MicrobiologyBytes

Viruses are small infectious agents responsible for many human diseases, including acquired immunodeficiency syndrome (AIDS). Like other viruses, the human immunodeficiency virus 1 (HIV-1; the cause of AIDS) enters human cells and uses the cellular machinery to replicate before bursting out of its temporary home. During the initial stage of HIV infection, a particular group of cells in the human immune system, CD8⁺ T cells, are thought to be important in controlling the level of the virus. These immune system cells recognize pieces of viral protein called antigens displayed on the surface of infected cells; different subsets of CD8⁺ T cells recognize different antigens. When a CD8⁺ T cell recognizes its specific antigen (or more accurately, a small part of the antigen called an epitope ), it releases cytotoxins (which kill the infected cells) and cytokines, proteins that stimulate CD8⁺ T cell proliferation and activate other parts of the immune system. With many viruses, when a person first becomes infected (an acute viral infection), antigen-specific CD8⁺ T cells completely clear the infection. But with HIV-1 and some other viruses, these cells do not manage to remove all the viruses from the body and a chronic (long-term) infection develops, during which the immune system is constantly exposed to viral antigen.

In HIV-1 infections (and other chronic viral infections), virus-specific CD8⁺ T cells lose their ability to proliferate, to make cytokines, and to kill infected cells as patients progress to the longterm stages of infection. That is, the virus-specific CD8⁺ T cells gradually lose their effector functions and become functionally impaired or exhausted. Polyfunctional CD8⁺ T cells (those that release multiple cytokines in response to antigen) are believed to be essential for an effective CD8⁺ T cell response, so scientists trying to develop HIV-1 vaccines would like to stimulate the production of this type of cell. To do this they need to understand why these polyfunctional cells are lost during chronic infections. Is their loss the cause or the result of viral persistence? In other words, does the constant presence of viral antigen lead to the exhaustion of CD8⁺ T cells during chronic HIV infection? In this study, the researchers investigate this question by looking at the polyfunctionality of CD8⁺ cells responding to several different viral epitopes at various times during HIV-1 infection, starting very early after infection with HIV-1 had occurred.

The researchers enrolled 18 patients recently infected with HIV-1 and analyzed their CD8⁺ T cell responses to specific epitopes at various times after enrollment using a technique called flow cytometry. They found that the epitope-specific CD8⁺ cells produced several effector proteins after antigen stimulation during the initial stage of HIV-1 infection, but lost their polyfunctionality in the face of persistent viral infection. The CD8⁺ T cells also increased their production of programmed death 1 (PD-1), a protein that has been shown to be associated with the functional impairment of CD8⁺ T cells. Some of the patients began antiretroviral therapy during the study, and the researchers found that this treatment, which reduced the viral load, reversed CD8⁺ T cell exhaustion. Finally, the appearance in the patients blood of viruses that had made changes in the specific epitopes recognized by the CD8⁺ T cells to avoid being killed by these cells, also reversed the exhaustion of the T cells recognizing these particular epitopes.

These findings suggest that the constant presence of HIV-1 antigen causes the functional impairment of virus-specific CD8⁺ T cell responses during chronic HIV-1 infections. Treatment with antiretroviral drugs reversed this functional impairment by reducing the amount of antigen in the patients. Similarly, the appearance of viruses with altered epitopes, which effectively reduced the amount of antigen recognized by those epitope-specific CD8⁺ T cells without reducing the viral load, also reversed T cell exhaustion. These results would not have been seen if the functional impairment of CD8⁺ cells were the cause rather than the result of antigen persistence. By providing new insights into how the T cell response to viruses evolves during persistent viral infections, these findings should help in the design of vaccines against HIV and other viruses that cause chronic viral infections.

Antigen load and viral sequence diversification determine the functional profile of HIV-1 specific CD8 T cells. PLoS Med 5(5): e100

Related:

• HIV-1 gp120 induces immunosuppressive responses from dendritic cells
• HIV “can never be cured”
• How does HIV cause AIDS?

