| MicrobiologyBytes: Infection & Immunity: Antiviral immunity | Updated: August 23, 2007 | Search |
Viruses are small, obligate intracellular parasites which cause infection by invading cells of the body and multiplying within them. Within their life cycle they have a relatively short extracellular period, prior to infecting the cells, and a longer intracellular period during which they undergo replication. The immune system has mechanisms which can attack the virus in both these phases of its life cycle, and which involve both non-specific and specific effector mechanisms.
Natural Killer Cells: Natural killer (NK) cells are a subset of lymphocytes found in the blood and tissues, which lack antigen specific surface receptors (TcR or immunoglobulin receptors). Phenotypically, NK cells do not express the characteristic cell surface markers that define T cells and B cells, and so NK cells represent a distinct lineage of lymphocytes. NK cells possess the ability to recognise and lyse virally infected cells and certain tumour cells. Whilst not showing antigen specificity, they clearly exhibit some degree of selectivity in targeting "abnormal" cells for lysis. The nature of the receptor (or receptors) that confer this selectivity of target recognition has not been clearly defined, but it has been shown recently that the expression of "self" MHC molecules inhibits NK lysis of target cells. The main advantage that NK cells have over antigen-specific lymphocytes in antiviral immunity is that there is no "lag" phase of clonal expansion for NK cells to be active as effectors, as there is with antigen-specific T and B lymphocytes. Thus NK cells may be effective early in the course of viral infection, and may limit the spread of infection during this early stage, while antigen-specific lymphocytes are being recruited and clonally expanded.
Antibody: Specific antibodies are important in and may protect against viral infections. Antibody production per se has been dealt with in detail already in the course, and so is only described here in relation to its role in antiviral immunity. The most effective type of antiviral antibody is "neutralizing" antibody - this is antibody which binds to the virus, usually to the viral envelope or capsid proteins, and which blocks the virus from binding and gaining entry to the host cell. Virus specific antibodies may also act as opsonins in enhancing phagocytosis of virus particles - this effect may be further enhanced by complement activation by antibody-coated virus particles. In addition, in the case of some viral infections, viral proteins are expressed on the surface of the infected cell. These may act as targets for virus-specific antibodies, and may lead to complement-mediated lysis of the infected cell, or may direct a subset of natural killer cells to lyse the infected cell through a process known as antibody-directed cellular cytotoxicity (ADCC). At mucosal surfaces (such as the respiratory and gastrointestinal tracts), virus infection may induce the production of specific antibodies of the IgA isotype, which may be protective against infection at these surfaces. (This is the basis of immunisation with the current oral polio vaccine). Not all antibodies to viruses are protective, however, and in certain cases antibody to the virus may facilitate its entry into a cell through Fc receptor-mediated uptake of the antibody coated particle. Such antibodies are called enhancing antibodies.
During the course of a viral infection, antibody is most effective at an early stage, before the virus has gained entry to its target cell. In this respect, antibody is relatively ineffective in primary viral infections, due mainly to the lag phase in antibody production. Preformed antibody, particularly neutralising antibody, however, is an effective form of protective immunity against viral infections, as witnessed by the success of many viral vaccines, which work by stimulating virus-neutralising antibody responses.
Cytotoxic T Cells: The principal effector cells which are involved in clearing established viral infections are the virus specific CD8+ cytotoxic T lymphocytes (CTL). These cells recognise (viral) antigens which have been synthesised within cell's nucleus or cytosol, and which have been degraded. They are presented at the cell's surface as short peptides associated with self class I MHC molecules. The recognition of antigen by CD8+ T cells is, therefore, distinct from that of CD4+ T cells in several respects. It requires synthesis of the target antigen within the cell (and is therefore restricted largely to virally infected or tumour cells); it is "restricted" by class I MHC molecules (as opposed to MHC class II restriction for CD4+ T cells); MHC class I molecules are expressed on almost all somatic cells, so virtually any cell, on infection with virus, can act as a "target" cell for antigen specific CTL (contrasts with the limited tissue distribution of class II MHC); recognition of an antigen presenting cell (APC) by an antigen-specific CTL usually results in the destruction of the APC.
The importance of CTL in the clearance of virus infection has been demonstrated in a wide variety of viral infections in both laboratory animals and in man. In addition, adoptive transfer of virus-specific CTL in mice has been shown to protect the recipient against infections with the virus. As with virus-specific antibody responses, however, not all CTL responses to virus are beneficial to the host, and in some cases the tissue destruction caused by the virus-specific CTL is greater than the damage done by the virus itself; and example of this would be the fulminant hepatitis associated in a small proportion of cases with infection with hepatitis B virus, in which the liver damage is caused by virus-specific CTL rather than directly by the virus.
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Infection with HIV is associated in the majority of cases with the production of virus specific antibody, some of which can be shown to neutralise the virus in vitro. In addition, there is a strong virus specific CTL response to the virus in the majority of patients (which is associated with an initial and dramatic fall in virus titre). This CTL response does not appear able to clear the virus, however, and persistent infection follows. There is a progressive decline in the number of CD4+ T cells over time, which often accelerates as the patient progresses towards AIDS, at which the CTL response falls away and viral titres rise.
HIV uses the CD4 surface marker as its receptor for gaining entry to cells. HIV therefore predominantly infects CD4+ cells, and leads to a disruption of the function of these cells, and a progressive decline in their numbers. As described previously, CD4+ T cells play a central role in regulating the immune response, and so HIV infection leads to a disregulation of many aspects of the immune response, including defective antibody and T cell responses to new antigens, and decreased NK responses. These effects can be detected even when numbers of CD4+ T cells are relatively normal. As CD4+ T cell numbers decline, however, the defects become more marked, leading to a state of immunodeficiency which leaves the host susceptible to infection with a variety of common or opportunistic infections and to certain types of tumours.
How does HIV manage to persist in the face of such a strong antiviral immune response ? Like many persistent viruses, HIV has a number of strategies for evading the host's immune response. One of the most important of these is the ability to undergo "antigenic variation" - the ability to mutate key epitopes which are recognised by the immune response. This has been shown for both antibody and T cell epitopes in HIV infection. (The antigenic "drift" and "shift" in the coat proteins of influenza virus is another example of antigenic variation.) In addition, HIV is capable of existing within an infected cell as a provirus - a state known as viral latency, in which the virus exists within the cell but does not replicate, so that very few viral antigens are expressed in the cell. The fact that HIV infects cells of the immune system also plays a role - in attacking the virus, the host progressively damages its own immune system, contributing to the immune dysfunction and ultimately to the survival of the virus. It has also been proposed that HIV infection leads to a disregulation of the balance between Th1 and Th2 cells in the body generally. This may contribute to the susceptibility of the HIV-infected individual to infections with intracellular organisms such as Mycobacteria.
© AJC 2007.