Discuss mechanisms of viral persistence illustrating your answer with specific examples

Viruses could also escape immunological attack by hiding at privileged sites, for example inside the brain in which the blood brain barrier act as a source of protection where the host's immune system is unable to detect the virus or can take no action to remove the virus. Presence of antigenic proteins brings about recognition and activates the immunological functions of cytotoxic T cells and T helper cells against pathogens and viruses. However, strategy have been developed by viruses that for some viral proteins, the endogenous or exogenous pathways of antigen presentation can be interfered. This may lead to prevention in synthesizing certain molecules, redirection of substances to a different destination or destruction of particular protein molecules such as the CD4 or CD8 molecules in HIV. The result of these sequences of events is to block antigenic protein presentation to stop the actions of the immune cells thus viruses can escape host's immunity attack. Cytokines of one's immune system are responsible for activation of immune cells and chemotaxis. Viruses have developed methods to disrupt the synthesis of cytokines and the binding of such molecules to their receptors by encoding substances similar to normal cytokines. Moreover the cytokine signaling pathway is interfered and leads to incorrect signals initiation causing up or down regulation of configuration of the cell receptors. Inhibition of binding to receptors may occur and the normal cytokine pathway is interrupted and the outcome is dysfunctional cytokines on viruses hence another mechanism for immunity evasion. Apoptosis is the mechanism for infected or damaged cells to be programmed to death. Viruses must be able to block this process in some way to prolong viral survival until they have reached their infectious stage and can release its progeny. Their strategy for blocking the apoptotic process would be to up-regulate Bcl production where this substance is responsible for apoptosis blockade.

The prime of an immune response is to destroy free viruses and its cycle to stop its replication as this time of viruses is most vulnerable due to the encoding of antigenic protein. At the same time, viruses have developed methods to escape host's immunity but not destroying it at all because of its dependence on the hosts for survival and providing sites for creating new viruses for further infection to new hosts. Viruses achieve the evasion generally by 'encoding and expressing many different proteins to cause restriction, modification and redirection upon the cells of host's immune system'. Viral proteins could act as 'ligands or receptors serving as an agonist or antagonist in host cells activities', which causes changes in host immune function to the viruses' benefits. (Maurice R Hilleman, 2004)

The mechanisms of the viral persistence can also be illustrated by using examples such as HIV-1 infection in which its virus has a high rate of evolution and are responsible for the acquired immunodeficiency syndrome. HIV infection is caused by the RNA retroviruses; they are RNA virus and have its distinct morphological characterizations. The virus is round- shaped and surrounded by a lipid envelope with 72 glycoprotein projections. These glycoproteins are important for the antigen recognition and providing binding sites for other substances. The virus possess the reverse transcriptase enzyme and through the action of this enzyme, retroviruses disobey the rule of central dogma which states that genetic information will flow from DNA to RNA to proteins and now the direction flow of genetic material is reversed. Retroviruses hijack the translation machinery of the host, using viral RNA as template to produce DNA intermediates which are called provirus through the action of RT. These materials are then integrated and inserted into the host's chromosome thus causing rapid and continuous replication of the virus and virus-producing cells as well as mast viral protein production. This particular stage of virus and host cells interactions is largely targeted by therapeutic antiretroviral drugs. However, the virus becomes latent after a few months which could lead to misinterpretation of complete eradication of the infection. The major contribution to the long term persistence of HIV infection is the reservoirs and due to the long period of latency of the virus it adds on the difficulty for virus detection clinically, patients were then unaware of being carriers and could spread to others easily if they decide not to use contraception. Contrarily hepatitis B and hepatitis C viruses continuously express their antigen proteins and replicates.

To be able to instigate an infection from pathogenic bacteria or viruses, adhesion is the significant step and the initiation of the virulence mechanism. Without this, viruses are unable to bring about colonization, invasion and escaping from the host's immune system. Using HIV as an example, the virus derived proteins, embedded in the virus envelope interacts with the target host cell surface. The proteins that are inserted in the virus envelopes are the transmembrane subunit gp41, the gp120 surface subunit and they are glycoproteins. The gp120 guides the virion to attach to the lymphocytes' cell-surface receptors with the presence of CD4 protein on the lymphocytes membrane and interaction of gp120 and CD4 are induced. Besides, gp41 promotes the fusion of membrane of the viruses and host cells. The interaction between the two leads binding of gp120 with CD4. This causes a conformational change and brings about of gp120 binding with a second protein: The chemokine receptor 5, known as CCR-5. This further brings the HIV virus into close proximity with the host's membrane and the final stage is the fusion of the virus-cell membrane allowing virus to gain access into the host cell's cytoplasm.

Vaccinations have been considered to be the possible solutions for persistence infections, however, it turns out to be 'low-level probability and high-level of uncertainty'. (Maurice R Hilleman, 2004) There are more successful developments on the prophylactic vaccines for the hit and run viruses than the hit and stay viruses for example the RNA viruses such as HIV or the hepatitis B virus. The alternative treatment for these infections can be treated by antiviral chemotherapeutic drugs which brings the viral load to the minimum and to retain hosts immune function for the least protection against pathogens.

References

http://arjournals.annualreviews.org/doi/abs/10.1146/annurev.immunol.18.1.665

http://www.pnas.org/cgi/reprint/101/suppl_2/14560.pdf

www.ucl.ac.uk/webct ( IMMN2002)

( Pathogen mechanism, Human retroviruses and AIDS, Virus - cell interactions)

Human virology 2nd Edition- Leslie collier & John oxford

Flora Tong