Herpes Simplex Virus Cell Entry Mechanisms: An Update

Abstract

Herpes simplex virus (HSV) can infect a broad host range and cause mild to life threating infections in humans. The surface glycoproteins of HSV are evolutionarily conserved and show an extraordinary ability to bind more than one receptor on the host cell surface. Following attachment, the virus fuses its lipid envelope with the host cell membrane and releases its nucleocapsid along with tegument proteins into the cytosol. With the help of tegument proteins and host cell factors, the nucleocapsid is then docked into the nuclear pore. The viral double stranded DNA is then released into the host cell’s nucleus. Released viral DNA either replicates rapidly (more commonly in non-neuronal cells) or stays latent inside the nucleus (in sensory neurons). The fusion of the viral envelope with host cell membrane is a key step. Blocking this step can prevent entry of HSV into the host cell and the subsequent interactions that ultimately lead to production of viral progeny and cell death or latency. In this review, we have discussed viral entry mechanisms including the pH-independent as well as pH-dependent endocytic entry, cell to cell spread of HSV and use of viral glycoproteins as an antiviral target.

The Importance of Glycans of Viral and Host Proteins in Enveloped Virus Infection

“…Herpes simplex viruses 1 (HSV-1) and herpes simplex viruses 2 (HSV-2) are globally prevalent pathogens, which often lead to recurrent oral and genital ulcers ( 42 ). HSV encodes at least 12 different glycoproteins, and at least four of them are necessary and sufficient to mediate membrane fusion when they infect target cells, namely glycoprotein B (gB), gD, gH and gL ( 43 – 45 ). Similarly, mutations of N390, N483 or N668 in total seven potential N -glycosylation sites on gB of HSV-2 can reduce the ability of cell-cell fusion and virus entry.…”

Heparan Sulfate Proteoglycans in Viral Infection and Treatment: A Special Focus on SARS-CoV-2

“…Some viruses take advantage of the electrostatic interactions between the negatively charged sulfated HS chains and the basic residues of their surface or capsid proteins to increase their concentration at the host cell surface, thus enhancing their binding to specific entry receptors [ 24 , 25 ]. Table 1 lists the viruses whose infection in the human organism is strictly dependent on their ability to bind the cell surface HSPGs [ 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 ].…”

“…At times, HSPGs may serve as viral receptors themselves [ 24 , 36 , 55 , 62 , 70 , 71 , 72 , 73 ]. This is the case for herpes simplex virus serotypes 1 and 2 (HSV-1 and HSV-2), whose viral envelope glycoproteins gB and gC bind HSPGs to promote attachment, to slide down membrane projections such as filopodia, and to reach the cell body for membrane penetration [ 73 ].…”

“…This is the case for herpes simplex virus serotypes 1 and 2 (HSV-1 and HSV-2), whose viral envelope glycoproteins gB and gC bind HSPGs to promote attachment, to slide down membrane projections such as filopodia, and to reach the cell body for membrane penetration [ 73 ]. Then the binding of gD to nectin-1 or 3- O -sulfated HS triggers conformational changes recruiting gB, gH, and gL for membrane fusion leading to capsid release in the cytoplasm [ 36 ]. Similarly, the human respiratory syncytial virus (RSV), which is characterized by three envelope proteins—the attachment glycoprotein (G), the fusion protein (F), and the small hydrophobic protein (SH)—uses its G and F proteins to interact directly with HSPGs and to infect host cells [ 62 ].…”

Synthesis and Evaluation of Some Uracil Nucleosides as Promising Anti-Herpes Simplex Virus 1 Agents

“…The target of all currently available drugs for treating herpes infections is a viral DNA polymerase [ 33 ]. Chemically, polymerase inhibitors are classified into two main groups [ 34 , 35 ]: nucleoside analogues and non-nucleoside inhibitors (pyrophosphate derivatives) [ 36 , 37 ]. Among these drugs, cidofovir is an acyclic nucleoside phosphonate approved to treat AIDS and used to treat many other DNA viral infections (e.g., HSV and the papillomavirus) [ 38 , 39 ].…”