Host-Cell Reactions

Possible consequences of viral infection for the host cell:

-Cytocidal infection (necrosis): viral replication results directly in cell destruction (cytopathology, so-called “cytopathic effect” in cell cultures).

-Apoptosis: the virus initiates a cascade of cellular events leading to cell death (“suicide”), in most cases interrupting the viral replication cycle.

-Noncytocidal infection: viral replication per se does not destroy the host cell, although it may be destroyed by secondary immunological reactions.

-Latent infection: the viral genome is inside the cell, resulting in neither viral replication nor cell destruction.

-Tumor transformation: the viral infection transforms the host cell into a cancer cell, whereby viral replication may or may not take place depend­ing on the virus and/or cell type involved.

Cell Destruction (Cytocidal Infection, Necrosis)

Cell death occurs eventually after initial infection with many viral species. This cytopathological cell destruction usually involves production of viral progeny. Virus production coupled with cell destruction is termed the “lytic viral life cycle.” Cell destruction, whether necrotic or apoptotic (see below) is the reason (along with immunological phenomena) for the disease mani­fested in the macroorganism.

Structural changes leading to necrosis: morphological changes characteris­tic of a given infecting virus can often be observed in the infected cell. The effects seen in virally infected cell cultures are well-known and are desig­nated by the term “cytopathic effect” (CPE). These effects can also be exploited for diagnostic purposes. They include rounding off and de­tachment of cells from adjacent cells or the substrate, formation of multi- nuclear giant cells, cytoplasmic vacuoles, and inclusion bodies. The latter are structures made up of viral and/or cellular material that form during the viral replication cycle, e.g., viral crystals in the nucleus (adenoviruses) or collections of virions and viral material in the cytoplasm (smallpox viruses). Although these structural changes in the host cell do contribute to necrotic cytopathy, their primary purpose is to support specific steps in viral synthesis. For example, RNA synthesis and viral assembly in picornavirus infections requires specific, new, virus-induced membrane structures and vesicles that subsequently manifest their secondary effect by causing a CPE and eventual cell death.

Apoptosis. Cells possess natural mechanisms that initiate their self-destruc­tion (apoptosis) by means of predetermined cytoplasmic and nuclear changes. Infections with some viruses may lead to apoptosis. In rapidly re­plicating viruses, the viral replication process must be decelerated to allow the slow, energy-dependent process of apoptosis to run its course before the cell is destroyed by virus-induced necrosis. The body rapidly eliminates apoptotic cells before an inflammatory reaction can develop, which is appar­ently why virus-induced apoptosis used to be overlooked so often. Apoptosis can thus be considered a defense mechanism, although certain viruses are able to inhibit it.

Virus Replication without Cell Destruction (Noncytocidal Infection)

This outcome of infection is observed with certain viruses that do not cause any extensive restructuring of the host cell and are generally released by “budding” at the cell surface. This mode of replication is seen, for example, in the oncornaviruses and myxoviruses and in the chronic form of hepatitis B virus infection. However, cell destruction can follow as a secondary result of infection, however, if the immune system recognizes viral antigens on the cell surface, classifies it as “foreign” and destroys it.

Latent Infection

In this infection type, the virus (or its genome) is integrated in a cell, but no viral progenies are produced. The cell is accordingly not damaged and the macro­organism does not manifest disease. This form of infection is found, for instance, with the adenovirus group and in particular the herpesviruses, which can re­main latent for long periods in the human body. Latency protects these viruses from immune system activity and thus is part of their survival strategy. How­ever, a variety of initiating events can initiate a lytic cycle leading to manifest disease and dissemination of the virus. Repeated activation of a latent virus is termed recidivation (e.g., herpes labialis).

Tumor Transformation

Infections by a number of viruses do not result in eventual host cell death, but rather cause tumor transformation of the cell. This means the cell is altered in many ways, e.g., in its growth properties, morphology, and metabolism. Fol­lowing an infection with DNA tumor viruses, the type of host cell infected determines whether the cell reaction will be a tumor transformation, viral replication or lytic cycle. The transformation that takes place after infection with an RNA tumor virus either involves no viral replication (nonpermissive infection) or the cell produces new viruses but remains vital (permissive in­fection).

Carcinogenic Retroviruses (“Oncoviruses”)

Genome structure and replication of the oncoviruses. The genomes of all oncoviruses possess gag (group-specific antigen), pol (enzymatic activities: polymerase complex with reverse transcriptase, integrase, and protease), and env (envelope glycoproteins) genes. These coding regions are flanked by two control sequences important for regulatory functions called LTR (= long terminal repeats), Fig. 1. These sequences have a promoter/enhancer function and are responsible for both reverse transcription and insertion of the viral genome into the cell DNA. Certain oncoviruses possess a so-called “onc gene" instead of the pol region (onc gene = oncogene, refers to a cellular gene segment acquired by recombination, see below). These viruses also of­ten have incomplete gag and/or env regions. Such viruses are defective and require a helper virus to replicate (complementation). An excep­tion to this principle is the Rous sarcoma virus, which possesses both an onc gene and a complete set of viral genes and can therefore replicate itself.

Fig. 1 a Autonomously reproducing oncoviruses with the three replication genes gag, pol, env, flanked by the LTR regions. b Defective oncoviruses contain an onc gene instead of the entire pol region and parts of the gag and env regions.

Tumor induction by oncoviruses. Both types of carcinogenic retroviruses, i.e., those with no oncogene and intact replication genes (gag, pol, env, flanked by the LTR regions) and those that have become defective by taking on an oncogene, can initiate a tumor transformation. On the whole, oncoviruses play only a subordinate role in human tumor induction.

-Retroviruses without an oncogene: LTR are highly effective promoters. Since the retrovirus genome is integrated in the cell genome at a random

position, the LTR can also induce heightened expressivity in cellular proto­oncogenes (“promoter insertion hypothesis” or “insertion mutagenicity”), which can lead to the formation of tumors. This is a slow process (e.g., chronic leukemias) in which cocarcinogens can play an important role. The trans­formed cells produce new viruses.

-Retroviruses with an oncogene: a viral oncogene always represents a changed state compared with the original cellular proto-oncogene (deletion, mutation). It is integrated in the cell genome together with the residual viral genome (parts) after reverse transcription, and then expressed under the influence of the LTR, in most cases overexpressed. This leads to rapid devel­opment of acute malignancies that produce no new viruses.

Overproduction of oncogene products can be compensated by gene products from antioncogenes. The loss or mutation of such a suppressor gene can therefore result in tumor formation.

DNA Tumor Viruses

Genes have also been found in DNA tumor viruses that induce a malignant transformation of the host cell. In contrast to the oncogenes in oncoviruses, these are genuine viral genes that have presumably developed independently of one another over a much longer evolutionary period. They code for viral regulator proteins, which are among the so-called early proteins. They are produced early in the viral replication cycle and assume essential functions in viral DNA replication. Their oncogenic potential derives among other things from the fact that they bind to the products of tumor suppressor genes such as p53, Rb (antioncogenes, “antitransformation proteins” see above) and can thus inhibit their functions. DNA viruses are more important indu­cers of human tumors than oncoviruses (example: HHV8, papovaviruses, hepatitis B viruses, Epstein-Barr viruses).

References

Fritz H. Kayser, M.D. Emeritus Professor of Medical Microbiology Institute of Medical Microbiology, University of Zurich, Zurich, SwitzerlandThieme 2005, Stuttgart ! New York.