x x






Dr Gene Mayer
Emeritus Professor
Department of Pathology, Microbiology and Immunology
University of South Carolina School of Medicine

En Español
Let us know what you think
Logo image © Jeffrey Nelson, Rush University, Chicago, Illinois  and The MicrobeLibrary

To describe host specific and nonspecific defense mechanisms involved in resistance to and recovery from virus infections

To discuss the role of interferon in viral infections

To review the mechanisms by which interferon exerts its antiviral activity

To discuss the relative contributions of various host defense mechanisms in viral infections

Resistance to and recovery from viral infections will depend on the interactions that occur between virus and host. The defenses mounted by the host may act directly on the virus or indirectly on virus replication by altering or killing the infected cell. The non-specific host defenses function early in the encounter with virus to prevent or limit infection while the specific host defenses function after infection in recovery immunity to subsequent challenges. Although the host defense mechanisms involved in a particular viral infection will vary depending on the virus, dose and portal of entry, some general principals of virus-host interactions are summarized below.


Inherent Barriers
The host has a number of barriers to infection that are inherent to the organism. These represent the first line of defense which function to prevent or limit infection.

The skin acts a formidable barrier to most viruses and only after this barrier is breached will viruses be able to infect the host.

Lack of Membrane Receptors 
Viruses gain entry into host cells by first binding to specific receptors on cells (Table 1; adapted from: Roitt, Immunology, 5th Ed).

Inherent defenses
Induced defenses
 2'5' Oligo A synthetase
IFN-activated protein kinase
Intrinsic antiviral activity
Extrinsic antiviral activity
Immune adherence
NK cells

Table 1



Cell Type Infected



TH cells

Epstein-Barr virus

CR2 (complement receptor type 2)

B cells

Influenza A

Glycophorin A

Many cell types

Rhino virus


Many cell types

The host range of the virus will depend upon the presence these receptors. Thus, if a host lacks the receptor for a virus or if the host cells lacks some component necessary for the replication of a virus, the host will inherently be resistant to that virus.  For example, mice lack receptors for polio viruses and thus are resistant to polio virus. Similarly, humans are inherently resistant to plant and many animal viruses.

The mucus covering an epithelium acts as a barrier to prevent infection of host cells. In some instances the mucus simply acts as a barrier but in other cases the mucus can prevent infection by competing with virus receptors on cells.  For example, orthomyxo- and paramyxovirus families infect the host cells by binding to sialic acid receptors. Sialic acid-containing glycoproteins in mucus can thus compete with the cell receptors and diminish or prevent binding of virus to the cells.

Ciliated epithelium 
The ciliated epithelium which drives the mucociliary elevator can help diminish infectivity of certain viruses. This system has been shown to be important in respiratory infections since, when the activity of this system is inhibited by drugs or infection, there is an increased infection rate with a given inoculum of virus.

Low pH 
The low pH of gastric secretions inactivate most viruses. However, enteroviruses are resistant to gastric secretions and thus can survive and replicate in the gut.

Humoral and cellular components 
See below


Induced Barriers
Changes that occur in the host in response to infection can also help diminish virus infectivity.

Fever can help to inhibit virus replication by potentiating other immune defenses and by decreasing virus replication. The replication of some viruses is reduced at temperatures above 37degrees C.

Low pH 
The pH of inflammatory infiltrates is also low and can help limit viral infections by inactivating viruses.

Humoral and cellular components 
See below



A number of humoral components of the nonspecific immune system function in resistance to viral infection. Some of theses are constitutively present while others are induced by infection.

