Efficient destruction of human immunodeficiency virus in human serum by inhibiting the protective action of complement factor H and decay accelerating factor (DAF, CD55).

Abstract

Activation of the human complement system leads to complement deposition on human immunodeficiency virus (HIV) and HIV-infected cells without causing efficient complement-mediated lysis. Even in the presence of HIV-specific antibodies, only a few particles are destroyed, demonstrating that HIV is intrinsically resistant to human complement. Here we report that, in addition to decay accelerating factor (DAF) being partially responsible, human complement factor H (CFH), a humoral negative regulator of complement activation, is most critical for this resistance. In the presence of HIV-specific antibodies, sera devoid of CFH (total genetic deficiency or normal human serum depleted of CFH by affinity chromatography) lysed free virus and HIV-infected but not uninfected cells. In the presence of CFH, lysis of HIV was only obtained when binding of CFH to gp41 was inhibited by a monoclonal antibody against a main CFH-binding site in gp41. Since CFH is an abundant protein in serum, and high local concentration of CFH can be obtained at the surface of HIV as the result of specific interactions of CFH with the HIV envelope, it is proposed that the resistance of HIV and HIV-infected cells against complement-mediated lysis in vivo is dependent on DAF and CFH and can be overcome by suppressing this protection. Neutralization of HIV may be achieved by antibodies against DAF and, more importantly, antibodies against CFH-binding sites on HIV envelope proteins.

A high affinity inhibitor of human CD59 enhances complement-mediated virolysis of HIV-1: Implications for treatment of HIV-1/AIDS

“…Incomplete activation of complement enabling HIV-1 to escape Ab-dependent, complement-mediated lysis is due in part to the presence of hCD59 in the viral envelope, which the virus recruits from the host cell in the budding process (3,10,11). In addition, binding of the fluid phase complement regulator factor H to HIV-1 confers onto the virus further protection from complement attack (36). In summary, the HIV-1 virus, like other pathogens such as Schistosoma mansoni (37), manipulates the delicate balance between complement activation and restriction in a manner that is favorable to the virus.…”

Secretory IgA Specific for a Conserved Epitope on gp41 Envelope Glycoprotein Inhibits Epithelial Transcytosis of HIV-1

“…Third, the tolerance induced by self-peptide (56): self-peptide could originate from a soluble protein like the human complement factor H present at high concentration in the plasma, which has been shown to bind to TM-gp41 at a site overlapping the 2F5 epitope (57).…”

Characterization of Human Class-Switched Polymeric (Immunoglobulin M [IgM] and IgA) Anti-Human Immunodeficiency Virus Type 1 Antibodies 2F5 and 2G12

“…For each medium composition, we confirmed the virus titer by back titration. After 5 days, syncytium-negative wells were counted and the IC 50 (the antibody concentration resulting in a 100% inhibition in 50% of the wells) was determined according to the method described in reference 41. Neutralization assay.…”