Many pathogens, such as viruses and bacteria, cause disease in humans. Pathogen infections result in illness and death for millions of people each year. Pathogens communicate with human cells through physical interactions with various human proteins on the surface of the cell and within the interior of the cell. These interactions allow the pathogen to enter the host cell, manipulate important cellular processes, multiply, and invade other cells. A recent paper compares the interactions between human and pathogen proteins from 190 different pathogens to provide important insights into strategies used by pathogens to infect human cells. This shows that both viral and bacterial proteins interact with human proteins that themselves interact with many human proteins or with human proteins that lie on many communication channels between other human proteins. Pathogens may have evolved to interact with these human proteins since they may control critical human cellular process. We also demonstrate that many viruses share common infection strategies, e.g. lengthening particular stages of the cell cycle, controlling programmed cell death, and interacting with the nuclear membrane to transfer viral genetic material into and out of the nucleus. Such studies may help us better understand the process of infection and identify better strategies to prevent or cure infection.

The Landscape of Human Proteins Interacting with Viruses and Other Pathogens. 2008 PLoS Pathog 4(2): e32

Related:

• Toll-Like Receptors

Dendritic cells (DCs) initiate immune responses to pathogens or vaccine antigens. The HIV-1 gp120 envelope glycoprotein is an antigen that is a focus of vaccine design strategies. gp120 can signal via several cell surface receptors. A recent paper studied how gp120 proteins interact with DCs in cell culture. Certain gp120s stimulate DCs from some, but not all, human donors to produce IL-10, a cytokine that is generally immunosuppressive. In addition, whether or not the DCs produce IL-10, their ability to mature properly when activated is impaired by gp120 – the gp120-treated DCs have a reduced ability to stimulate T cell growth when the two cell types are cultured together. These various effects of gp120 are caused by its binding to cell surface receptors of the mannose C-type lectin receptor family, including (but probably not exclusively) one called DC-SIGN. gp120 binds to these receptors via mannose residues that are present on some of the glycan structures that overlay much of its protein surface. Removing the mannoses by digesting gp120 with a suitable enzyme prevents IL-10 induction and impairment of DC maturation, as does the use of inhibitors of the binding of gp120 to DC-SIGN and similar receptors. Such immunosuppressive mechanisms might suppress immune responses to Env-containing vaccines, demannosylation may be a way to improve the immunogenicity of gp120 or gp140 proteins.

HIV-1 gp120 Mannoses Induce Immunosuppressive Responses from Dendritic Cells. PLoS Pathog 2007 3(11): e169

Related:

• Hurting rather than helping?
• Variation in two key genes can predict the course of progression to AIDS
• HIV vaccines – bad news, good news

Most reviews of skin microbes concentrate on understanding the population of bacteria inhabiting the skin, or on how a subset of these microbes can become pathogens. In the past decade, interdisciplinary collaborations at the interface between microbiology and immunology have greatly advanced our understanding of the host-pathogen relationship (Skin microbiota: a source of disease or defence? British Journal of Dermatology 2008 158: 442-455).
Does the hygiene hypothesis apply to the skin? Several studies have shown that the surface microflora can influence the host innate immune system. These findings complement studies that suggest disruption in microbial exposure early in development may lead to allergies. The beneficial effect of microbes in the gut has been used to support the use of probiotics. But unlike the intestine, the role of microbes on the skin surface has not been well studied.

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The relationship between the skin flora and the host can fall into three categories: parasitism, commensalism or mutualism. Symbiotic relationships can exist in which only one organism benefits while the other is harmed (parasitism, predation and competition), one organism benefits and no harm occurs to the other (commensalism) or both organisms benefit (mutualism and co-operation). Microbes found on the surface of the skin that are only infrequently associated with disease are typically referred to as commensal. This term implies that the microbe lives in peaceful coexistence with the host while benefiting from a sheltered ecological niche. An example of such a microbe is the Gram-positive bacterium Staphylococcus epidermidis. Emerging evidence indicates that this species and other so-called skin commensals may play an active role in host defence, such that they may represent a mutualistic association.