Interferon (IFN) 
IFN was discovered over 40 years ago by Issacs and Lindemann who showed that supernatant fractions from virus-infected cells contained a protein that could confer resistance to infection to other cells. This substance did not act directly on the virus, rather it acted on the cells to make them resistant to infection (Figure 1).

v-h1.jpg (83913 bytes)  Fig. 1. The discovery of interferon

v-h2.jpg (43722 bytes)  Fig. 2. Typical response to an acute virus infection

IFN is one of the first lines of defense against viruses because it is induced early after virus infection before any of the other defense mechanisms appear (e.g. antibody, Tc cells etc.) (Figure 2). The time after which IFN begins to be made will vary depending on the dose of virus.

a) Types and Properties of Interferons
Table 2; Adapted from: Murray, Medical Microbiology, 5th Ed. Table 14-3)

Table 2

Types and Properties of Interferon







Previous designations

Leukocyte IFN

Type I

Fibroblast IFN

Type I

Immune IFN

Type II





pH2 stability





Viruses (RNA>DNA)




Antigens, Mitogens

Principal source

Leukocytes, Epithelium



There are three types of interferon, IFN-alpha (also known as leukocyte interferon), IFN-beta (also known as fibroblast interferon) and IFN-gamma (also known as immune interferon). IFN-alpha and IFN-beta are also referred to as Type I interferon and IFN-gamma as Type II. There are approximately 20 subtypes of IFN-alpha but only one IFN-beta and IFN-gamma.

The interferons have different characteristics that could be used to distinguish them (e.g. pH stability and activity in the presence of SDS) but currently they are identified by using specific antibodies to the interferons.

b) Inducers of Interferons - Normal cells do not contain preformed IFN nor do they secret interferon constitutively. This is because the interferon genes are not transcribed in normal cells. Transcription of the IFN genes occurs only after exposure of cells to an appropriate inducer. Inducers of IFN-alpha and IFN-beta include virus infection, double stranded RNA (e.g. poly inosinic:poly cytidylic acid; [poly I:C]), LPS, and components from some bacteria. Among the viruses, the RNA viruses are the best inducers while DNA viruses are poor IFN inducers, with the exception of poxviruses. Inducers of IFN-gamma include mitogens and antigen (i.e. things that activate lymphocytes).

v-h3.jpg (148328 bytes)  Fig. 3. Mode of action of interferon

c) Cellular Events in the Induction of Interferons
The IFN genes are not expressed in normal cells because the cells produce a labile repressor protein that binds to the promoter region upstream of the gene and inhibits transcription. In addition, transcription of the genes require activator proteins to bind to the promoter region and turn on transcription. Inducers of IFN act by either preventing synthesis of the repressor protein or increasing the levels of the activator proteins, thereby turning the IFN gene on. After the inducer is gone, the IFN gene is again turned off by the repressor protein and/or the lack of activator proteins. Once the gene is turned on, it is transcribed, the mRNA is translated and the protein is secreted from the cell. The IFN will bind to IFN-receptors on neighboring cells and induce an antiviral state in the second cell (Figure 3)

v-h4.jpg (122784 bytes)  Fig. 4  Molecular basis of the antiviral state

d) Cellular Events in the Action of Interferons - The binding of IFN to its receptor results in the transcription of a group of genes that code for antiviral proteins involved in preventing viral replication in that cell. As a consequence the cell will be protected from infection with a virus until the antiviral proteins are degraded, a process which takes several days. The antiviral state in IFN-treated cells results from the synthesis of two enzymes that result in the inhibition of protein synthesis. One protein indirectly affects protein synthesis by breaking down viral mRNA the other directly affects protein synthesis by inhibiting elongation (Figure 4).

One protein, called 2'5'Oligo A synthetase, is an enzyme that converts ATP into a unique polymer (2'5' Oligo A) containing 2'- 5'phophodiester bonds. Double stranded RNA is required for the activity of this enzyme. The 2'5'Oligo A in turn activates RNAse L which then breaks down viral mRNA. The second protein is an protein kinase that, in the presence of double stranded RNA, is autophosphorylated and thereby activated. The activated protein kinase in turn phosphorylates elongation factor eIF-2 and inactivates it. By the action of these two IFN-induced enzymes protein synthesis is inhibited. Although the infected cell may die as a consequence of the inhibition of host protein synthesis, the progress of the infection is stopped. Uninfected cells are not killed by IFN treatment since activation of the two enzymes requires double stranded RNA, which is not produced. Some viruses have means of inhibiting the antiviral effects of IFN. For example the adenoviruses produce an RNA which prevents the activation of the protein kinase by double stranded RNA thereby reducing the antiviral effects of IFN.

