Host virus interaction

Non-Specific responses 2. Non-specific responses 1. Types of interferons They are classified into three types 1. This leads to inhibition of viral protein synthesis but does not affect host protein synthesis Immunological responses 1. Cell-mediated immunity CMI CMI prevents infection of target organs and promotes recovery from disease by destroying virus and virus-infected cells.

The different mechanisms involved for virus destruction are as follows 1. Cytolysis by cytotoxic T-cells and Natural-killer NK cells 2. Antibody-dependent cell-mediated cytotoxicity ADCC 3.

Antibody-complement-mediated cytotoxicity Laboratory diagnosis of viral infections Following are indications for laboratory diagnosis of viral infections 1. For proper management of certain diseases 2. Diagnosis of diseases caused by viruses for which antiviral chemotherapy is available herpes viruses 3.

Early detection of epidemics like influenza, poliomyelitis, encephalitis etc to initiate appropriate control measures In the laboratory, the following methods are commonly employed 1. Direct demonstration of virus and its components 2. Isolation of virus 3. Detection of the specific antibodies Serological diagnosis of viral infections Immunoprophylaxis 1. Active immunisation 2. Passive immunisation Active immunisation Viral vaccines a Live viral vaccines b Killed viral vaccines A single dose of live vaccine is usually sufficient 2.

They may be administered by the route of natural infection so that local immunity is induced They induce a wide spectrum of immunoglobulins against the whole range of viral antigens 4. They also induce cell mediated immunity 5. This along with the evidence that a large number of these cellular genes including CD28 are well documented to be down regulated in HIV pathogenesis, points to the possible cross-talk between the virus and host at the microRNA level.

This is perhaps the first experimental evidence of a virus encoded microRNA targeting cellular transcripts. Such a mechanism could operate in other related herpes viruses like Epstein-Barr virus, which not only causes latent infection, but also associated with a wide spectrum of neoplasms in humans including Burkitts lymphoma and nasopharyngeal carcinoma.

This is especially so in the case of EBV encoded microRNAs as they have been shown to be differentially expressed in different phases of the viral life [ 45 ]. Our analysis of cellular targets of 32 EBV encoded microRNAs using robust computational approaches using consensus of microRNA target prediction software revealed that the target genes are involved in apoptosis and tumor suppressor pathways, suggesting that EBV encoded microRNAs play crucial roles in oncogenic transformation induced by the virus unpublished results.

The discovery of virus encoded microRNAs playing crucial roles in pathogenesis of diseases caused by viruses not only throws light on a new level of host-pathogen interactions, but also would help in designing novel preventive and therapeutic strategies. Omoto et al , using a combinatorial approach incorporating both computational prediction and experimental validation demonstrated the possibility that a virus-encoded microRNA could auto-regulate itself. A nef derived microRNA could down regulate nef expression in vitro suggesting that it could be a mechanism of maintaining low viremia in Long term non-progressor LTNP states [ 46 ].

This finding was later expanded by the same group with an additional discovery that nef derived microRNA also suppress transcription [ 49 ] by reducing HIV-1 promoter activity through the negative responsive element in the 5'-LTR, thus contributing to an additional layer of auto regulation. In yet another instance, a virus encoded microRNA, is effectively used by the virus to tune down a set of genes and thereby evade cytotoxic T cell response [ 41 ].

Curiously, the expression of the viral microRNAs did not have any untoward effect on the viral replication. Further analysis revealed that the microRNAs had near perfect complementary matches in the early expressed genes of the virus which would target them for interference mediated degradation. The genes include the T antigen which is a determinant for invasion of T cells, thus providing an advantage in camouflaging the virus infected cells from the cellular immune system. MicroRNA expression has been shown to be specific to various stages of infection in Herpesviruses [ 45 ] and have been proposed to be associated with latency in HIV infection [ 31 , 50 ], promising an early biomarker for cancers caused by oncogenic viruses.

MicroRNA profiles have also been explored in a number of patho-physiological conditions [ 51 ]. Recent reports suggest that microRNA profiles can be used not only to classify different classes of cancers [ 52 - 54 ], but could also be used as biomarkers for diagnosis and prognosis of disease states [ 54 ]. Recent advances in nucleotide chemistry like Locked Nucleic Acids LNA [ 57 ], and other backbone modifications have made it possible to design small RNA oligonucleotides which are highly stable in biological systems circumventing one major hurdle in using microRNAs as future therapeutics.

Oligonucleotide modifications have already made their way to the microRNA experimental biologists workbench [ 58 ]. This would include delivery strategies [ 34 ]. This would be even more important as siRNA based therapeutics for viral pathogens in different stages of clinical trials and are showing promising results. MicroRNAs are promising candidates for developing novel bio-therapeutics against viruses, as it requires only partial complementarity unlike siRNAs and thus can tackle the high rate of mutations in viruses better than siRNAs.

Our group has recently developed an algorithm for design of highly specific microRNAs on against sequences to be targeted unpublished results. This would allow design of microRNAs against highly conserved sequences in viral genome.

Artificial microRNAs also offer the advantage that they can be optimized to create less off-target events in the host thus substantially reducing untoward side effects. MicroRNAs or microRNA target sequences could also be engineered into transforming viruses and could enable tissue specific and environment sensitive expression of genes.

The challenge would be to integrate bioinformatics with gene expression and proteomics data. This would not only enable them to design novel diagnostic and therapeutic strategies to combat deadly viruses, but also empower researchers to understand basic biological processes involved in latency and oncogenic transformation mediated by viruses.

Complexity of microRNA mediated host-pathogen Interaction. The authors thank Dr. Elayanambi Sundaramoorthy for reviewing the manuscript and providing valuable suggestions. National Center for Biotechnology Information , U. Journal List Retrovirology v. Published online Oct Author information Article notes Copyright and License information Disclaimer. Corresponding author. Vinod Scaria: ni. Received Aug 30; Accepted Oct This article has been cited by other articles in PMC. Biogenesis and mechanism of action of microRNAs MicroRNA gene location MicroRNAs have been classically thought to be transcribed from intergenic regions, but recent large-scale genome-wide cloning experiments [ 11 ] have shown that microRNAs can be derived from introns as well.

Mechanisms of action The mechanism of action of microRNAs is considered to be by two modes — translational repression and target degradation.

Open in a separate window. Figure 1. Schematic overview of biogenesis and action of microRNAs in eukaryotic cells. Non-classical mechanisms of action Recent evidence suggests that microRNAs can also regulate protein expression through non-classical ways. Computational tools for discovery of microRNA and their targets Computational predictions have been the mainstay for discovery of microRNAs and their targets.

MicroRNAs as an antiviral defense mechanism Viruses are obligate intracellular parasites and use the cellular machinery for their survival and replication. Primate Foamy Virus Lecellier et al [ 30 ], for the first time demonstrated that a mammalian microRNA, mir restricts the accumulation of the retrovirus primate foamy virus type 1 PFV-1 in human cells.

Human Immunodeficiency Virus We have earlier shown [ 31 ], using robust computational tools, that involve consensus prediction approaches that five human encoded microRNAs can potentially target the entire repertoire of accessory genes in HIV, including nef. Mutations affecting segment number and polarity in Drosophila.

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It exerts its antiviral function by inhibiting protein synthesis. Positive selection The process that increases the frequency of advantageous traits in a population Pseudosubstrate inhibitor An inhibitor that mimics the substrate of an enzyme and inhibits its activity Ortholog A gene found in multiple species that evolved from a single ancestral gene through the process of speciation.

Viral antagonist A viral molecule that has evolved to inhibit host factors. Often antiviral or host restriction factors.

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