It is important to recognize that the distinction between what we consider to be harmless flora or a pathogenic agent often lies in the skin’s capacity to resist infection, and not the inherent properties of the microbe. Host cutaneous defence occurs through the combined action of a large variety of complementary systems. These include the physical barrier, a hostile surface pH, and the active synthesis of gene-encoded host defence molecules such as antimicrobial peptides, proteases, lysozymes and cytokines and chemokines that serve as activators of the cellular and adaptive immune responses. Virulence factors expressed by a microbe may enable it to avoid host defences, but it is ultimately the effectiveness of the host response that determines if a microbe is a commensal (or mutual) organism, or a dangerous pathogen for the host.

Staphylococcus epidermidis:
Staphylococcus epidermidis comprises more than 90% of the resident aerobic skin flora. Despite its generally innocuous nature, S. epidermidis is a frequent cause of infections. This species primarily infects compromised patients including drug abusers, those on immunosuppressive therapy, AIDS patients, premature babies and patients with an indwelling medical device such as a catheter. After entry, virulent strains of S. epidermidis form biofilms that partially shield the dividing bacteria from the host’s immune system and from exogenous antibiotics. In addition to catheter infections, patients with necrotic tumour masses also have a high tendency towards infection by S. epidermidis. In other conditions, S. epidermidis normally resides benignly on the skin surface, with infections arising only in conjunction with specific host predispositions.

Corynebacterium diphtheriae:
Coryneforms are Gram-positive, nonmotile, facultative anaerobic actinobacteria. The common members of the skin flora are divided into two species: Corynebacterium diphtheriae and nondiphtheriae corynebacteria (called diphtheroids). Toxinogenic C. diphtheriae produce the highly lethal diphtheria toxin, which can induce fatal toxaemia. Nontoxinogenic (nontoxin-producing) C. diphtheriae are capable of producing septicaemia, septic arthritis, endocarditis and osteomyelitis. Both non-toxigenic and toxigenic C. diphtheriae can be isolated from cutaneous ulcers of alcoholics, intravenous drug users and from hosts with poor hygiene standards, such as in endemic outbreaks in areas of low socioeconomic status.
The nondiphtheriae corynebacteria (diphtheroids) are a diverse group, containing 17 different species, not all of which are present on human skin. Several species commonly colonize cattle, while others, such as Corynebacterium jeikeium are normal inhabitants of human epithelium. C. jeikeium causes infections in immunocompromised patients, in conjunction with underlying malignancies, on implanted medical devices. Once the bacterium has penetrated the skin barrier, this bacterium can cause sepsis or endocarditis.

Propionibacterium acnes:
Propionibacterium acnes is an aerotolerant anaerobic, Gram-positive bacillus that produces propionic acid as a metabolic byproduct. This bacterium resides in the sebaceous glands, derives energy from the fatty acids of sebum, and is susceptible to ultraviolet radiation due to the presence of endogenous porphyrins (so step away from the computer and spend some time in the sun). The most well-known ailment associated with P. acnes is the skin condition known as acne vulgaris, affecting up to 80% of adolescents in the USA. Several factors are thought to contribute to an individual’s susceptibility. Hormones, medications (including steroids and oral contraceptives), the keratinization pattern of the hair follicle, stress and genetic factors all contribute to acne. In the sebaceous gland, P. acnes produces free fatty acids as a result of triglyceride metabolism. These byproducts can irritate the follicular wall and induce inflammation through neutrophil chemotaxis to the site of residence. Inflammation due to host tissue damage or production of immunogenic factors by P. acnes subsequently leads to cutaneous infections. Like S. epidermidis, P. acnes causes many postoperative infections. Prosthetic joints, catheters and heart valves transport the cutaneous microflora into the body. Sepsis and endocarditis result from systemic infections. Another common port of entry for P. acnes is through eye injuries or operations. Propionibacterium acnes can cause endophthalmitis (inflammation of the interior of the eye causing blindness) weeks or months after trauma or eye surgery. The infection delay probably results from low-virulence phenotypes of P. acnes.

