Herpes Simplex Virus - The Evasion Of Early Host Antiviral Responses
Similar to varicella zoster virus (VZV), herpes simplex viruses (HSVs) type 1 (HSV-1 or human herpesvirus 1, HHV-1) and type 2 (HSV-2 or human herpesvirus 2, HHV-2) are members of the Herpesviridae family and Alphaherpesvirinae subfamily.
HSVs are very common in humans, with HSV-1 infecting two-thirds of the world population and HSV-2 infecting ~11% of the global population.
HSV-1 and HSV-2 are linked to a number of symptoms, but the severity of illness varies greatly from person to person. About 40% of people who are infected show symptoms during the first infection.
Also, most people don't have any symptoms when the virus keeps coming back. Only 5–15% of those who are infected show clinical signs of herpes simplex virus infections.
Although only a small fraction of infected people develop clinical symptoms, the large number of people infected with these viruses results in a large number of people suffering from HSV-related disorders.
At the nucleotide level, HSV-1 and HSV-2 share ~74% similarity and are structurally highly similar. Both viruses have a linear, double-stranded DNA (dsDNA) genome that is between 150 and 154 kbp in size and codes for about 70 open reading frames (ORFs).
The viral genomes are encased in a 125 nm icosahedral capsid that is encircled by a tegument made up of numerous proteins (>20). This protein layer is then surrounded by a lipid bilayer. Many viral glycoproteins stick out of the lipid bilayer and help the virus get in and out, control the immune system, and get away from the immune system.
Although HSV-1 and HSV-2 share several characteristics during cell invasion, they also vary. In contrast to HSV-1, HSV-2 does not need its glycoprotein C (gC) to connect to target cells.
However, for the virus to adhere to heparan sulfate proteoglycans on the cell surface, both of these HSVs need the viral glycoprotein B (gB). Glycoprotein B has been shown to connect to the paired immunoglobulin-like type 2 receptor (PILR) on immune cells like dendritic cells (DCs) and natural killer cells (NK cells) so that viruses can attach to them.
Once on the cell surface, the viral glycoprotein D (gD) will bind to either nectin-1 (or nectin-2) found on the surface of most anchored cells in the organism, such as epithelial and neuronal cells, or the herpesvirus entry mediator (HVEM), a member of the tumor necrosis factor receptor (TNFR) family that sends signals inside the cell depending on the orientation of its ligand, either in cis or trans.
A virus needs an infected cell to stay alive for as long as possible in order to replicate its genetic material and make its proteins.
HSVs have been shown to control cell death in more than one type of cell, either to make cells live longer so they can make more viruses or to make cells die, which could hurt their ability to replicate and shed.
For example, the HSV-1 glycoproteins J (gJ) and D (gD) have been shown to block Fas-mediated apoptosis in a neuroblastoma cell line and Jurkat cells, at least partly. Surprisingly, gJ expression alone caused more reactive oxygen species (ROS) to be made, which may lead to apoptosis in the end.
Despite evoking mechanisms that include FLICE-inhibitory protein (c-FLIP) downregulation, which is an inhibitor of caspase-8 that normally leads to cell death, HSV-1 has been shown to suppress cell apoptosis in epithelial cells.
This difference was caused by the presence of latency-associated transcript (LAT) sequences, which have been shown to stop infected neuronal cells from dying when caspase-8 is involved.
Immune cells and non-immune cells both make a lot of molecular sensors that can pick up on virus parts or infection-related signals. This speeds up the production of antiviral responses that stop viruses from spreading and multiplying.
Pathogen-associated molecular patterns (PAMPs), as well as danger signals generated in response to viral replication and known as damage-associated molecular patterns (DAMPs), are examples of stimuli that may be encountered or created during virus infection (DAMPs).
Toll-like receptors (TLRs), which comprise both cytosolic and nuclear proteins, are host receptors that detect these stimuli. When these receptors interact with ligands, signaling pathways are turned on. This leads to the expression of antiviral factors and the creation of soluble and membrane-bound molecules that change how the infected cell and nearby cells work.
The host's early identification of viral components immediately after infection will promote efficient pathogen management and impede pathogen reproduction and spread, all while likely supporting the building of protective and long-lasting immunity.
Other host receptors, such as cytosolic retinoic-acid-inducible gene-1 (RIG-1)-like receptors and a diverse class of putative DNA sensors, detect nucleic acids produced during HSV infection in addition to TLRs. Importantly, viral nucleic acids can strongly turn on host signaling pathways, which can lead to antiviral responses from cells.
Furthermore, the identification of viral nucleic acids typically results in the release of pro-inflammatory cytokines as well as the creation of IFNs, both of which inhibit viral replication and infection. Interferon-inducible protein 16 (IFI16) is a nucleic acid host sensor that has been shown to find episomal double-stranded DNA (dsDNA), which is DNA that is replicating in the nucleus of cells. This causes IFI16 to become acetylated.
Then, IFI16 moves from the nucleus to the cytoplasm, which makes the cell make more IFN-β and turns on the inflammasome, a multiprotein complex in the host that can start an inflammatory response.
Importantly, HSV-1 and HSV-2 identification by IFI16 activates the transcription factors IRF3 and NF-B, which, once translocated to the nucleus, stimulate IFN-α/β and IL-6 production in vaginal epithelial cells.
IFI16 identification of foreign DNA is most likely dependent on bare DNA sensing. IFI16 may suppress viral gene expression in human fibroblasts during HSV-1 infection by attaching nucleosomes and heterochromatin marks to the viral DNA, preventing the host transcription machinery from accessing the viral genome.