v-h5.jpg (195718 bytes)  Fig. 5  Effects of interferons alpha, beta and gamma

e) Other Biological Activities of Interferons - IFN not only induces the production of antiviral proteins, it also has other effects on cells, some of which indirectly contribute to the ability of the host to resist or recover from a viral infection (Figure 5). IFN can help modulate immune responses by its effects on Class I and Class II MHC molecules. IFN-alpha, IFN-beta and IFN-gamma increase expression of Class I molecules on all cells thereby promoting recognition by Tc cells which can destroy virus infected cells. IFN-gamma can also increase expression of Class II MHC molecules on antigen presenting cells resulting in better presentation of viral antigens to CD4+ T helper cells. Furthermore, IFN-gamma can activate NK cells which can kill virus infected cells. IFNs also activate the intrinsic and extrinsic antiviral activities of macrophages. Intrinsic antiviral activity is the ability of macrophages to resist infection with a virus and extrinsic antiviral activity is the ability of macrophages to kill other cells infected with virus. The IFNs also have anti-proliferative activity making them useful in the treatment of some malignancies.


f) Clinical Uses of Interferons - IFNs have been used in the treatment of a number of viral and other diseases (Table 3; Adapted from: Mims, Medical Microbiology, Fig 37.5 )

Table 3 

Clinical Uses of Interferons


Therapeutic use

IFN-alpha, IFN-beta

Hepatitis B (chronic)

Hepatitis C

Herpes zoster

Papilloma virus

Rhino virus (prophylactic only)



Lepromatous leprosy



Chronic granulomatous disease (CGD)



In addition due to its anti proliferative effects IFNs have also been used in the treatment of a variety of cancers (Table 4; Adapted from: Zinsser, Microbiology, 20th Ed, Table 58.3).


Table 4

Use of Interferons on Cancer Treatment


Percent Complete or Partial Remissions

Hairy cell leukemia


Chronic myelocytic leukemia


T cell lymphoma


Kaposi's sarcoma


Endocrine pancreatic neoplasms


Non-Hodgkin's lymphomas

25 - 35



However, the side effects of IFN therapy limits their casual use in clinical medicine (Table 5; Adapted from: Mims, Medical Microbiology, Fig. 37.6).

Table 5

Common Side Effects of Interferons


Muscle pains

Toxicity to: 

bone marrow



Most viruses do not fix complement by the alternative route. However, the interaction of a complement-fixing antibody with a virus infected cell or with an enveloped virus can result in the lysis of the cell or virus. Thus, by interfacing with the specific immune system, complement also plays a role in resistance to viral infections.

Cytokines other than IFN also may play a role in resistance to virus infection. Tumor necrosis factor alpha (TNF-α), interleukin-1 (IL-1) and IL-6 have been shown to have antiviral activities in vitro. These cytokines are produced by activated macrophages but their contribution to resistance in vivo has not been fully elucidated.



Antibody produce by the specific immune system is involved primarily in the recovery from viral infection and in resistance to subsequent challenge with the virus. IgG, IgM and IgA antibodies can all play a role in immunity to virus infection but the relative contributions of the different classes depends on the virus and the portal of entry. For example, IgA will be more important in viruses that infect the mucosa while IgG antibodies will be more important in infections in which viremia is a prominent feature. Antibodies can have both beneficial and harmful effects for the host.

Beneficial effects
(Table 6; Adapted from: Roitt, Immunology 5th Ed., Fig 16.5)
Antibody can directly neutralize virus infectivity by preventing the attachment of virus to receptors on host cells or entry of the virus into the cell. Antibodies can also prevent uncoating of virus by interfering with the interaction of viral proteins involved in uncoating. Complement fixing antibodies can assist in the lysis of viral infected cells or enveloped viruses. Antibodies can also act as an opsonins and augment phagocytosis of viruses either by promoting their uptake via Fc or C3b receptors or by agglutinating viruses to make them more easily phagocytosed. Antibody coated virus infected cells can be killed by K cells thereby preventing the spread of the infection.