Group A Streptococcus (Streptococcus pyogenes):
Known for causing superficial infections as well as invasive diseases, GAS (such as S. pyogenes) form chains of Gram-positive cocci. GAS strains are further subclassified by their M-protein and T-antigen serotypes, which indicate the strain’s potential to cause superficial or invasive disease. GAS infections are diverse in their symptoms, with strep throat, mucosal infections and impetigo being most common. GAS is also associated with deeper-seated skin infections such as cellulitis, infections of connective tissue and underlying adipose tissue. These types of disease occur frequently in the elderly and in people in densely populated accommodation. The invasive necrotizing fasciitis, or flesh-eating disease, carries a high degree of morbidity and mortality and is frequently complicated by streptococcal toxic shock syndrome. GAS can also cause infections in many other organs including lung, bone and joint, muscle and heart valve, essentially mimicking the disease spectrum of S. aureus.

Pseudomonas aeruginosa:
Pseudomonas aeruginosa is commonly found in nonsterile areas on healthy individuals and, much like S. epidermidis, is considered a normal constituent of a person’s natural microflora. The bacteria normally live innocuously on human skin and in the mouth, but are able to infect practically any tissue with which they come into contact. Flexible, nonstringent metabolic requirements allow P. aeruginosa to occupy a variety of niches, making it the epitome of an opportunistic pathogen. Due to the general harmlessness of the bacteria, infections occur primarily in compromised patients and in hospital-acquired infections. Immunocompromised individuals with AIDS, cystic fibrosis and haematological and malignant diseases develop systemic or localized P. aeruginosa infections. Transmission often occurs through contamination of inanimate objects and can result in ventilator-associated pneumonia and other medical device-related infections. The main route of entry is through compromised skin, with burn victims commonly suffering from P. aeruginosa infections. On the skin, P. aeruginosa occasionally causes dermatitis or deeper soft-tissue infections. Dermatitis occurs when skin comes into contact with infected water, for example in hot tubs. The infection is very mild and is treated easily with topical antibiotics.

Much current research related to infectious diseases of the skin targets microbial virulence factors and aims to eliminate harmful organisms. Some of these same microbes potentially also play an opposite role by protecting the host. The complex host-microbe and microbe-microbe interactions that exist on the surface of human skin illustrate that the microbiota have a beneficial role, much like that of the gut microflora.

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• Staphylococcus aureus: superbug
• Microbes and puberty: a teenager’s guide
• Bad Hair Day

An estimated 15 percent of all human cancers worldwide may be caused by viruses (Viruses and Human Cancer. Yale J Biol Med. 2006 79: 115 122). Both DNA and RNA viruses are capable of causing cancer in humans. Although it is convenient to consider human tumor viruses as a discrete group of viruses, the six viruses which cause human cancers have very different genomes, replication cycles, and come from five different virus families. The path from virus infection to tumour formation is slow and inefficient. Only a minority of infected individuals progress to cancer, usually years or even decades after primary infection. Virus infection alone is generally not sufficient for cancer, and additional events and host factors, such as immunosuppression, somatic mutations, genetic predisposition, and exposure to carcinogens must also play a role.

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Hepatitis B and C viruses
Hepatitis C virus (HCV) is an enveloped RNA virus of the Flavivirus family. It is capable of causing both acute and chronic hepatitis in humans by infecting liver cells. It is estimated that approximately 3 percent of the world s population are hepatitis C carriers. Chronic infection with hepatitis C virus results in cirrhosis, which in turn can lead to primary hepatocellular carcinoma. Between 1 and 2 percent of infected patients with cirrhosis of the liver will develop primary hepatocellular carcinoma per year of infection. Transmission of HCV occurs through the blood, by shared needles in intravenous drug abuse, sexual activity, and birth being the primary routes.
The hepatitis B virus (HBV) of the family Hepadnaviridae is a DNA virus, but uses reverse transcription as part of its replication cycle. Hepatitis B virus also is a blood-borne pathogen that can result in acute and chronic hepatitis. Chronic hepatitis (infections lasting more than three months) can lead to cirrhosis and liver failure, and to the development of hepatocellular carcinoma. Hepatitis B infections is a significant global health problem with an estimated 2 billion people infected and 1.2 million deaths per year attributed to subsequent hepatitis, cirrhosis and hepatocellular carcinoma.

