The main patterns of viral infection are acute and persistent. In an acute infection, there is rapid production of virus particles, producing symptoms after an incubation period (which may be as short as a few days, or last for weeks or months). Symptoms tend to resolve relatively quickly, and immunity may result. In a persistent infection, the primary infection is not cleared by the immune system for some reason, so virus particles continue to be produced. Sometimes the virus will be detectable, while at other times it may "hide" by remaining latent in certain cells. Persistent infections may be problematic as they can be reactivated, may be associated with immunopathological diseases, and may even be associated with certain cancers.
Understand the different types of persistent infections and be able to give examples of viruses that pertain to each type
The different types of persistent infection are latent, chronic, and slow.
Latent infections
In a latent infection, after an initial acute infection, the virus remains latent in cells of the body. The virus may reactivate every now and again throughout a person's lifetime, which may or may not cause symptoms. As mentioned in previous posts, herpes simplex virus and varicella zoster virus are good examples of latent infections.
Another example of a latent infection is cytomegalovirus (CMV), which can remain dormant in CD34+ myeloid progenitor cells and CD14+ monocytes. CMV is usually asymptomatic, but can be shed and spread in the urine and saliva of healthy carriers. This can be problematic, as while CMV is usually asymptomatic, it can have nasty consequences for the immunosuppressed or for foetuses.
Yet another example of a latent infection is Epstein-Barr Virus (EBV), which can remain latent in B-cells. It usually infects epithelial cells, such as the mouth mucosa, which shed the virus for months after infection. Like CMV, it is often carried asymptomatically. Reactivation is usually caused by immunosuppression, but unlike CMV, it usually will not cause symptoms. EBV is, however, associated with some cancers (*cough*Burkitt's lymphoma*cough*), so don't get too complacent.
Chronic infections
In a chronic infection, the virus continues to be produced, though usually there are long periods with no symptoms. The virus, however, can still be shed in the blood, which may be problematic in cases of blood transfusions.
Hepatitis B is one example of a chronic infection. The virus replicates in the liver, and infectious virus particles (Dane particles) and Hep B surface antigen (HBsAg) circulate in the plasma. Usually, virions and HBsAg are cleared (so no chronic infection), but around 5-10% of those infected with Hep B will have a chronic infection. A small proportion of the chronically affected may also experience liver cirrhosis and cancer later on. As Hep B can be shed in the blood, blood donations are screened for this virus.
Lymphocytic choriomeningitis virus (LCMV) is a chronic infection that mainly affects rodents. (It can also infect humans, but only rarely.) It is transferred from mother to child. Infant mice with LCMV tend to be normal, but have persistent viraemia. Some antibodies may be produced, and if antigen-antibody complexes are deposited in the kidney, kidney disease may result. No cell-mediated immunity develops, and no cellular dysfunction is evident as a result of the disease.
Slow infections
Slow infections normally start with an acute infection with symptoms, which is followed by a long period in which the virus is kept at low levels by the immune system, and finally a phase where viral load continues to rise until death of the host. One of the main causes of slow infection are lentiviruses, which is a group of virus including HIV, SIV (simian immunodeficiency virus- affects monkeys) and FIV (feline immunodeficiency virus- affects cats). Lentiviruses, which can also exist as an integrated DNA provirus, replicate in lymphocytes and macrophages.
As I just mentioned, HIV is an example of a slow virus. The acute phase is usually mildly symptomatic, with some flu-like symptoms. Following the acute phase, the patient can remain asymptomatic for up to 10 years. Eventually, the virus comes back with a vengeance and kills off a lot of CD4 T-cells, compromising the immune system to the point where opportunistic infections can kill. Nasty.
The measles virus can also cause a slow infection. In rare cases, someone who has been infected with measles may get a complication called subacute sclerosing panencephalitis (SSPE) 1-10 years after measles infection. In SSPE, virus is replicated slowly in the central nervous system, and nucleocapsids are transmitted from cell to cell. High levels of neutralising antibody are produced, but because a lot of viral replication is still occurring within cells, the infection can still progress until death occurs.
For some reason, this lecture also included transmissible spongiform encephalopathies, which are brain diseases caused by prions (self-replicating proteins). Scrapie is a prion disease that affects sheep, and can be transmitted from ewe to lamb. It progresses to paralysis and death. Creutzfeldt-Jacob Disease (CJD) is a prion disease in humans that causes a pre-senile dementia. A variant form (vCJD) can be caused by ingesting beef infected with bovine spongiform encephalopathy. (This is also known as "Mad Cow Disease," and since it's hard to test for, it's the reason why many Brits can't donate blood in Australia.) Another transmissible spongiform encephalopathy, Kuru, is confined mainly to the New Guinea Highlands. It is spread by ritual cannibalism, but education campaigns have seen a decrease in Kuru infection.
Understand the pathogenesis of persistent infection
Persistent infections hang around because they have properties that allow them to hang around and/or are able to avoid the host defences. Let's take a look at their strategies.
- Non-immunogenic agents: Not all pathogens are immunogenic (i.e. they do not induce immune responses, like production of type I interferon, and/or are not susceptible to the actions of the immune system). That makes things rather tricky...
- Integrated genomes: Retroviral DNA can be integrated into the host genome, allowing a virus to remain part of the host genome indefinitely. Viruses may also exist as episomes (separate segments of DNA within the host cell), which also stops them from being destroyed by the host.
- Antigenic variation: Some viruses, particularly lentiviruses, can undergo mutations that change their cell surface antigens, making it difficult to form antibodies against them.
- Growth in protected sites: Viruses can grow in sites where the immune system is not very strong. For example, HSV and VZV reside in neurons, which don't usually express MHC-I. Some other infections grow in epithelial cells and are shed in secretions, which may not provoke an immune response.
- Growth in macrophages: Viral growth in macrophages also impairs some macrophage functions, including antigen presentation, phagocytosis, and cytokine production.
- Non-neutralising antibodies: Viruses can induce the formation of non-neutralising antibodies, which can form complexes with viral antigens, leading to immune complex diseases. Non-neutralising antibodies can also block the binding of C1 antibody, which usually binds to and modulates lysis of infected cells.
- Immunological tolerance: Many viruses only induce a very weak antibody response, which is not effective at wiping out the virus.
- Suppression of cell-mediated immunity: Viruses may reduce MHC-I expression on cell surfaces, replicate inside and impair the function of immune system cells (e.g. macrophages), or have other immunosuppressive effects.
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