Abstract
BackgroundThe complement system is one of the most potent weapons of innate immunity. It is not only a mechanism for direct protection against invading pathogens but it also interacts with the adaptive immunity to optimize the pathogen-specific humoral and cellular defense cascades in the body. Complement-mediated lysis of HIV is inefficient but the presence of HIV particles results in complement activation by the generation of many C3-fragments, such as C3dg and C3d. It has been demonstrated that activation of complement can enhance HIV infection through the binding of special complement receptor type 2 expression on the surface of mature B cells and follicular dendritic cells.Presentation of the hypothesisPrevious studies have proven that the complement-mediated antibody-dependent enhancement of HIV infection is mediated by the association of complement receptor type 2 bound to the C3 fragment and deposited on the surface of HIV virions. Thus, we hypothesize that a new activator of complement, consisting of a target domain (C3-binding region of complement receptor type 2) linked to a complement-activating human IgG1 Fc domain (CR2-Fc), can target and amplify complement deposition on HIV virions and enhance the efficiency of HIV lysis.Testing the hypothesisOur hypothesis was tested using cell-free HIV-1 virions cultivated in vitro and assessment of virus opsonization was performed by incubating appropriate dilutions of virus with medium containing normal human serum and purified CR2-Fc proteins. As a control group, viruses were incubated with normal human serum under the same conditions. Virus neutralization assays were used to estimate the degree of CR2-Fc-enhanced lysis of HIV compared to untreated virus.Implications of the hypothesisThe targeted complement activator, CR2-Fc, can be used as a novel approach to HIV therapy by abrogating the complement-enhanced HIV infection of cells.
Highlights
The complement system is one of the most potent weapons of innate immunity
There are no effective vaccines against human immunodeficiency virus (HIV) infection due to a number of issues
In 2003, two phase 3 trials using gp120 protein for vaccination that were aimed to raise sterilizing, antibody-mediated immunity, failed to protect vaccinees from HIV infection [1,2]. Another vaccine trial using a different strategy (V520 of Merck) was stopped prematurely in September 2007 due to evidence that vaccinees may have been more susceptible to HIV infection than placebo control individuals [3]
Summary
The human immunodeficiency virus (HIV) causes severe immune deficiency in humans and currently affects up to 42 million people worldwide. A major mechanism of FDC trapping is binding of antibody and complement-opsonized HIV to CR2 [24,27] Viruses retained in this way, even in the presence of neutralizing antibodies, have been shown to remain infectious in vivo for months and comprise a viral archive that can be transmitted to T cells and other target cells migrating through germinal centers. The hypothesis Recent findings have generated renewed interest in socalled "non-neutralizing" antibodies that are unable to directly inhibit free virus entry into target cells, but exhibit antiviral activity mediated by the Fc region of the antibody molecule These antibody effector mechanisms include complement binding and viral lysis, phagocytosis of antibody-coated virions, and antibodydependent cellular cytotoxicity [29,30]. It is meaningful to investigate the potential role of CR2-Fc for the abrogation of HIV infection in humans, as this new finding would suggest a novel approach for HIV therapy
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