Epstein-Barr virus (EBV) and human herpesvirus 8 (HHV-8)
EBV and HHV-8 (also known as Kaposi sarcoma herpesvirus) are both herpesviruses that possess large double-stranded DNA genomes. As with all herpesviruses, they encode enzymes involved in DNA replication and repair and nucleotide biosynthesis. They also both possess the ability to establish latency in B lymphocytes and reactivate into the lytic cycle. Both also are associated with naturally occurring tumors in humans.
EBV is a ubiquitous virus that is most commonly known for being the primary agent for infectious mononucleosis (glandular fever). Up to 95 percent of all adults are estimated to be seropositive for EBV, and most infections are subclinical. EBV is associated with a number of malignancies: B and T cell lymphomas, Hodgkin s disease, post-transplant lymphoproliferative disease and nasopharyngeal carcinoma. Burkitt’s lymphoma, post-transplant lymphoproliferative disease show an increased frequency in patients with immunodeficiency, suggesting a role for immunosurveillance in the suppression of malignant transformation.
In 1994, HHV-8 DNA was identified in biopsies from tumors of a patient with Kaposi sarcoma, a relatively rare malignancy prior to the AIDS epidemic. In addition to it likely being an essential cofactor for the development of Kaposi sarcoma, HHV-8 also is believed to have a role in Castleman’s disease and primary effusion lymphoma. The HHV-8 genome is expressed in these tumors and encodes transforming proteins and anti-apoptotic factors. As with EBV, the predominant cell type infected is the B lymphocyte, although in these cells the lytic cycle occurs rather than being repressed. This may play a crucial role in the pathogenesis of Kaposi sarcoma by elaboration of virus and host cytokines promoting cell proliferation, angiogenesis, and enhancement of virus spread.

Human Papillomavirus (HPV)
Human papillomaviruses are small non-enveloped DNA tumour viruses that commonly cause benign papillomas or warts in humans. Persistent infection with high-risk subtypes of HPV is associated with the development of cervical cancer. HPV infects epithelial cells, and, after integration in host DNA, the production of oncoproteins, mainly E6 and E7, disrupts natural tumor suppressor pathways and is required for proliferation of cervical carcinoma cells. HPV is also believed to play a role in other human cancers, such as head and neck tumors, skin cancers in immunosuppressed patients, and other anogenital cancers.
Cervical cancer is the second leading cause of cancer mortality in women worldwide, causing 240,000 deaths annually. Of approximately 490,000 cases reported each year, more than 80 percent occur in the developing world, where effective but costly Pap smear screening programs are not in place. Early precancerous changes and early cancers detected by Pap smears are effectively treated and cured with surgical therapy or ablation. In the absence of effective screening, the disease is detected late.
The immune system plays an important role in the prevention of persistent HPV infection and progression of precancerous lesions. Human papillomavirus is a poor natural immunogen. As a double stranded DNA virus, there is no RNA intermediate, nor does infection cause cytolysis, allowing initiation of innate immune responses. HPV mainly encodes non-secreted nucleoproteins, which are poorly cross-presented and compared to other viruses its non-structural proteins are expressed at low levels. However, genital infection with HPV is usually transient. Additionally, inadequate T cell responses may lead to failure to clear HPV-infected cells. AIDS patients, renal transplant patients receiving immunosuppressive therapy, and individuals with T cell deficiencies have increased rates of HPV persistence, anogenital lesions, and cervical cancer.

