A novel approach to inhibit HIV-1 infection and enhance lysis of HIV by a targeted activator of complement.
BACKGROUND
The 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.


OBJECTIVE
Previous 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.


METHODS
Our 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.


CONCLUSIONS
The targeted complement activator, CR2-Fc, can be used as a novel approach to HIV therapy by abrogating the complement-enhanced HIV infection of cells.
Xu
Yuanyong
Y
Institute of Disease Control and Prevention, Academy of Military Medical Science, Beijing, PR China. xyy_827@sina.com
Zhang
Chuanfu
C
Jia
Leili
L
Wen
Cuirong
C
Liu
Huihui
H
Wang
Yong
Y
Sun
Yansong
Y
Huang
Liuyu
L
Zhou
Yusen
Y
Song
Hongbin
H
D003176:Complement C3 / Q000276:immunology* / Q000378:metabolism; D015497:HIV-1 / Q000276:immunology*; D007141:Immunoglobulin Fc Fragments / Q000276:immunology* / Q000378:metabolism; D050296:Microbial Viability; D009500:Neutralization Tests; D017464:Receptors, Complement 3d / Q000276:immunology* / Q000378:metabolism
D003176:Complement C3; D007141:Immunoglobulin Fc Fragments; D017464:Receptors, Complement 3d