MicrobiologyBytes: Infection & Immunity: Complement Updated: January 7, 2007 Search

THE INTERACTION OF MICROORGANISMS WITH THE COMPLEMENT SYSTEM:

VIRUSES

Ample evidence exists that specific antibody (IgG or IgM) alone efficiently neutralizes many viruses (278). This, however appears to be a concentration-dependent phenomenon and can be enhanced by complement activation (279). Complement is activated by a variety of viruses directly and on the surface of virus-infected cells. Activation of the system can result in the inactivation of the pathogen or the lysis of infected cells. However, some viruses such as herpes simplex virus and vaccinia virus, have developed mechanisms to escape complement mediated inactivation. In addition, viruses can take advantage of opsonisation by complement to enter complement receptor-carrying cells more easily. Vesicular stomatitis virus is efficiently neutralised (measured by plaque reduction assays) with suboptimal amounts of specific antibody, only under conditions that permit activation of the classical complement pathway (280). Although there is evidence that neutralization of some viruses (for example, herpes simplex and Newcastle disease viruses) occurs after activation of only C1 and C4 (281,282), the most efficient neutralization with suboptimal concentrations of specific antibody requires sequential activation of C2 and C3 (280). Thus C4-deficient sera are completely incapable of neutralizing viruses. Furthermore, complement-mediated ultrastructural lesions in the viral envelope (283) and virolysis depend upon the action of the terminal attack sequence C5b-9, but these components are not required for virus neutralization. These findings substantiate the concept that neutralization of viruses is mediated by progressive accumulation of exogenous protein on the viral envelope, either as antibody alone or as a more limited quantity of antibody plus C1-C3b molecules (280,281). Although this mechanism may be important in the early phase of infection in a non-immune host, patients with inherited deficiencies of early-acting complement components are not uniquely susceptible to severe viral infections. This evidence seems to suggest that it is the cell-mediated processes which are of major importance in the resolution of virus infections.

The virus of interest for many researchers at the moment is, of course, HIV. For this reason, we will briefly look at the effects of this virus on the complement system. Various recent experiments have been carried out to investigate the effects of Human Immunodeficiency Virus (HIV) on complement (284,285,286,287). Several reports provide evidence for complement activation in the blood of HIV-infected individuals (288,289,290). Although this can be explained by circulating immune complexes found in the sera, there are data that indicate direct activation of the complement system by HIV-1 and HIV-1-infected cells.

Purified HIV-1 activates the classical pathway of complement, leading to the deposition of C3 fragments on the viral particle (291). This activation has been shown to be triggered by binding of the C1q subcomponent of C1 to the transmembrane protein gp41 (a protein on the HIV viral particle) and subsequent C1 activation (292). This antibody-independent direct complement activation by the virus was originally shown to enhance infection of cells carrying complement receptor type 3 (293). Later, this concept was extended to cells expressing complement receptor type 2 (294). In contrast, HIV-1-infected cells have been found to activate complement via the alternative pathway (291). Deposition of C3 fragments on the surface of infected cells can cause binding to complement-receptor carrying cells (291).

Considerable variation of complement activation has been found with two different HIV isolates, HIV-1 and HIV-2, on the surface on infected cells (295). Some HIV-1, as well as HIV-2 isolates, activate the complement system on the surface of infected cells independent of anti-HIV antibodies, while other isolates fail to do so. Complement activation on the cell surface is mediated by the alternative and, to a lesser extent, the classical pathway. The differences in complement activation on the cell surface are not caused by a modified expression of membrane-bound complement inhibitors or regulators. C3 deposition on the cell surface correlates with the expression of an epitope lying within the major complement activating domain of gp41. Results have suggested a role for gp41 in complement activation on HIV-infected cells, similar to that for purified HIV (295).

The deposition of C3 fragments on the surface of infected cells can lead to an interaction with complement receptor-carrying cells like macrophages, B lymphocytes (296), T lymphocytes (297), and natural killer cells (298). Depending on the cell-types involved, this interaction may facilitate the cell to cell spreading of infection, or may cause destruction of the infected cells. The latter mechanism may contribute to the CD4 cell depletion observed in AIDS patients. The differential ability of certain HIV strains to activate complement on the surface of infected cells could be one of the factors determining the variable progression of the disease (295).

   

© AJC 2007.