Human T lymphotropic virus type I (HTLV-1)
HTLV-1 is a retrovirus and is associated with adult T-cell leukemia. This virus has a worldwide distribution, with an estimated 12 to 25 million people infected. However, disease is only observed in less than 5 percent of infected individuals. It is transmitted through blood transfusions, sexual contact, and during birth. HTLV-1 displays a special tropism for CD4 cells, which clonally proliferate in adult T cell leukemia, though how this is caused is not known.
HTLV-1 infection has a very long latency period of 20 to 30 years, but once tumor formation begins, progression is rapid. Standard chemotherapy often can bring about an initial response with a partial or complete remission; however, relapse is common, and median survival is eight months. The HTLV-1 Tax gene has been postulated to play an important role in tumour formation through the activation of virus transcription and the hijacking of cellular growth and cell division machinery, but the mechanisms leading to adult T cell leukemia are not well understood.

These six viruses illustrate the diverse biological pathways to malignancy and the challenges of treating the resulting diseases. The study of viruses and human cancer has led to optimism about the development of new strategies for the prevention of the infections that can lead to carcinogenesis. Antiviral drugs such as lamuvidine used against heptatitis B and ganciclovir for Kaposi sarcoma specifically target the virus replication machinery. The presence of virus gene products in tumour cells can provide important targets for directed therapies that specifically can distinguish tumour cells from normal cells. The inability of traditional cancer therapy, such as chemotherapy and radiation, to distinguish cancer cells from normal cells is a significant drawback and leads to toxicities for patients undergoing treatment. Targeted therapies directed against virus proteins or generate immune responses in order to either prevent infection or kill infected cells or cancer cells hold much promise for more effective and tolerable treatment strategies for virus-related tumours.

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The antiviral and anti-tumor actions of interferons are caused, in part, by a remarkable regulated RNA cleavage pathway known as the 2-5A/RNase L system. 2′-5′ linked oligoadenylates (2-5A) are produced from ATP by interferon-inducible synthetases. 2-5A activates pre-existing RNase L, resulting in the cleavage of RNAs within single-stranded regions. Activation of RNase L by 2-5A leads to an antiviral response, although precisely how this happens is a subject of ongoing investigations. Recently, RNase L was identified as the hereditary prostate cancer 1 gene. That finding has led to the discovery of a novel human retrovirus, XMRV. This scientific journey through the 2-5A system recounts some of the highlights of these efforts. Knowledge gained from studies on the 2-5A system could have an impact on development of therapies for important viral pathogens and cancer.

A scientific journey through the 2-5A/RNase L system.
Cytokine Growth Factor Rev. 2007 18: 381-388

Related:

• The Interferon Antiviral Response
• Interferon – 50 years on
• The history of interferon

The first thing you need to know about this topic is how to pronounce it! If you were an Ancient Greek, you may have said “ap-a-tow-sis”, but most people these days say “a-pop-tow-sis”, and everyone knows what they mean, so don’t worry about it. Apoptosis or “programmed cell death”, is a critical mechanism in tissue remodeling during embryonic development, and in cell killing by the immune system.

If you think about the immune response to infection, the first thing which might come to your mind are antibodies. These are frequently of importance in fighting invading microbes, but in the case of intracellular organisms such as viruses, parasites and some bacteria, antibodies are of limited help. In these cases, a cellular immune response is required which can detect and kill infected body cells and prevent the infection from spreading.

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There are two basics ways in which a cell can die: necrosis or apoptosis. Necrosis is the normal response of cells to injury caused by toxins or environmental stress and is marked by a non-specific changes such as:

• disruption of the plasma membrane and nuclear envelope
• rupture of membrane-bounded organelles such as mitochondria and lysosomes
• cell swelling
• random fragmentation of DNA/RNA
• influx of calcium ions into the cell and loss of membrane electrical potential

The release of cellular components from dying (necrotic) cells causes a localized inflammatory response by the cells of the immune system. This frequently leads to damage to adjacent cells/tissue – sometimes called “bystander” cell damage. In contrast to necrosis, apoptosis is a tightly regulated process controlled by complex molecular cascades, and is marked by:

• cell shrinkage
• condensation and clumping of chromatin
• a regular pattern of DNA fragmentation
• “bubbling off” of cellular contents into small membrane bounded vesicles (“blebbing”) which are subsequently phagocytosed by macrophages, preventing inflammation.

