Anti-glycoprotein D antibodies that permit adsorption but block infection by herpes simplex virus 1 prevent virion-cell fusion at the cell surface.

Abstract

Certain monoclonal antibodies specific for glycoprotein D of herpes simplex virus have potent neutralizing activity but fail to block attachment of virus to cells. Here we have investigated the fate of neutralized and infectious virus after attachment to primate cells. Infectious virions fused with the cell surface such that naked nucleocapsids were detectable in the cytoplasm near or just under the plasma membrane. Neutralized virions did not fuse with the cell. They remained attached to the cell surface and could be rendered infectious by treatment with polyethylene glycol. We conclude that some anti-glycoprotein D neutralizing antibodies can inhibit the penetration of herpes simplex virus by blocking fusion of the virion envelope with the plasma membrane. These results identify a pathway of entry that initiates successful herpes simplex virus infection and a step in this pathway that is highly sensitive to neutralizing antibodies. A role for glycoprotein D in virion-cell fusion is indicated.Investigation of the mechanisms by which antibodies neutralize viral infectivity can provide information about route of entry of the virus into a cell as well as identify steps in the infectious process that can be blocked by antibodies. For enveloped viruses, entry leading to successful infection requires attachment to the cell and penetration of the nucleocapsid into the cytoplasm by fusion of the virion envelope with a cell membrane. In some instances, endocytosis of the virion may be a prerequisite for this membrane fusion, so that nucleocapsid penetration occurs by fusion of the virion envelope with the membrane of an endosome. The low pH of endosomes may be required to trigger the fusion activity (see ref. 1 for review).For other enveloped viruses, nucleocapsid penetration by fusion of the virion envelope directly with the plasma membrane has been observed by EM (2-5). It is difficult to prove, however, that such events observed by EM actually lead to viral gene expression and a replicative cycle. Here we provide evidence that fusion of herpes simplex virus (HSV) with the plasma membrane of human and monkey cells is relevant to infection. We found that fusion of HSV with the cell surface (but not virus attachment) is blocked by certain neutralizing monoclonal antibodies (mAbs).More than six membrane glycoproteins are present in the envelope of HSV, the causative agent of oral and genital herpetic lesions and, more rarely, systemic infection and encephalitis. Antibodies capable of neutralizing HSV infectivity in the absence of complement are specific for one of several glycoproteins, including gB, gD, and gH (see ref. 6 for review). Other HSV envelope glycoproteins seem not to be targets of complement-independent neutralizing antibodies.We have previously characterized eight mAbs specific for gD (Table 1). These mAbs fall into two groups-those that neutralize infectivity at relatively low concentrations without inhibiting virion adsorption to cells (first five listed) and those that neutralize and inhibit viri...

Characterization of neutralizing monoclonal antibodies to murine cytomegalovirus

“…With the exception of high concentrations of AC1 all MAbs, regardless of neutralizing capacity, were unable to prevent the adsorption of MCMV, a phenomenon that has been observed in other virus systems, including influenza virus (Dimmock, 1984;Possee & Dimmock, 1981), rabies virus (Dietzschold et al, 1987) and herpes simplex virus type 1 (Fuller & Spear, 1987). Our results suggest that MCMV that has been neutralized by antibody can still adsorb to the cell membrane, although infection does not ensue.…”

Binding of herpes simplex virus to cellular heparan sulphate, an initial step in the adsorption process

“…Binding to the cell, and fusion of the viral envelope and the plasma membrane of the cell by which penetration is accomplished (Fuller & Spear, 1987;Lycke et al, 1988;Morgan et al, 1968), includes activities of glycoproteins B, C, D and H (Cai et al, 1988;Campadelli-Fiume et al, 1990;Desai et al, 1988;Kfihn et al, 1990;Ligas & Johnsson, 1988;Muggeridge et al, 1990), but it has not been established whether and how the glycoproteins interact and whether nonglycosylated envelope proteins are involved also in the attachment of the virion to the plasma membrane (Langeland et al, 1990;Spear, 1985).…”

Inhibiting the Arp2/3 Complex Limits Infection of Both Intracellular Mature Vaccinia Virus and Primate Lentiviruses

“…In support of this, enveloped viruses (HSV-1, MLV, and VSV-G HIV-1) were able to infect GFP-VCA-positive cells as efficient as GFP-positive cells ( Figures 1E and 2B). In particular, when HSV-1 and ampho MLV enter cells, like HIV-1, the membrane fusion takes place at the cell surface (Fuller and Spear, 1987;McClure et al, 1990;Wittels and Spear, 1991;Nussbaum et al, 1993). These data indicated that the virus-cell membrane fusion was not inhibited by GFP-VCA.…”