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Baron S, editor. Medical Microbiology. 4th edition. Galveston (TX): University of Texas Medical Branch at Galveston; 1996.

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Medical Microbiology. 4th edition.

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Chapter 44Effects on Cells

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General Concepts


Cells that support viral replication are called permissive. Infections of permissive cells are usually productive because infectious progeny virus is produced. Most productive infections are called cytocidal (cytolytic) because they kill the host cell. Infections of nonpermissive cells yield no infectious progeny virus and are called abortive. When the complete repertoire of virus genes necessary for virus replication is not transcribed and translated into functional products the infection is referred to as restrictive. In persistent and in some transforming infections, viral nucleic acid may remain in specific host cells indefinitely; progeny virus may or may not be produced.

Cytocidal Infections

Infection by cytocidal viruses is usually associated with changes in cell morphology, in cell physiology and sequential biosynthetic events. Many of these changes are necessary for efficient virus replication.

Morphologic Effects: The changes in cell morphology caused by infecting virus are called cytopathic effects (CPE). Common examples are rounding of the infected cell, fusion with adjacent cells to form a syncytia (polykaryocytes), and the appearance of nuclear or cytoplasmic inclusion bodies. Inclusion bodies may represent either altered host cell structures or accumulations of viral components.

Effects on Cell Physiology: The interaction of virus with the cell membrane and/or subsequent events, (for example, de novo synthesized viral proteins) may change the physiological parameters of infected cells, including movement of ions, formation of secondary messengers, and activation cascades leading to altered cellular activities.

Effects on Cell Biochemistry: Many viruses inhibit the synthesis of host cell macromolecules, including DNA, RNA, and protein. Viruses may also change cellular transcriptional activity, and protein-protein interactions, promoting efficient production of progeny virus. For some viruses, specific cellular biochemical functions may be stimulated in order to enhance virus replication.

Genotoxic Effects: Following virus infection, breakage, fragmentation, rearrangement and/or changes in the number of chromosomes may occur.

Biologic Effects: Virus-specified proteins may alter the cell's antigenic or immune properties, shape, and growth characteristics.

Persistent Infections

Some viruses evolved the ability to remain in specific cells for long periods of time. These infections include: latent, chronic, and slow virus infections. The type of persistent infection usually influences the extent of cellular changes.

Latent Infection: Latent infections are characterized by restricted expression of the episomal or integrated virus genome. The viral genomic product(s) are associated with few, if any, changes in the latently infected cell.

Chronic Infection: The cellular effects of chronic infection are usually the same as those of acute cytocidal infections, except that production of progeny may be slower, intermittent or limited to a few cells. The long-term cellular changes may result in severe disease, immune suppression or may trigger immune responses to damaged, or undamaged cells or tissues.

Slow Infection: This type of virus-cell interaction is characterized by a prolonged incubation period, without significant morphological and physiological changes of infected cells. A slow progression of cellular injury may take years and is followed by extensive cellular injury and disease.

Transforming Infections

DNA or RNA tumor viruses may mediate multiple changes that convert a normal cell into a malignant one. RNA tumor viruses usually transform cells to a malignant phenotype by integrating their own genetic material into the cellular genome and may also produce infectious progeny. DNA tumor virus infections are often cytocidal; thus transformation is associated with abortive or restrictive infections in which few viral genes are expressed.

Stages of Transformation: Transformation involves at least two processes: first, the cell gains the capacity for unlimited cell division (immortalization), and second, the immortalized cells acquire additional heritable genetic changes by which the cell is able to produce a tumor in an appropriate host.

Mechanisms of Oncogenic Transformation: There are two general patterns by which cell transformation may be accomplished: 1) the tumor virus may introduce and express a so-called transforming gene in the cells or 2) the tumor virus may alter the expression and (or) coding capacity of preexisting cellular genes. After development of a malignant phenotype the relevant segment(s) of the viral genome may or may not be retained in the transformed cells, depending on the mechanism of transformation. These mechanisms are not mutually exclusive, and both may occur in the same cell.


In most cases, the disturbances of bodily function that are manifested as the signs and symptoms of viral disease result from the direct effects of viruses on cells. Knowledge of the morphologic, physiologic, biochemical, and immunologic effects of viruses on cells is essential in understanding the pathophysiology of viral disease and in developing accurate diagnostic procedures and effective treatment.

