Virus latency (or viral latency) is the ability of a pathogenic virus to lie dormant (latent) within a cell, denoted as the lysogenic part of the viral life cycle. [1] A latent viral infection is a type of persistent viral infection which is distinguished from a chronic viral infection. Latency is the phase in certain viruses' life cycles in which, after initial infection, proliferation of virus particles ceases. However, the viral genome is not eradicated. The virus can reactivate and begin producing large amounts of viral progeny (the lytic part of the viral life cycle) without the host becoming reinfected by new outside virus, and stays within the host indefinitely. [2]
Virus latency is not to be confused with clinical latency during the incubation period when a virus is not dormant.
Episomal latency refers to the use of genetic episomes during latency. In this latency type, viral genes are stabilized, floating in the cytoplasm or nucleus as distinct objects, either as linear or lariat [ clarification needed (complicated jargon)] structures. Episomal latency is more vulnerable to ribozymes or host foreign gene degradation than proviral latency (see below).
One example is the herpes virus family, Herpesviridae, all of which establish latent infection. Herpes virus include chicken-pox virus and herpes simplex viruses (HSV-1, HSV-2), all of which establish episomal latency in neurons and leave linear genetic material floating in the cytoplasm. [3]
The Gammaherpesvirinae subfamily is associated with episomal latency established in cells of the immune system, such as B-cells in the case of Epstein–Barr virus. [3] [4] Epstein–Barr virus lytic reactivation (which can be due to chemotherapy or radiation) can result in genome instability and cancer. [5]
In the case of herpes simplex (HSV), the virus has been shown to fuse with DNA in neurons, such as nerve ganglia [6] or neurons, and HSV reactivates upon even minor chromatin loosening with stress, [7] although the chromatin compacts (becomes latent) upon oxygen and nutrient deprivation. [8]
Cytomegalovirus (CMV) establishes latency in myeloid progenitor cells, and is reactivated by inflammation. [9] Immunosuppression and critical illness (sepsis in particular) often results in CMV reactivation. [10] CMV reactivation is commonly seen in patients with severe colitis. [11]
Advantages of episomal latency include the fact that the virus may not need to enter the cell nucleus, and hence may avoid nuclear domain 10 (ND10) from activating interferon via that pathway.
Disadvantages include more exposure to cellular defenses, leading to possible degradation of viral gene via cellular enzymes. [12]
A provirus is a virus genome that is integrated into the DNA of a host cell.
Advantages include automatic host cell division results in replication of the virus's genes, and the fact that it is nearly impossible to remove an integrated provirus from an infected cell without killing the cell. [14]
A disadvantage of this method is the need to enter the nucleus (and the need for packaging proteins that will allow for that). However, viruses that integrate into the host cell's genome can stay there as long as the cell lives.
One of the best-studied viruses that exhibits viral latency is HIV. HIV uses reverse transcriptase to create a DNA copy of its RNA genome. HIV latency allows the virus to largely avoid the immune system. Like other viruses that go latent, it does not typically cause symptoms while latent. HIV in proviral latency is nearly impossible to target with antiretroviral drugs. Several classes of latency reversing agents (LRAs) are under development for possible use in shock-and-kill strategies in which the latently infected cellular reservoirs would be reactivated (the shock) so that anti-viral treatment could take effect (the kill). [15]
Both proviral and episomal latency may require maintenance for continued infection and fidelity of viral genes. Latency is generally maintained by viral genes expressed primarily during latency. Expression of these latency-associated genes may function to keep the viral genome from being digested by cellular ribozymes or being found out by the immune system. Certain viral gene products (RNA transcripts such as non-coding RNAs and proteins) may also inhibit apoptosis or induce cell growth and division to allow more copies of the infected cell to be produced. [16]
An example of such a gene product is the latency associated transcripts (LAT) in herpes simplex virus, which interfere with apoptosis by downregulating a number of host factors, including major histocompatibility complex (MHC) and inhibiting the apoptotic pathway. [17]
A certain type of latency could be ascribed to the endogenous retroviruses. These viruses have incorporated into the human genome in the distant past, and are now transmitted through reproduction. Generally these types of viruses have become highly evolved, and have lost the expression of many gene products. [18] Some of the proteins expressed by these viruses have co-evolved with host cells to play important roles in normal processes. [19]
While viral latency exhibits no active viral shedding nor causes any pathologies or symptoms, the virus is still able to reactivate via external activators (sunlight, stress, etc.) to cause an acute infection. In the case of herpes simplex virus, which generally infects an individual for life, a serotype of the virus reactivates occasionally to cause cold sores. Although the sores are quickly resolved by the immune system, they may be a minor annoyance from time to time. In the case of varicella zoster virus, after an initial acute infection (chickenpox) the virus lies dormant until reactivated as herpes zoster.
