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Screening And Identification Of Monoclonal Antibodies Against Glycoproteins Of Herpes Simplex Virus And Evaluation Of Theirs Neutralizing Effect

Posted on:2020-06-20Degree:MasterType:Thesis
Country:ChinaCandidate:Y D ZouFull Text:PDF
GTID:2370330572982554Subject:Public Health
Abstract/Summary:PDF Full Text Request
Herpes simplex virus(HSV),which is also known as human herpesvirus(HHV),is extensively spreading and will spread constantly across the wrold.HSV belongs to the herpesvirus family,alphaherpesvirinae subfamily and routinely infects humans HSV can be devided into two virus species:type 1 and type 2 herpes simplex virus(HSV-1 and HSV-2).According to the WHO,more than 3.7 billion people aged 0 to 49 were infected with HSV-1,and 417 million people aged 15 to 49 were infected with HSV-2 in 2012Once establishing infection in host cells,HSV can invade different types of tissues and organs of patients,causing disease mild to severe.HSV-1 can cause herpes labialis and eye diseases such as conjunctivitis and keratitis in patients and is also one of the leading pathology of blindness.Considering the neurotropic nature of HSV-1,infection with the virus may cause encephalitis.Genital herpes are mainly caused by HSV-2.The virus can establish latency in the patient's trigeminal ganglion or sacral nerve root ganglia,causing repeated genital lesion.During acquisition or reactivation,systemic complications such as pneumonitis and hepatitis may occur,expecially among patients with AIDS or organ transplantation,whose T cell immunity is fragle.During childbirth,newborns can be infected with HSV-2 from their mothers.And the infection can results in high mortality(>80%)and morbidity when untreated.Furthermore,epidemiological studies have revealed recently that the risk of HIV infection can be increased dramatically by HSV-2The interaction of viral glycoproteins,such as gB,gC,gD,gH and gL.with the cell receptors,namely HVEM,nectin-1/2 and 3-O-HS are required during initial entry and subsequent spread of HSV Specifically,the attachment of HSV to the host cell surface is a charge-based process,by which gB and gC can bind reversibly with HSPG and CSPG expressed on cell surface.The attachment lays a foundation for virus to surf on the cell surface and bind to receptors with gD.Once binding to the relevant receptors,gD undergoes conformational changes.The step is the core in activating the profusion glycoprotein such as gH/gL and gB.All the reactions ultimately lead to the fusion of cell membrane and the entry of the virusThe prevalence of HSV has caused mild to severe disease globally and is often associated with economic losses.The current antiviral treatments are far from meeting the medical demand of patients,so it is urgent to develop related vaccines and new therapeutic drugs.Monoclonal antibodies(mAbs)are important tools for studying the function and structure of target proteins,and the interaction between viruses and hosts Moreover,mAbs can also be developed into promising therapeutic drugs.Considering the important roles of HSV envelope glycoproteins in viral replication and infection,screening corresponding neutralizing antibodies against HSV envelope glycoproteins have a good theoretical basisThis study aims to screen mAbs with cross-neutralizing activity against HSV-1/2 and to evaluate the neutralizing effect of the mAbs in vitro and in vivo.And an exploratory investigation of the neutralization mechanism of the mAbs will be done sequentially.For this purpose,the following work was carried out:Firstly,14 mAbs against HSV envelope glycoprotein were screened.In subsequent experiments we demonstrated that two of these mAbs,which can recognize the native form of gD,have high levels of cross-neutralizing activity.In vitro,the mAbs can abrogated cell-to-cell spread of HSV-1/2 completely,and interfere the attachment between HSV-2 and host cells.In vivo,the neutralizing antibody also demonstrated good protective effects in HSV-2 infected BALB/C mouse.Finally,the study also investigated the specific epitope recognized by the mAbsTaken together,all the works of this study porve that the neutralizing antibodies 4A3 and 8H2 which recognize the native form of gD have significant cross-neutralizing activity against HSV-1/2 in vitro.It was also demonstrated that neutralizing antibody 4A3 had a good protective effect on BALB/C mice challenged with lethal dose of HSV-2.The two neutralizing antibodies screened in this study have the potential value of clinical transformation.In addition,the study also throws a light on the development of vaccine design in the filed of HSV treament.
Keywords/Search Tags:HSV, envelope glycoprotein, neutralizing antibody, gD, antibody therapy
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