Is nectin-1 the “master” receptor for deadly herpes B virus infection?

The family Herpesviridae is a large, diverse family of double-stranded enveloped DNA viruses. Herpes B virus (BV) and Cercopithecine herpesvirus 2 (CeHV-2) are simian herpesvi-ruses. Like herpes simplex virus 1 (HSV-1), they belong to the a-herpesvirus subfamily. interest in BV infections results from the observation that zoonotic infections often result in death of humans, whereas infection of macaques, the natural host of BV, results in disease similar to that observed on HSV infections of humans. We recently reported in cell-cell fusion assays in which nectin-1, a HSV-1 gD receptor, mediated fusion of cells expressing glycoproteins from both BV and CeHV-2. However, HVEM, another HSV-1 gD receptor, did not mediate fusion by BV and CeHV-2 glycoproteins. Paired immunoglobulin-like type 2 receptor a (PiLRa), an HSV-1 gB fusion receptor, did not mediate fusion with BV or CeHV-2 glycopro-teins. These results were further confirmed by BV infection. Our results may indicate that differential receptor usage by BV in humans when compared with macaques may have pathological consequences. Understanding human and simian receptor usage for BV and HSV may provide clues to understand the pathogenesis of these viruses, as well as related viruses, in their natural host as well zoonotic infections. This broader understanding may result in the development of novel therapeutics to control deadly BV infections as well as herpesvirus infections in general. Herpes B virus (BV, officially named as Macacine herpesvirus 1, formerly Herpesvirus simiae, monkey B virus, or Cercopithecine her-pesvirus 1) and Cercopithecine herpesvirus 2 (CeHV-2, formerly simian agent 8) are primate herpesviruses belonging to the a-herpesvirus subfamily and are closely related to herpes simplex virus 1 (HSV-1) and HSV-2. HSV causes recurrent mucocutaneous lesions on the mouth, face, or genitalia and in rare cases can cause meningitis or encephalitis. BV naturally infects macaques whereas zoonotic infections of foreign hosts, such as humans, can result in encephalitis, encephalomyelitis and death. BV infection has high mortality in humans (greater than 50% in documented infections) and as such is recognized as a deadly virus for humans requiring biosafety level 4. Similarly to the high level of pathogenicity of BV in humans, HSV infection of marmosets can also be fatal. CeHV-2 is a pathogen of baboons and is not known to cause disease in primates outside the natural hosts. Since the receptors for HSV are well described, we chose to explore the receptor usage of the BV and CeHV-2. HSV entry into target cells …