When triggered by the appropriate signals, immune effector cells such as cytotoxic T lymophocytes (CTLs) and natural killer (NK) cells release previously manufactured lytic granules stored in their cytoplasm. These act on the target cell and induce apoptosis by two mechanisms. The first of these is the release of cytotoxins such as perforin (also known as cytolysin), a peptide related to complement component C9. On release, this polymerizes to form polyperforin, which forms trans-membrane channels, resulting in permeability of the target cell membrane. Other granules contain granzymes, which are serine proteases related to trypsin. The perforin and the granzymes act collaboratively, the membrane pores formed by polyperforin allowing the entry of granzymes into the target cell. In addition, these membrane channels allow the release of intracellular calcium from the target cell, which also triggers apoptotic pathways. The second method by which CTLs (but not NK cells) can induce apoptosis is by expression of Fas ligand on their surface. This protein binds to Fas (CD95) on the surface of the target cell, triggering apoptosis by activation of cellular proteases known as caspases, which in turn trigger a cascade of events leading to apoptosis.

Apoptosis is an important response to virus infection. The regulation of apoptosis is complex, but in brief, virus infections disturb normal patterns of cellular biochemistry and frequently trigger an apoptotic response. Many different mechanisms may be involved:

• Receptor signalling: Binding of virus particles to cellular receptors may trigger signalling mechanisms resulting in apoptosis.
• PKR activation: The interferon effector PKR may be activated by some viruses.
• p53 activation: Viruses which interact with p53 may cause either growth arrest or apoptosis.
• Transcriptional disregulation: Viruses transcriptional regulatory proteins may trigger an apoptotic response.
• Foreign protein expression: Overexpression of virus proteins at late stages of the replication cycle can cause apoptosis by a variety of mechanisms.

To counteract this cellular burglar alarm, many if not most viruses have evolved mechanisms to repress apotosis:

• Bcl-2 homologs: negative regulator of apoptosis.
• Caspase inhibition
• Fas/TNF inhibition: signals blocked.
• p53 inhibition: viruses which interact with p53 have evolved proteins to counteract triggering of apoptosis.
• and many other mechanisms.

That’s a very brief overview of apoptosis and its role in cell killing by the immune system. If you want more details here are some references:

• A time to kill: viral manipulation of the cell death program. J Gen Virol. 2002 83: 1547-1564
• How apoptosis got the immune system in shape. Eur J Immunol. 2007 37: S61-70
• PubMed

The interferon (IFN) system is an extremely powerful antiviral response that is capable of controlling most, if not all, virus infections in the absence of adaptive immunity. However, viruses can still replicate and cause disease in vivo, because they have some strategy for at least partially circumventing the IFN response. A great deal has been discovered about the molecular mechanisms of the IFN response and how different viruses circumvent it. This information is of fundamental interest, but may also have practical application in the design and manufacture of attenuated virus vaccines and the development of novel antiviral drugs.

In the first part of this review, the authors describe how viruses activate the IFN system, how IFNs induce transcription of their target genes and the mechanism of action of IFN-induced proteins with antiviral action. The second part describes how viruses circumvent the IFN response and reflects on possible consequences for both the virus and host of the different strategies that viruses have evolved and discuss whether certain viruses have exploited the IFN response to modulate their life cycle (e.g. to establish and maintain persistent/latent infections), whether perturbation of the IFN response by persistent infections can lead to chronic disease, and the importance of the IFN system as a species barrier to virus infections. Lastly, it discusses applied aspects that arise from an increase in our knowledge in this area, including vaccine design and manufacture, the development of novel antiviral drugs and the use of IFN-sensitive oncolytic viruses in the treatment of cancer.

Interferons and viruses: an interplay between induction, signalling, antiviral responses and virus countermeasures.
J Gen Virol. 2008 89:1-47