Virus-host cell interactions (Table 44-1) may produce either 1) cytocidal (cytolytic) infections, in which production of new infectious virus kills the cell; 2) persistent infections, in which the virus or its genome resides in some or all of the cells without killing most of them; or 3) transformation, in which the virus does not kill the cell, but produces genetic, biochemical, physiologic, and morphologic changes that may result in the acquisition of malignant properties (see also Ch. 47). The type of virus infection and the virus-induced effects on cells are dependent on the virus, the cell type and species, and often the physiologic state of the cell.

Table 44-1. Virus-Cell Interactions and Representative Effect on Cells.

Table 44-1

Virus-Cell Interactions and Representative Effect on Cells.

Cytocidal Infections

Morphologic and Structural Effects

Infection of permissive cells with virus leads to productive infection and often results in cell death (cytocidal, cytolytic infection). The first effects of the replication of cytocidal viruses to be described were the morphologic changes known as cytopathic effects. Cultured cells that are infected by most viruses undergo morphologic changes, which can be observed easily in unfixed, unstained cells by a light microscope. Some viruses cause characteristic cytopathic effects; thus, observation of the cytopathic effect is an important tool for virologists concerned with isolating and identifying viruses from infected animals or humans (Fig. 44-1).

Figure 44-1. Development and progression of viral cytopathology.

Figure 44-1

Development and progression of viral cytopathology. Human embryo skin muscle cells were infected with human cytomegalovirus and stained at selected times to demonstrate (A) uninfected cells, (more...)

Many types of cytopathic effects occur. Often the first sign of viral infections is rounding of the cells. In some diseased tissues, intracellular structures called inclusion bodies appear in the nucleus and/or cytoplasm of infected cells. Inclusion bodies were first identified by light microscopy in smears and stained sections of infected tissues. Their composition can often be clarified by electron microscopy. In an adenovirus infection, for example, crystalline arrays of adenovirus capsids accumulate in the nucleus to form an inclusion body.

Inclusions may alternatively be host cell structures altered by the virus. For example, in reovirus-infected cells, virions associate with the microtubules, giving rise to a crescent-shaped perinuclear inclusion. Infection of cells by other viruses causes specific alterations in the cytoskeleton of cells. For example, extensive changes in cellular intermediate filaments in relation to formation of viral inclusions may be observed after cytomegalovirus infection (Fig. 44-4). Some characteristics of inclusion bodies produced by various viruses are listed in Table 44-2.

Figure 44-4. Alteration of cytoskeleton organization by virus infection.

Figure 44-4

Alteration of cytoskeleton organization by virus infection. Normal cells have networks of microtubules, and intermediate filaments throughout the cytoplasm. Infection with reovirus causes (more...)

Table 44-2. Viral Inclusion Bodies in Some Human Diseases.

Table 44-2

Viral Inclusion Bodies in Some Human Diseases.

A particularly striking cytopathic effect of some viral infections is the formation of syncytia, or polykaryocytes, which are large cytoplasmic masses that contain many nuclei (poly, many; karyon, nucleus) and are usually produced by fusion of infected cells (Fig. 44-2). The mechanism of cell fusion during viral infection probably results from the interaction between viral gene products and host cell membranes. Cell fusion may be a mechanism by which virus spreads from infected to uninfected cells.

Figure 44-2. Formation of multinucleated cells.

Figure 44-2

Formation of multinucleated cells. The figure represents the cytopathology of measles virus-induced syncytia.

Effects on Cell Physiology

Research into the pathogenesis of virus infections suggests a close correlation between cellular physiologic responses and the replication of some viruses (Fig. 44-3). In other words, the physiological state of living cells has a significant effect on the outcome of the virus infection, since the host cell provides the synthetic machinery, key regulatory molecules, and precursors for the newly synthesized viral proteins and nucleic acids. The optimal intracellular environment for virus replication develops through events that begin to take place with attachment of virus to the cell membrane. Binding of virus to the cell membrane receptor(s) may be followed by cascades of events that are associated with biochemical, physiological and morphological changes in the cells. The virus receptor is a cell membrane component that participates in virus binding, facilitates viral infection, and is a determinant of virus host range, as well as tissue tropism. Some viruses recognize more than one cellular receptor (e.g., HIV, adenoviruses) and the binding is a multistage process (see Table 44-3). Multiple receptors may act together either to modulate each other's activity or to contribute complementary functions.