More serious ramifications of a latent infection could be the possibility of transforming the cell, and forcing the cell into uncontrolled cell division. This is a result of the random insertion of the viral genome into the host's own gene and expression of host cellular growth factors for the benefit of the virus. In a notable event, this actually happened during gene therapy through the use of retroviral vectors at the Necker Hospital in Paris, where twenty young boys received treatment for a genetic disorder, after which five developed leukemia-like syndromes. [20]
This is also seen with infections of the human papilloma virus in which persistent infection may lead to cervical cancer as a result of cellular transformation. [21] [22] [23]
In the field of HIV research, proviral latency in specific long-lived cell types is the basis for the concept of one or more viral reservoirs, referring to locations (cell types or tissues) characterized by persistence of latent virus. Specifically, the presence of replication-competent HIV in resting CD4-positive T cells allows this virus to persist for years without evolving despite prolonged exposure to antiretroviral drugs. [24] This latent reservoir of HIV may explain the inability of antiretroviral treatment to cure HIV infection. [24] [25] [26] [27]
A retrovirus is a type of virus that inserts a DNA copy of its RNA genome into the DNA of a host cell that it invades, thus changing the genome of that cell. After invading a host cell's cytoplasm, the virus uses its own reverse transcriptase enzyme to produce DNA from its RNA genome, the reverse of the usual pattern, thus retro (backward). The new DNA is then incorporated into the host cell genome by an integrase enzyme, at which point the retroviral DNA is referred to as a provirus. The host cell then treats the viral DNA as part of its own genome, transcribing and translating the viral genes along with the cell's own genes, producing the proteins required to assemble new copies of the virus. Many retroviruses cause serious diseases in humans, other mammals, and birds.
Varicella zoster virus (VZV), also known as human herpesvirus 3 or Human alphaherpesvirus 3 (taxonomically), is one of nine known herpes viruses that can infect humans. It causes chickenpox (varicella) commonly affecting children and young adults, and shingles in adults but rarely in children. As a late complication of VZV infection, Ramsay Hunt syndrome type 2 may develop in rare cases. VZV infections are species-specific to humans. The virus can survive in external environments for a few hours.
Kaposi's sarcoma-associated herpesvirus (KSHV) is the ninth known human herpesvirus; its formal name according to the International Committee on Taxonomy of Viruses (ICTV) is Human gammaherpesvirus 8, or HHV-8 in short. Like other herpesviruses, its informal names are used interchangeably with its formal ICTV name. This virus causes Kaposi's sarcoma, a cancer commonly occurring in AIDS patients, as well as primary effusion lymphoma, HHV-8-associated multicentric Castleman's disease and KSHV inflammatory cytokine syndrome. It is one of seven currently known human cancer viruses, or oncoviruses. Even after many years since the discovery of KSHV/HHV8, there is no known cure for KSHV associated tumorigenesis.
Human herpesvirus 6 (HHV-6) is the common collective name for human betaherpesvirus 6A (HHV-6A) and human betaherpesvirus 6B (HHV-6B). These closely related viruses are two of the nine known herpesviruses that have humans as their primary host.
HHV Latency Associated Transcript is a length of RNA which accumulates in cells hosting long-term, or latent, Human Herpes Virus (HHV) infections. The LAT RNA is produced by genetic transcription from a certain region of the viral DNA. LAT regulates the viral genome and interferes with the normal activities of the infected host cell.
Herpesviridae is a large family of DNA viruses that cause infections and certain diseases in animals, including humans. The members of this family are also known as herpesviruses. The family name is derived from the Greek word ἕρπειν, referring to spreading cutaneous lesions, usually involving blisters, seen in flares of herpes simplex 1, herpes simplex 2 and herpes zoster (shingles). In 1971, the International Committee on the Taxonomy of Viruses (ICTV) established Herpesvirus as a genus with 23 viruses among four groups. As of 2020, 115 species are recognized, all but one of which are in one of the three subfamilies. Herpesviruses can cause both latent and lytic infections.
Human Herpes Virus (HHV) Infected Cell Polypeptide 0 (ICP0) is a protein, encoded by the DNA of herpes viruses. It is produced by herpes viruses during the earliest stage of infection, when the virus has recently entered the host cell; this stage is known as the immediate-early or α ("alpha") phase of viral gene expression. During these early stages of infection, ICP0 protein is synthesized and transported to the nucleus of the infected host cell. Here, ICP0 promotes transcription from viral genes, disrupts structures in the nucleus known as nuclear dots or promyelocytic leukemia (PML) nuclear bodies, and alters the expression of host and viral genes in combination with a neuron specific protein. At later stages of cellular infection, ICP0 relocates to the cell cytoplasm to be incorporated into new virion particles.
Herpes simplex virus1 and 2, also known by their taxonomic names Human alphaherpesvirus 1 and Human alphaherpesvirus 2, are two members of the human Herpesviridae family, a set of viruses that produce viral infections in the majority of humans. Both HSV-1 and HSV-2 are very common and contagious. They can be spread when an infected person begins shedding the virus.
