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Interferon Levels Increased in Persistent Viral Infection
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Interferons are a type of protein associated with the immune response to help protect the host against infection. Generally, Type I Interferons (IFN-I) will help put the cell in an antiviral state, by stalling the cell cycle to prevent viral replication. IFN-I will also alert nearby cells to the presence of virus, and helps prevent the infection from spreading. A strong IFN-I response is normally associated with rapid control of viral infection. The result of IFN-I production by infected cells can lead to activation of the adaptive immune system, including CD8+ cytolytic T cells. CD8+ T cells are rapidly activated during viral infection, and can help clear the infection by killing infected cells.

While many viral infections can often be cleared by the immune system, there are viruses that can remain in the host persistently. These viruses seem to work by changing the proteins that are expressed by the host immune cells. The viruses are able to induce expression of proteins that limit the immune response, such as interleukin-10 (IL-10) and PD-1, a death receptor on the immune cells. This means that immune cells, such as T cells, are not able to function as well against the viral infection, which results in a condition termed exhaustion of the immune system. When the immune system is unable to destroy the virus, the infection becomes persistent.

Recently, however, researchers at the Scripps Research Institute in California demonstrated that IFN-I levels were actually much higher in mice infected with a chronic viral infection, compared to mice infected with an acute viral infection. This occurred as early as one day post infection. The results lead the researchers to speculate that IFN-I played a role in maintaining persistent viral infection. To test this hypothesis, they used antibodies to block IFN-I receptors. The antibodies would prevent the IFN-I from performing its function in the cell. When the receptors were blocked with antibody, the researchers found decreased expression of immune inhibiting proteins, including IL-10 and PD-L1, the ligand for PD-1. The decrease in these inhibitory proteins allowed the adaptive immune system to mount a response, and CD8+ T cells were able to kill the virus-infected cells and clear the infection. The researchers also found that blocking IFN-I receptors in a previously established persistent infection helped remove the signals that cause T cell exhaustion. The T cells were then able to function properly, and again, could clear the infection.

It is not clear how IFN-I assists the virus in establishing chronic infection. As the researchers discovered, IFN-I appears to play a role in increasing production of immune inhibitory cytokines such as IL-10 and PD-1, which prevents T cells from carrying out their proper function. In addition, IFN-I seemed to play a role in causing excessive production of inflammatory cytokines, a condition called cytokine storm. The cytokines may cause inflammation, and may even be responsible to damage to architecture in lymphatic organs such as the spleen. When these organs are damaged, Dendritic Cells (DCs), the innate immune cells that present antigen to and activate T cells, are not able to meet with the T cells. This prevents T cell activation, which would also be a contributing factor to chronic viral infection. When the researchers blocked IFN-I receptors, they also noticed decreased production of these hyperinflammatory cytokines, and the structure of the lymphatic organs was restored.

The researchers hope this information can be used to help treat chronic viral infections in humans, such as HIV; Hepatitis B and Hepatitis C; and Epstein-Barr Virus. They plan to not only study the effects of antibody blockade of IFN-I receptors, but also small pharmacologic molecules. Because there are more than 20 different molecules in the IFN-I family, it may be beneficial to study precisely which molecules are involved in establishing and maintaining viral persistence. This would allow researchers and clinicians to selectively inhibit problematic IFN-I molecules, but still permit helpful IFN-I molecules to function. This could prevent the early increase in viral load detected in the blood after IFN-I receptors were inhibited in mice, and reduce the severity of illness suffered by the patient. By lifting immune restrictions imposed by the chronic viral infection, the adaptive immune response may be able to better fight these infections and clear the virus.



References:

http://www.sciencedaily.com/releases/201...142815.htm

http://pathmicro.med.sc.edu/mhunt/interferon.htm
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