Figure 44-3. Relationship of morphological, physiological, and biochemical cellular effects to the replication of human cytomegalovirus.

Figure 44-3

Relationship of morphological, physiological, and biochemical cellular effects to the replication of human cytomegalovirus. Examples for biochemical and physiological cellular responses: aformation (more...)

Table 44-3. Proposed Cell Membrane Receptors for Viruses.

Table 44-3

Proposed Cell Membrane Receptors for Viruses.

Other virus-associated alterations in cell physiology are related to insertion of viral proteins or other changes in the cell membrane. One example is the leaky cell membrane that appears after infection with picornaviruses or Sindbis virus; the change in intracellular ion concentrations that results from the leaky membrane may favor translation of the more salt-stable (e.g., Na+ or K+) viral mRNA over cellular, mRNA. These and other effects may be maintained or modified by immediate early and/or early viral gene products (e.g., changes in transcription and protein levels of cell cycle regulatory molecules). Figure 44-3 demonstrates the coordination of cellular physiologic responses with the replication of a herpesvirus (human cytomegalovirus).

Effects on Cell Biochemistry

Virus binding to the cell membrane in concert with immediate early (e.g., IE proteins of herpesviruses), early non-structural proteins (e.g., E-6, E-7 of HPVs) or virion components (e.g., ICP0, ICP4, VP16 of herpes simplex virus, penton protein of adenoviruses) may mediate a series of biochemical changes that optimize the intracellular milieu for use of cellular synthetic machinery, low molecular weight precursors for productive virus replication or to achieve latency, chronic, slow or transforming infection. For example, studies of transcriptional regulation of viral genes and post-transcriptional modification of gene products (splicing, polyadenylation of RNA) demonstrate that the nature of the basic biochemical processes for virus replication are similar to the mechanisms used to regulate expression of cellular genes. Viruses have sequence motifs in their nucleic acid for binding of known transcriptional regulators of cellular origin. Thus, promoter regions of regulatory and structural proteins for many viruses (Table 44-4) contain contiguous binding sites for a large array of identifiable mammalian cellular transcription factors (e.g., NFκ B, Sp1, CRE/B, AP-1, Oct-1, NF-1). These cellular transcription factors in concert with regulatory viral proteins are involved in activation or repression of viral and cellular genes to develop latent, persistent, transforming virus infections, as well as to produce progeny virus. Most cellular transcription factors must be activated prior to binding to their specific recognition (consensus) sequences. The biochemical events may include phosphorylation, dephosphorylation, disassociation (from inhibitory subunit) and dimerization. These activation processes can be accomplished as a result of the cascade of events initiated by the virus and cell receptor interaction. Events associated with these cascades may include, for example, formation of secondary messengers (phosphatidyl inositols, diacylglycerols, cAMP, cGMP, etc.), activation of protein kinases, and ion (e.g., Ca2+) influxes.

Table 44-4. Cellular Transcription Factors that are Involved in Regulation of Viral Gene Expression.

Table 44-4

Cellular Transcription Factors that are Involved in Regulation of Viral Gene Expression.

To maintain cell activation processes, viruses have evolved unique mechanisms to regulate these cellular processes, adapting their proteins to interact with cellular proteins. Examples include the association of early virus gene products (e.g., E-6, E-7 of papillomaviruses; IE proteins of herpesviruses; SV40 T antigen) with the Rb tumor suppresser protein which results in liberation of the E2F transcription factor that is required for modification (activation/inhibition) of cellular biochemical pathways, for synthesis of viral DNA, or initiation of cellular apoptotic processes (programmed cell death).

In some cases the virus directly incorporates cellular biochemical regulatory strategies by triggering the cells to overproduce and excrete regulatory molecules (e.g., transforming growth factors, tumor necrosis factors, interleukins), which may activate in an autocrine fashion cellular biochemical cascades involved in virus (e.g., HIV, herpesviruses, papillomaviruses) replication, maintenance of or reactivation from a latent state, or maintaining a transformed phenotype. On the other hand, these soluble cellular regulatory molecules may inhibit biochemical reactions of immune cells in a paracrine manner to compromise elimination of infected cells.