Table 6 

Antiviral Effects of Antibody






Free virus

Antibody alone

Blocks binding to cell

Blocks entry into cell

Blocks uncoating of virus

Antibody + Complement

Damage to virus envelope

Opsonization of virus



Virus-infected cell

Antibody + Complement

Lysis of infected cell

Opsonization of infected cell

Antibody Bound to Infected Cells

ADCC by K cells, NK cells and/or macrophages


Harmful effects

  •  Immunopathological damage
    Fixation of complement by immune complexes can result in the release of vasoactive amines, recruitment of inflammatory cells and subsequent damage to host tissue. Some viruses such a lymphocytic choriomeningitis virus produce large amounts of immune complexes in the circulation which lodge in the vascular beds and in the kidneys where they fix complement and result in tissue damage. Other examples of viruses that cause these effects are: measles, respiratory syncytial virus, dengue and serum hepatitis virus.

  • Immune adherence
    Opsonization of viruses with antibody can enhance their uptake by phagocytic cells. If the virus is able to survive in the phagocyte, this allows for the spread of virus infection. Dengue and HIV are examples of viruses that can survive in macrophages.

Since the isolation and identification of viruses is not commonly done in the clinical laboratory, the clinical picture and serology plays a greater role in the diagnosis of viral disease. The major types of antibodies that are assayed for are neutralizing, hemagglutination inhibiting and complement fixing antibodies. Complement fixing antibodies follow the kinetics of IgM and are most useful in indicating a current or recent infection. In contrast the neutralizing and hemagglutinating antibodies follow the kinetics of IgG, persist for a long time and are used to assess immunity. The development of antibodies to different components of the virus is used in staging the disease. For example in hepatitis B and HIV infections this approach is used.




In addition to the barriers and humoral components involved in resistance to and recovery from viral infections, there are several different cells that play a role in our antiviral defenses.


By virtue of the location at various sites in the body, macrophages are one of the first cells to encounter viruses. Experimental evidence suggest that these cells play an important role in resistance to viral infection. For example, newborn mice are susceptible to infection with herpes virus type 1 due to a defect in the ability of macrophages to prevent replication of the virus. Macrophages from adult mice however, are able to prevent replication of the virus and these mice are resistant to infection with this virus. Also, animals in which macrophages have been depleted are more susceptible to infection with a variety of viruses. Macrophages contribute to antiviral defenses in a number of ways.

  • Intrinsic antiviral activity - Macrophages can be infected with viruses but many viruses are incapable of replicating in macrophages. Macrophages that are activated (e.g. by IFN-γ) are even more capable of resisting viral replication. Thus, macrophages help limit viral infections by virtue of their intrinsic ability to prevent replication of viruses. However some viruses are able to replicate or at least survive in macrophages and thus can be spread by macrophages (see above).

  • Extrinsic antiviral activity - Macrophages are also able to recognize virus infected cells and to kill them. Thus, macrophages also contribute to antiviral defenses by virtue of their cytotoxic activity.

  • ADCC - Virus infected cells that are coated with IgG antibodies can be killed by macrophages by ADCC

  • IFN production - Macrophages are a source of IFN.

NK Cells 
Experimental evidence also suggests that NK cells also play a role in resistance to viral infection. Mice that are depleted of NK cells are more susceptible to infection with certain viruses. Also, patients with low NK cell activity are more susceptible to reoccurrences with herpes simplex type 1 virus. NK cells act by recognizing and killing virus infected cells. The recognition of virus infected cells is not MHC-restricted or antigen specific. Thus, NK cells will kill cells infected with many different viruses. NK cells can also mediate ADCC and can kill virus infected cells by this mechanism. The activities of NK cells can be enhanced by IFN-γ and Il-2 (see above).



