Immune Response to Viral Infections

1.         Host Defenses

a.         Host defenses against viruses fall into two major categories:

i.            nonspecific, of which the most important are interferons.

ii.            specific, including both humoral and cell-mediated immunity.

b.            Interferons are an early, first-line defense, whereas humoral immunity and cell-mediated immunity are effective only later since it takes several days to induce an immune response.

c.            Processes contributing to Recovery:

i.            production of interferon which limits viral replication and spread.

ii.            ingestion and destruction of virus by phagocytes.

iii.            destruction of infected cells.

iv.            neutralization of the infectivity of viruses.

2.            Interferons

a.            Interferons are a heterogenous group of glycoproteins produced by human and other animal cells after viral infection (or after exposure to other inducers).

b.         They inhibit the growth of viruses by blocking the translation of viral proteins.

c.         Types of Interferons:

d.            Induction of Alpha and Beta Interferons:

i.          the strong inducers of these interferons are viruses and double-stranded RNAs.

ii.            induction is not specific for a particular virus.

iii.         their inhibitory action is not specific for any particular virus.

e.         Action of Alpha and Beta Interferons:

i.            interferons inhibit the intracellular replication of a wide variety of viruses but have little effect on the metabolism of normal cells.

ii.          they act by inducing the synthesis of 3 proteins that inhibit the translation of viral mRNA without affecting the translation of cellular mRNA.

iii.         these proteins are a oligonucleotide synthase, a ribonuclease and a protein kinase.

f.            Because interferons are produced within a few hours of the initiation of viral replications, they may act in the early phase of viral diseases to limit the spread of virus.

g.         In contrast, antibody begins to appear in the blood several days after infection.

h.         Clinical Applications of Interferons:

i.            interferon alpha has been approved for use in patients with condyloma acuminatum and chronic active hepatitis caused by hepatitis C virus.

ii.            interferon gamma reduces recurrent infections in patients with chronic granulomatous disease.

iii.            interferons are also used clinically in patients with cancers such as Kaposi’s sarcoma and hairy cell leukemia.

3.            Phagocytosis of Virion particles

a.         Shortly after infection, some virus particles are phagocytosed by macrophages.

b.         Except in the case of certain viruses that are capable of growing in macrophages, the engulfed virions are destroyed.

c.         Their proteins are cleaved into short peptides which are presented on the surface of the macrophage in association with class II MHC protein.

d.            Activation of Helper T cells:

i.          the combination of both antigen and class II MHC protein is recognized by naive helper T cells which are activated to differentiate into TH1 or TH2 cells.

ii.            secretion of IL-12 by macrophages induce naive helper cells to become TH1 cells.

e.         The T lymphocytes respond by clonal proliferation and release of lymphokines, which attract blood monocytes to the site and induce them to proliferate and differentiate into activated macrophages, the basis of the inflammatory response.

4.            Immune Cytolysis of Virus-infected cells

a.            Destruction of infected cells is mediated by:

i.            cytotoxic T cells

ii.            antibody-complement mediated cytotoxicity

iii.            antibody-dependent cell-mediated cytotoxicity

iv.         NK cells

b.         Since some viral proteins, or peptides derived therefrom, appear in the plasma membrane before any virions have been produced, lysis of the cell at this stage brings viral replication to a halt before significant numbers of progeny virions are released.

c.         CD8 cytotoxic T cells are activated following recognition of viral peptides in association with MHC class I on infected cells.

d.         They kill virus-infected cells by:

i.            releasing perforins, which make holes in the cell membranes of the infected cells.

ii.            releasing enzymes called granzymes into the infected cell which degrade the cell contents.

iii.            activating the FAS protein, which causes apoptosis.

e.         The T cell response usually peaks at about a week after infection, compared with the antibody response which peaks later (2-3 weeks).

f.            Antibody-complement mediated cytotoxicity:

i.            antibody binds to new virus-specific antigens on the cell surface and then binds complement, which enzymatically degrades the cell membrane.

ii.            because the cell is killed before the full yield of virus is produced, the spread of virus is significantly reduced.

g.            Antibody-dependent cell-mediated cytotoxicity: antibody bound to the surface of the infected cell is recognized by IgG receptors on the surface of macrophages or NK cells and the infected cell is killed.

h.         Natural Killer cells:

i.          the NK cells are activated by interferon, or directly by viral glycoproteins.

ii.          they demonstrate no specific immunologic specificity but preferentially lyse virus-infected cells by secreting perforins.

iii.         they are active without prior exposure to the virus, but antibody enhances their effectiveness.