Gammaherpesvirinae is a subfamily of viruses in the order Herpesvirales and in the family Herpesviridae. Viruses in Gammaherpesvirinae are distinguished by reproducing at a more variable rate than other subfamilies of Herpesviridae. Mammals serve as natural hosts. There are 43 species in this subfamily, divided among 7 genera with three species unassigned to a genus. Diseases associated with this subfamily include: HHV-4: infectious mononucleosis. HHV-8: Kaposi's sarcoma.
Human betaherpesvirus 5, also called human cytomegalovirus (HCMV,HHV-5), is a species of virus in the genus Cytomegalovirus, which in turn is a member of the viral family known as Herpesviridae or herpesviruses. It is also commonly called CMV. Within Herpesviridae, HCMV belongs to the Betaherpesvirinae subfamily, which also includes cytomegaloviruses from other mammals. CMV is a double-stranded DNA virus.
Cyclic AMP-responsive element-binding protein 3 is a protein that in humans is encoded by the CREB3 gene.
A virus is a submicroscopic infectious agent that replicates only inside the living cells of an organism. Viruses infect all life forms, from animals and plants to microorganisms, including bacteria and archaea. Viruses are found in almost every ecosystem on Earth and are the most numerous type of biological entity. Since Dmitri Ivanovsky's 1892 article describing a non-bacterial pathogen infecting tobacco plants and the discovery of the tobacco mosaic virus by Martinus Beijerinck in 1898, more than 11,000 of the millions of virus species have been described in detail. The study of viruses is known as virology, a subspeciality of microbiology.
Neurovirology is an interdisciplinary field which represents a melding of clinical neuroscience, virology, immunology, and molecular biology. The main focus of the field is to study viruses capable of infecting the nervous system. In addition to this, the field studies the use of viruses to trace neuroanatomical pathways, for gene therapy, and to eliminate detrimental populations of neural cells.
Herpes simplex research includes all medical research that attempts to prevent, treat, or cure herpes, as well as fundamental research about the nature of herpes. Examples of particular herpes research include drug development, vaccines and genome editing. HSV-1 and HSV-2 are commonly thought of as oral and genital herpes respectively, but other members in the herpes family include chickenpox (varicella/zoster), cytomegalovirus, and Epstein-Barr virus. There are many more virus members that infect animals other than humans, some of which cause disease in companion animals or have economic impacts in the agriculture industry.
ICP8, the herpes simplex virus type-1 single-strand DNA-binding protein, is one of seven proteins encoded in the viral genome of HSV-1 that is required for HSV-1 DNA replication. It is able to anneal to single-stranded DNA (ssDNA) as well as melt small fragments of double-stranded DNA (dsDNA); its role is to destabilize duplex DNA during initiation of replication. It differs from helicases because it is ATP- and Mg2+-independent. In cells infected with HSV-1, the DNA in those cells become colocalized with ICP8.
David Mahan Knipe is the Higgins Professor of Microbiology and Molecular Genetics in the Department of Microbiology at the Harvard Medical School in Boston, Massachusetts and co-chief editor of the reference book Fields Virology. He returned to the Chair of the Program in Virology at Harvard Medical School in 2019, having previously held the position from 2004 through 2016 and served as interim Co-Chair of the Microbiology and Immunobiology Department from 2016 through 2018.
Human herpes viruses, also known as HHVs, are part of a family of DNA viruses that cause several diseases in humans. One of the most notable functions of this virus family is their ability to enter a latent phase and lay dormant within animals for extended periods of time. The mechanism that controls this is very complex because expression of viral proteins during latency is decreased a great deal, meaning that the virus must have transcription of its genes repressed. There are many factors and mechanisms that control this process and epigenetics is one way this is accomplished. Epigenetics refers to persistent changes in expression patterns that are not caused by changes to the DNA sequence. This happens through mechanisms such as methylation and acetylation of histones, DNA methylation, and non-coding RNAs (ncRNA). Altering the acetylation of histones creates changes in expression by changing the binding affinity of histones to DNA, making it harder or easier for transcription machinery to access the DNA. Methyl and acetyl groups can also act as binding sites for transcription factors and enzymes that further modify histones or alter the DNA itself.
HSV epigenetics is the epigenetic modification of herpes simplex virus (HSV) genetic code.
Since antiretroviral therapy requires a lifelong treatment regimen, research to find more permanent cures for HIV infection is currently underway. It is possible to synthesize zinc finger nucleotides with zinc finger components that selectively bind to specific portions of DNA. Conceptually, targeting and editing could focus on host cellular co-receptors for HIV or on proviral HIV DNA.
Human Immunodeficiency Virus (HIV) has the capability to enter a latent stage of infection where it exists as a dormant provirus in CD4+ T-cells. Most latently infected cells are resting memory T cells, however a small fraction of latently infected cells isolated from HIV patients are naive CD4 T cells.
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