Virus latency (orviral latency) is the ability of apathogenicvirus to liedormant (latent) within a cell, denoted as thelysogenic part of the viral life cycle.[1] A latent viral infection is a type of persistent viral infection which is distinguished from achronic 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 (thelytic part of theviral 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 withclinical latency during theincubation period when a virus isnot dormant.
Episomal latency refers to the use of geneticepisomes during latency. In this latency type, viral genes are stabilized, floating in thecytoplasm ornucleus as distinct objects, either as linear orlasso-shaped structures. Episomal latency is more vulnerable toribozymes or host foreign gene degradation than proviral latency (see below).
One example is theherpes virus family,Herpesviridae, all of which establish latent infection. Herpes virus includechicken-pox virus andherpes simplex viruses (HSV-1, HSV-2), all of which establish episomal latency inneurons and leave linear genetic material floating in thecytoplasm.[3]
TheGammaherpesvirinae subfamily is associated with episomal latency established in cells of theimmune system, such asB-cells in the case ofEpstein–Barr virus.[3][4] Epstein–Barr viruslytic reactivation (which can be due tochemotherapy or radiation) can result ingenome instability andcancer.[5]
In the case of herpes simplex (HSV), the virus has been shown to fuse withDNA in neurons, such as nerveganglia[6] or neurons, and HSV reactivates upon even minorchromatin loosening with stress,[7] although the chromatin compacts (becomes latent) upon oxygen and nutrient deprivation.[8]
Cytomegalovirus (CMV) establishes latency inmyeloidprogenitor cells, and is reactivated byinflammation.[9]Immunosuppression and critical illness (sepsis in particular) often results in CMV reactivation.[10] CMV reactivation is commonly seen in patients with severecolitis.[11]
Advantages of episomal latency include the fact that the virus may not need to enter thecell nucleus, and hence may avoidnuclear domain 10 (ND10) from activatinginterferon via that pathway.
Disadvantages include more exposure to cellular defenses, leading to possible degradation of viral gene via cellularenzymes.[12]
Reactivation in herpesviruses may be due to stress stimuli imposed on neurons, at a nearby site innervated by the infected ganglion, or systemically, through means such as high temperature.[13]
Aprovirus 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 thecell.[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 isHIV. HIV usesreverse 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 withantiretroviral drugs. Several classes oflatency 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 theselatency-associated genes may function to keep the viral genome from being digested by cellularribozymes or being found out by theimmune system. Certain viral gene products (RNA transcripts such asnon-coding RNAs and proteins) may also inhibitapoptosis or inducecell growth and division to allow more copies of the infected cell to be produced.[16]
An example of such a gene product is thelatency associated transcripts (LATs) in herpes simplex virus, which interfere withapoptosis bydownregulating a number of host factors, includingmajor histocompatibility complex (MHC) and inhibiting the apoptotic pathway.[17]
A certain type of latency could be ascribed to theendogenous retroviruses. These viruses have incorporated into thehuman 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 activeviral shedding nor causes anypathologies orsymptoms, the virus is still able to reactivate via external activators, such as sunlight and stress, to cause anacute infection. In the case of herpes simplex virus, which generally infects an individual for life, aserotype of the virus reactivates occasionally to causecold sores. Although the sores are quickly resolved by the immune system, they may be a minor annoyance from time to time. In the case ofvaricella zoster virus, after an initial acute infection (chickenpox) the virus lies dormant until reactivated asherpes zoster.
More serious ramifications of a latent infection could be the possibility of transforming the cell, and forcing the cell intouncontrolled 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 duringgene therapy through the use of retroviral vectors at theNecker Hospital inParis, where twenty young boys received treatment for agenetic disorder, after which five developedleukemia-like syndromes.[20]
This is also seen with infections of thehuman papilloma virus in whichpersistent infection may lead tocervical cancer as a result ofcellular transformation.[21][22][23]
In the field ofHIV 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 restingCD4-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]