5.            Neutralization of Viral Infectivity

a.            Activation of TH2 cells:

i.          helper T cells recognize viral antigen in association with MHC class II proteins.

ii.          TH2 cells are activated to secrete the interleukins IL-4 and IL-5.

b.         These interleukins activate B cells to proliferate and differentiate and to produce antibodies.

c.            Synthesis of Antibodies:

i.          takes place principally in the spleen, lymph nodes, gut-associated lymphoid tissues and bronchus-associated lymphoid tissues.

ii.          the spleen and lymph nodes receive viral antigens via the blood or lymphatics and synthesize antibodies, mainly restricted to the IgM class early in the response and IgG subclasses subsequently.

iii.            submucosal lymphoid tissues of the respiratory and digestive tracts, such as the tonsils and Peyer’s patches, receive antigens directly from overlying epithelial cells, and they make antibodies mainly of the IgA class.

d.            Antibodies inhibit viruses by:

i.            neutralization of viral infectivity by antibody binding to proteins on outer surface of the virus.

ii.          lysis of virus-infected cells in the presence of antibody and complement.

iii.            opsonization of virus to facilitate ingestion by phagocytes.

e.         Effects of Antibody binding:

i.          it can prevent the interaction of the virus with cell receptors.

ii.          it can cross-link the viral proteins and stabilize the virus so that uncoating does not occur and therefore the virus cannot replicate.

6.            Recovery from Viral Infection

a.         Cell-mediated immunity, antibody, complement, phagocytes, and interferons and other cytokines are all involved in the response to viral infections and may alone or in concert be responsible for recovery, depending on the particular host-virus combination.

b.         Role of T lymphocytes:

i.            lymphocytes and macrophages normally predominate in the cellular infiltration of virus-infected tissues; in contrast to bacterial infections, polymorphonuclear leukocytes are not plentiful.

ii.            depletion of T cells by neonatal thymectomy increases the susceptibility of experimental animals to most viral infections.

c.         Role of Natural Killer cells:

i.          the role of NK cells in recovery from viral infections is not yet certain.

ii.          they probably represent an innate defense mechanism of particular relevance in the early stage of primary virus infections.

d.         Role of Antibody:

i.          in generalized diseases characterized by a viremia in which virions circulate free in the plasma, circulating antibody plays a significant role in recovery.

ii.          spread of virus via the bloodstream to other organs is prevented mainly by antibodies.

7.            Immunity to Reinfection

a.         Disease prevention and recovery:

i.          active immunity is important in the prevention of disease, but its ability to enhance the patient’s recovery from a viral disease is limited.

ii.          disease prevention is chiefly due to the presence of immunoglobulins.

iii.         cell-mediated immunity is important in the recovery from viral infections.

b.            Protection against subsequent infections:

i.          the first line of defense is antibody, which, if acquired by active infection with a virus that causes systemic infections, continues to be synthesized for many years, providing solid protection against reinfection.

ii.          the degree of acquired immunity generally correlates well with the titer of antibody in the serum.

iii.         further, transfer of antibody alone, whether by passive immunization or by maternal transfer from mother to fetus, provides excellent protection in the case of many viral infections.

iv.         if the antibody defenses are inadequate, the mechanisms that contribute to recovery are called into play again.

v.         the principal differences being that the dose of infecting virus is reduced by antibody and the preprimed memory T and B cells generate a more rapid secondary response.

c.            Duration of protection:

i.            disseminated viral infections such as measles and mumps confer lifelong immunity against recurrences.

ii.            localized infections such as the common cold usually impart only a brief immunity of several months.

iii.         IgA confers protection against viruses that enter through the respiratory and gastrointestinal mucosa.

iv.         IgM and IgG protect against viruses that enter or are spread through the blood.

v.         the lifelong protection against systemic viral infections such as measles, mumps and rubella is a function of the secondary response of IgG.

vi.         for certain respiratory viruses such as parainfluenza and respiratory syncytial viruses, the IgA titer in respiratory secretions correlate with protection, whereas IgG does not.

vii.            protection by IgA against most respiratory tract viruses usually lasts less than 5 years.

d.         Original antigenic sin:

i.          when a person is exposed to a virus that cross-reacts with another virus to which the individual was previously exposed, more antibody is produced against the original virus than against the current one.

ii.          seen in infections with orthomyxoviruses, reoviruses, paramyxoviruses, and togaviruses.

e.         This phenomenon has two practical consequences:

i.            attempts to vaccinate people against the different influenza virus strains may be less effective than expected.

ii.            epidemiologic studies based on measurement of antibody titers may yield misleading results.

f.          Passive Immunity:

i.          transfer of human serum containing the appropriate antibodies provides prompt short-term immunity for individuals exposed to certain viruses.

ii.          one type has a high titer of antibody against a specific virus, and the other is a pooled sample from plasma donors that contains a heterogeneous mixture of antibodies with lower titers.

iii.         the 3 most frequently used high-titer preparations are used after exposure to hepatitis B, rabies, and varicella-zoster viruses.

iv.         low-titer immune globulin is used mainly to prevent hepatitis A in people traveling to areas where this infection is hyperendemic.

g.         Natural immunization protects the newborn for the first few months of life against most of the infections that the mother has experienced.

h.         This occurs in two ways:

i.            maternal antibodies of IgG class cross the placenta and protect the fetus and newborn infant during pregnancy and for several months after birth.

ii.            antibodies of the IgA class are secreted in the mother’s milk at a concentration of 1.5 grams per liter, conferring protection against enteric infections as long as breast-feeding continues.