Newly Identified Roles of Glycoprotein C in Herpes Simplex Virus Infectivity

Tri   Komala Sari

Herpes simplex virus (HSV) infections are mainly asymptomatic, but are ubiquitous in the adult population, and can be fatal in individuals with suppressed immune systems. Prophylactic and treatment measures have not been sufficient to stop disease dissemination. HSV expresses at least 12 different glycoproteins and utilizes multiple entry pathways to infect cells. This combined with its ability to establish latent infection and evade immune responses have contributed to the challenges in developing effective control measures. HSV uses the concerted action of essential glycoproteins B, D, and H/L to execute entry. HSV carries more than a dozen surface glycoproteins, and this may pose evolutionary advantages. It is likely that HSV uses specific surface glycoprotein(s) to effectively enter one pathway, but not the other. Here we report novel roles of glycoprotein C in HSV infectivity. gB from HSV-1 fully deleted for the gC gene undergoes low-pH induced antigenic changes at a pH that is 0.4-0.6 units lower than wild type. Moreover, gC-null mutant HSV exits cellular endosomes at time points 10-20 min later than wild type, suggesting that gB present in gC-null HSV fuses with a more acidic (later) endosome. We also report for the first time, low-pH antigenic changes in domain II of HSV gB. Although gC plays a role in gB antigenic changes, its absence does not affect gB oligomeric changes nor reversibility of conformational changes under conditions tested. The threshold for reversibility of gB conformational changes in wild type and gC-null HSV is shown to be around pH 5.6. This suggests that at this pH gB exists at an equilibrium of pre- and post-fusion forms. We also tested the ability of gB antibodies to block HSV infectivity in the absence of gC. We found that gC-null HSV is significantly more sensitive to neutralization by gB antibodies. The level and composition of HSV glycoproteins in wild type and gC-null mutant are similar. Interestingly, reactivity of gB antibodies with gC-null virus is greater than wild type. Control gE-null HSV is not more sensitive to neutralization by gB antibodies. Together our results demonstrate newly identified functional interactions between HSV gC and gB.

Newly Identified Roles of Glycoprotein C in Herpes Simplex Virus Infectivity

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