On the other hand, it has been shown that the HSV-1 ICP0 protein limits IFI16 activation in epithelial cells by sending it to the proteasome to be broken down.
Pathogen recognition receptor (PRR) activation may activate immune and non-immune cells, triggering antiviral responses that limit and interfere with virus replication.
The IFN response is a strong antiviral response produced by virus sensing. IFNs are a type of cytokine that, when attached to their receptor, may boost the ability of the cell that makes them and nearby cells to fight viruses.
IFNs are characterized as type I, type II, or type III. Type-I IFNs are a diverse family of molecules that may be released by a variety of cell types in response to pathogens such as viruses, with some well-known members being IFN-α, IFN-β, and IFN-ε, and others more recently characterized as IFN-υ, IFN-ω, and IFN-ζ. Type-II IFNs, on the other hand, contain just one family member, IFN-γ, which is released by specific subsets of immune cells late in the infection.
Finally, type-III IFNs such as IFN-λ1, IFN-λ2, and IFN-λ3 are often released early during infection and have effects comparable to those of type-I IFNs, although their production is restricted to epithelial cells.
While type-I and type-III IFNs are associated with the production of different antiviral effects in a variety of cell types, type-II IFNs are more associated with regulatory activities among immune cells and are therefore mostly produced by cells such as T helper cells.
Dendritic cells (DCs) are important immune cells that drive and control immunological responses by influencing innate and adaptive immune cell activity. DCs are strategically placed all over the body so that they can act as sentries and check out the environment around mucosae, skin, and organs.
Finally, DCs detect and collect foreign and self-antigens for processing. DCs break up protein-based antigens and send them to T cells as tiny peptides loaded on MHC-I and II molecules (pMHC). TCRs on the surface of CD8+ and CD4+ T cells may be able to recognize these pMHC molecules.
The presentation of DC antigen to T cells may result in a process known as the immunological synapse, which includes intimate DC-T cell contacts that can result in T cell activation or inactivation.
Importantly, the interaction between DCs and antigen-specific T cells determines the T cell phenotype, which is dependent on the expression of membrane-bound and soluble molecules during the cell-cell interphase.
DC-T cell activation can cause T cells to become either cytotoxic or regulatory. This happens when T cells release soluble substances that kill infected cells, change immune and non-immune cells, or build tolerance to antigens so that they no longer react to cognate antigens.
If HSV-infected cells can't stop viral reproduction or spread, an innate immune response made up of both acellular and other cell types would likely attack the viruses or virus-infected cells to stop them from infecting other cells or tissues in the future.
HSVs, on the other hand, are capable of inhibiting the host complement's chain reactions, which are designed to impede pathogens by launching a cascade of protein activations that leads to a membrane assault complex (MAC).
Indeed, the gC glycoprotein of HSVs may bind to the complement component C3b and prevent alternative pathways that would otherwise lead to the development of a MAC on the pathogen or virus-infected cell surface. Also, gC binds to the complement parts C3 and C5, which stops the activation of this antiviral mechanism from happening.
Natural killer (NK) cells, on the other hand, are innate immunity cells capable of identifying and eliminating virus-infected cells that either lack the expression of MHC-I molecules or display NK-activating molecules on the surface as a result of aberrant cellular processes that indicate infection.
HSVs stop MHC-I from being made on the surface of infected cells, which should normally make NK cells work.
On the other hand, it has been shown that HSV-1 infection decreases the amount of MHC class I polypeptide-related sequence A (MICA) and UL16 binding proteins 1-3 (ULBP1, ULBP2, and ULBP3) on the surface of infected cells. MICA and ULBP1, ULBP2, and ULBP3 are activators of NK cells that start signaling events when they interact with NKG2D.
The virus is mostly spread by contact with sores, saliva, or surfaces in or around the mouth. Oral-genital contact can also spread HSV-1 to the genital area, which can lead to genital herpes.
One form (HSV-1) produces sores around the lips or within the mouth, which are sometimes known as fever blisters or cold sores. The other variety (HSV-2) commonly causes vaginal sores (private parts). Either kind could infect the mouth, the genital area, or another part of the body.
While there is no treatment for herpes, the virus's intensity fluctuates throughout the course of a person's lifetime. In fact, some people with the condition have no symptoms for lengthy periods of time. Even if no symptoms are evident, they may still discharge the virus.
Herpes simplex virus type 1 (HSV-1) or type 2 (HSV-2) causes genital herpes, a sexually transmitted illness (STD).
Herpes simplex viruses cause a wide range of disorders in humans, both in people with immune-related issues and in otherwise healthy people. The ability of HSVs to cause illness during first infections and recurrences after a lifetime infection is partly due to their ability to avoid and destroy antiviral systems in immune and non-immune cells of the host.
Importantly, HSVs mess up early antiviral stages like the host's ability to find viral markers, signaling pathways that lead to antiviral effects in cells, and the activity of innate immune cells that fight these viruses soon after infection.
By avoiding these defenses, HSVs are able to infect host cells and reach neurons, which promotes viral latency and infections that last a lifetime. It also reduces antiviral activities that could help immune cells build up an effective and protective defense against these viruses.
The host's failure to initiate an efficient early antiviral response may provide grounds for the creation of inadequate adaptive immunity, mostly via interference with DC function, which is critical for bridging innate and adaptive immunity.
So, improving the early antiviral responses of the host to HSVs should help with the development of better anti-HSV medicines and ways to keep from getting these viruses.