Inhibition of cellular macromolecule synthesis may result from virus infection and provide an advantage for synthesis of virus proteins and nucleic acids in the absence of competing synthesis of cellular products. This inhibition occurs in characteristic ways. In poliovirus or herpes simplex infections, for example, selective inhibition of host protein synthesis occurs prior to the maximal synthesis of viral proteins. In some cases, viral products inhibit both protein and nucleic acid synthesis. Purified adenovirus penton fibers significantly decrease the synthesis of host protein, RNA, and DNA. Total inhibition of host macromolecular synthesis also may occur when excess viral products accumulate in the cell late in the viral replicative cycle. Some picornaviruses specify a protein that causes cell damage independent of the viral proteins that inhibit cell macromolecular synthesis. Cellular mRNA may be degraded. For example, in influenza virus and herpes simplex virus infections, cellular mRNA stops binding with ribosomes to form polyribosomes; only virus-specific mRNA is bound, giving viral mRNAs a selective advantage. Cell DNA synthesis is inhibited in most cytolytic virus infections. This may be achieved by virus-induced apoptosis or by a decrease in cellular protein synthesis. Reoviruses and some herpesviruses may be exceptions in that they cause a decrease in cell DNA synthesis before a substantial decline in cellular protein synthesis occurs. Direct degradation of host DNA is seen in vaccinia virus infections due to a virion-associated DNase.

Genotoxic Effects

Chromosome damage may be caused directly by the virus particle or indirectly by events occurring during synthesis of new viral macromolecules (RNA, DNA, protein). The chromosome damage (Fig. 44-5) may or may not be faithfully repaired, and in either case, it may or may not be compatible with survival of the infected cell. When the cell survives, the virus genome may persist within the cell, possibly leading to continued instability of cellular genomic material or to altered expression of cellular genes (e.g., cellular oncogenes). Virus-induced genomic instability appears to be associated with accumulation of mutations and related to the process of cell immortalization and oncogenic transformation.

Figure 44-5. Chromosomal aberrations resulting from cytomegalovirus infection of human peripheral blood lymphocytes.

Figure 44-5

Chromosomal aberrations resulting from cytomegalovirus infection of human peripheral blood lymphocytes.

Biologic Effects

The biologic consequences of virus infection results from the aforementioned biochemical, physiological, structural, morphological and genetic changes. In productive infections virus-induced biological modifications of the cell may be closely related to the efficiency of virus replication or to the recognition of these cells by the immune system. For cells that are persistently infected, the cellular changes caused by the virus could lead to disease (e.g., subacute sclerosing panencephalitis after measles infection), cellular genetic damage (e.g., hepatitis B virus), immortalization (e.g., Epstein-Barr virus), or malignant transformation (e.g., HTLV-1, HTLV-2, hepatitis B virus). The wide variety of these effects of virus infection points to the complex interaction between the viruses and their host cell.

Relation of Cellular Effects to Viral Pathogenesis

Although most of the events that damage or modify the host cell during lytic infection are difficult to separate from viral replication, the effects are not always linked directly to the production of progeny virions. For example, changes in cell size, shape, and physiologic parameters may occur before progeny virions or even many virus proteins, are produced. These alterations in cell structure and function may be important aspects of the pathogenesis of a number of viral infections (see Ch. 45). For example, through their cellular effects many viruses (e.g., rotaviruses, caliciviruses, Norwalk viruses) induce gastrointestinal symptoms (ranging from mild alteration in absorption of ions to severe watery diarrhea). Cytocidal viral infections (e.g., herpesviruses, togaviruses, flaviviruses, bunyaviruses) of the central nervous system are related to necrosis, inflammation or phagocytosis by supporting cells. Rubella virus infections are associated with demyelination without neural degeneration. The long-term effects of persistent virus infections (see below) may also be related to such progressive diseases as atherosclerosis and demyelination in multiple sclerosis.

