibodies against Human Herpesvirus 6B

Humanization of Murine Neutralizing Antibodies against Human Herpesvirus 6B

HLA-E: exploiting pathogen-host interactions for vaccine development

Chemokines encoded by herpesviruses

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