Sialic Acid on Herpes Simplex Virus Type 1 Envelope Glycoproteins Is Required for Efficient Infection of Cells

Abstract

Herpes simplex virus type 1 (HSV-1) envelope proteins are posttranslationally modified by the addition of sialic acids to the termini of the glycan side chains. Although gC, gD, and gH are sialylated, it is not known whether sialic acids on these envelope proteins are functionally important. Digestion of sucrose gradient purified virions for 4 h with neuraminidases that remove both ␣2,3 and ␣2,6 linked sialic acids reduced titers by 1,000-fold. Digestion with a ␣2,3-specific neuraminidase had no effect, suggesting that ␣2,6-linked sialic acids are required for infection. Lectins specific for either ␣2,3 or ␣2,6 linkages blocked attachment and infection to the same extent. In addition, the mobility of gH, gB, and gD in sodium dodecyl sulfate-polyacrylamide gel electrophoresis gels was altered by digestion with either ␣2,3 specific neuraminidase or nonspecific neuraminidases, indicating the presence of both linkages on these proteins. The infectivity of a gC-1-null virus, ⌬gC2-3, was reduced to the same extent as wild-type virus after neuraminidase digestion, and attachment was not altered. Neuraminidase digestion of virions resulted in reduced VP16 translocation to the nucleus, suggesting that the block occurred between attachment and entry. These results show for the first time that sialic acids on HSV-1 virions play an important role in infection and suggest that targeting virion sialic acids may be a valid antiviral drug development strategy.Herpes simplex virus type 1 (HSV-1) is a widespread human pathogen with 70 to 90% of the adults in the United States testing seropositive for the virus (92). The most common manifestation is mucous membrane infection resulting in ulcerative lesions that are usually self-limiting in immunocompetent individuals. However, serious illnesses, including lethal neonatal HSV, encephalitis, and blinding keratitis, can occur (43,49,83,92). Primary and recurrent infections in the immunocompromised, such as transplant recipients, those on chemotherapy, or those infected with human immunodeficiency virus (HIV) can be life-threatening (64,80,94). A number of antivirals are approved for HSV-1 treatment (21, 39, 60), but they are not completely effective. One significant problem in dealing with HSV infections is the ability of the virus to persist in the host as a latent infection (65). None of the currently available antivirals can eliminate a latent infection. Preventing the establishment of a persistent infection, which could be accomplished either by blocking infection or the establishment of latency, would be an ideal strategy for dealing with this virus.The development of agents to block HSV infection requires a greater understanding of HSV entry. Infection is initiated by the binding of viral glycoprotein C (gC) or gB to cell surface heparan sulfate proteoglycans (37,73,74). After attachment, gD can bind to any of several cellular receptors including herpes virus entry mediator, nectin-1, nectin-2, or 3-O-sulfated heparan sulfate (17,30,54,70,84), triggering a conformational change...

Differential Effects on Cell Fusion Activity of Mutations in Herpes Simplex Virus 1 Glycoprotein B (gB) Dependent on Whether a gD Receptor or a gB Receptor Is Overexpressed

“…In a previous study, sialic acid moieties on HSV-1 virion glycoproteins were shown to be required for viral infectivity (21), although the specific glycoprotein that carries the critical sialic acid was not identified. All potential sites for the addition of O-glycans to gB are located in the N-terminal region and the disordered region near the middle of the ectodomain (Fig.…”

Sialic acid-modified antigens impose tolerance via inhibition of T-cell proliferation and de novo induction of regulatory T cells

“…However, certain viruses such as herpes simplex virus (HSV)-1 and -2 adopt latency as a strategy to evade immune defense and persist in the host (32). Infections caused by these viruses are characterized by low antigen expression and a low level of CD8 + T-cell activation (33). Because high levels of sialylated antigens have been found on the envelope glycoproteins of HSV-1/-2, it can be hypothesized that sialic acids on HSV contribute to HSV immune escape by tolerizing DCs.…”

Binding of Herpes Simplex Virus Glycoprotein B (gB) to Paired Immunoglobulin-Like Type 2 Receptor α Depends on Specific Sialylated O - Linked Glycans on gB

“…HSV gB is sialylated, and sialic acids on virions play an essential role in HSV-1 infection (14). Interestingly, sialic acids on O-glycans are required for recognition of CD99 by PILR␣ (13,15).…”