T Cells
T cells play a major role in recovery from viral infections. Cytotoxic T cells (CTLs) generated in response to viral antigens on infected cells can kill the infected cells thereby preventing the spread of infection. Helper T cells are involved in generation of CTLs and in assisting B cells to make antibody. In addition, lymphokines secreted by T cells can recruit and activate macrophages and NK cells thereby mobilizing a concerted attack in the virus.




Table 7 (Adapted from: Baron, Medical Microbiology, 2nd Ed., Table 69-2) summarizes the host defenses against viral infections and it indicates the targets for each of these defenses.


Table 7 

Host Effector Functions in Viral Infections

Host Defense


Target of Effector

Early nonspecific responses




NK cell activity


Virus replication


Virus replication

Virus-infected cell

Virus replication, immunomodulation

Immune responses mediated by cells

Cytotoxic T lymphocytes

Activated macrophages



Virus infected cell

Virus, virus-infected cell

Virus-infected cells, immunomodulation

Virus-infected cell

Humoral immune responses


Antibody + complement

Virus, Virus-infected cell

Virus, virus-infected cell



The relative contribution of the various host defense mechanisms will depend on the nature of the virus and the portal of entry. Antibodies will be more important in infections in which viremia is a prominent feature. However, antibodies may not be helpful in infections with herpes or paramyxoviruses in which the virus can be passed from cell to cell by cell fusion. In this instance cell mediated immunity is more important. If a virus only infects cells in the mucosal surface, IgA antibodies may be important.

An understanding of the host defense mechanisms is important for vaccine development and for proper administration of vaccines. If IgA antibodies are important for protection against a particular virus, then any vaccine must be able to stimulate production of IgA antibodies in the appropriate mucosal surface. Alternatively if CTLs are important then the vaccine must be able to stimulate CTL production. That is why live vaccines are often preferable to a killed vaccine because live vaccines usually lead to the generation of CTLs while killed vaccines do not.




Although the host has a variety of defenses to protect against viral infections, sometimes it is the immune response to the infection that is the direct cause of tissue injury. For example, infants infected with cytomegalovirus have circulating immune complexes that are deposited in the kidneys and joints resulting in pathology such as arthritis and glomerular nephritis. Another example is fatal hemorrhagic shock syndrome associated with dengue virus infection. In this instance fixation of complement by circulating immune complexes results in release of products of the complement cascade leading to sudden increased vascular permeability, shock and death.



Many virus are able to suppress immune responses and thereby overcome or minimize host defenses. The best example is HIV which infects the CD4+ cells thereby destroying the specific immune system. Other viruses ( e.g. measles virus) can also infect lymphocytes and affect their replication and differentiation. Virus-induced immunosuppression is major concern in vaccine development. Some of the mechanisms by which viruses can evade host defenses are illustrated in Table 8 (Adapted from: Roitt, Immunology 5th Ed., Fig 16.10).

Table 8

Viral Products that Interfere with Host Defenses

Host Defense Affected


Virus Product




EBERS (small RNAs)

Blocks protein kinase activation


eIF-2alpha  homolog

Prevents phosphorylation of eIF-2alpha by protein kinase



Homologues of complement control proteins

Blocks complement activation




Binds Fc-gamma and blocks function



IFN-gamma receptor homolog

Competes for IFN-gamma and blocks function

Shope fibroma virus

TNF receptor

Competes for TNF and blocks function


IL-10 homolog

Reduces IFN-gamma function

MHC Class I


Early protein

Prevents transport of peptide-loaded MHC



Blocks transport of MHC to surface




Inhibits capsases


Bcl-2 homolog


NK cells



MHC homolog inhibits NK cells


Return to the Virology section of Microbiology and Immunology On-line

back3.gif (1240 bytes) Return to the Home Page of Microbiology and Immunology On-line

This page last changed on Saturday, October 29, 2016
Page maintained by
Richard Hunt