Persistent Infections

Types of Persistent Infection

In a persistent infection the virus is not eliminated from all of the host tissues after initial infection or the acute phase of disease. The several types of persistent infection [chronic, slow, latent, and transforming (Table 44-1; see Chs. 46 and 47)] differ in the mechanisms controlling their pathogenesis. In chronic infections, a limited number of cells (in the target organs) are infected. These infected cells may demonstrate a cytopathic effect, synthesize virus macromolecules, and release infectious virus. The spread of infection is limited by host factors such as humoral and cell-mediated immune responses, interferons and other nonspecific inhibitors. Slow infections induced by conventional (e.g., measles) or unconventional viruses (e.g., prions) are characterized by long incubation periods (years), preceding the onset of clinical symptoms. In latent infections, infectious virus is seldom detected between clinical episodes of disease. Few cells are infected, and virus expression and replication are extensively restricted. Common features of latent infection are their ability to reactivate in response to various environmental stimuli (e.g., heat, ultraviolet irradiation), and immune suppression brought on by heterologous virus infection (e.g., HIV) or chemotherapy, often associated with organ transplantation. In transforming persistent infections, infectious virus (RNA tumor viruses) may or may not be released, but as a result of heritable genetic changes to cellular genes, acquisition of a viral oncogene, or the effect of integrated viral sequences, the cells undergo alterations that result in malignant phenotypes.

Responses to Persistent Infections

Autoimmune injury and other forms of cell damage may occur during persistent infections. Budding virions and viral peptides associated with the cell membrane change the antigenic characteristics of the cell so that the immune system may recognize it as foreign (see Chs. 1 and 50). The cell then may be attacked by the humoral and cellular immune systems of the host and may die, even if it was infected by a noncytocidal virus.

The immune response also may cause formation of circulating antigen-antibody complexes involving viral antigens. These complexes may deposit (e.g., in the glomeruli) and elicit inflammation by activating the classical pathway of complement. The long-term association of the virus with specific target cells may lead to altered function or responses; this type of mechanism is thought to be responsible for the progressive neurologic disease associated with slow virus infections such as kuru, Creutzfeldt-Jakob disease, or subacute sclerosing panencephalitis (see Ch. 71).

Transforming Infections

The term oncogenic transformation refers to the process through which control of cell proliferation is genetically modified, so that the cell becomes cancerous (see Ch. 47). In the context of virus-cell interactions, the cells can also undergo various types of heritable changes, that result in biochemical, antigenic, morphologic, and physiologic alterations, called non-oncogenic transformation.

Transforming Virus Host Cell Interactions

DNA viruses induce transformation only under conditions that restrict virus replication and permit survival of infected cells (e.g., in noncytolytic infections of selected cell types or animal hosts, or in infection with incomplete virions). Under such conditions, immediate early (e.g., EBNAs of Epstein-Barr virus) or early proteins (e.g., SV40 “T” or polyoma middle “t” antigen) are usually present, but infectious progeny virions are seldom produced. In contrast, because RNA tumor virus replication is usually noncytocidal, they can cause oncogenic transformation in permissive cells or in their natural hosts, and viral products may be produced whether or not virus is released. For specific details see Chapter 45.

Stages and Mechanisms of Cellular Transformation

Current data indicate that transformation of a cell involves at least two components: first, the cell gains the capacity for unlimited cell division (immortalization), and second, the immortalized cells acquire the ability to produce a tumor in an appropriate host. Some viral genes that can immortalize cells include, for example, T antigens (Fig. 44-6) of papovaviruses (e.g., polyoma, JC, SV40), early proteins (e.g., E6, E7) of papillomaviruses, and Epstein-Barr virus (e.g. EBNA-5). In these cases, the viral proteins may interact and inactivate one or more cellular tumor suppresser proteins (e.g., Rb, p53), resulting in a significantly impaired cell cycle regulation. During the perturbed cell cycling, accumulation of mutations may occur either spontaneously or as an effect of other agents (virus, chemical, radiation) in cellular oncogenes (e.g., H-ras, K-ras; c-myc), in anti-oncogenes (e.g., p53, Rb), or in other cellular genes. In vivo, the history of malignancies also suggests a multiple process of cellular evolution, involving cumulative genetic changes, selection of rare cells that have the ability to invade, metastasize, and avoid immune surveillance. The number of mutations supporting an oncogenic transformation is estimated to range from six to more. Virus infections may contribute both to immortalization and to the accumulation of mutations in growth related cellular genes during oncogenic processes. The characteristics of oncogenically transformed cells are summarized in Table 44-5.

Figure 44-6. Intranuclear transforming T antigen specified by simian virus 40 in transformed human cells.

Figure 44-6

Intranuclear transforming T antigen specified by simian virus 40 in transformed human cells.

Table 44-5. The Most Prominent Changes Associated with Transformed Cells.

Table 44-5

The Most Prominent Changes Associated with Transformed Cells.


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Copyright © 1996, The University of Texas Medical Branch at Galveston.
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