CD4-independent binding of HIV-1 to the B lymphocyte receptor CR2 (CD21) in the presence of complement and antibody

Abstract

SUMMARYComplement and antibody contribute to infection-enhancement and possible expanded cellular tropism of HI V-1 in vitro through a process requiring complement receptors. Until now, however, the ability of HIV-1 to bind complement receptors has not been documented or characterized. We investigated whether antibody and complement permitted HIV-1 to bind to the B lymphocyte receptor, CR2 (CD21), in an effort to learn more about infection-enhancement, and also because CR2 can mediate B cell proliferation and antigen localization in lymphoid organs in other systems. HIV-1 incubated with antibody and fresh human serum as a source of complement bound approximately 10-fold greater to cells expressing CR2 than to HIV-1-permissive cells lacking this receptor. A similar effect was observed using cells which expressed CR2 but no CD4. This binding was minimal in heat-inactivated and C3-deficient sera, and was significantly reduced by the anti-CR2 MoAb, OICB7, but not by the anti-CD4 MoAb, OKT4a. Thus, complement and antibody acted in concert to facilitate the binding of HIV-1 to CR2 independently of CD4. CD4-independent binding of HIV-1 to CR2 was not sufficient to produce infection in Raji-3 cells. Titres of antibodies mediating CR2 binding correlated with antibody titres as measured by immunofluorescenee (/'<001) and infection-enhancement (f <005) but were discordant with titres of neutralizing antibodies, a result consistent with the utilization of CR2 for enhanced infection of cells. The ability of complement and antibody to facilitate the binding of HIV-1 to CR2 in the absence of CD4 provides new insights into mechanisms of HIV-1-induced immunopathogenesis and infection-enhancement.

V1V2-specific complement activating serum IgG as a correlate of reduced HIV-1 infection risk in RV144

“…V1V2-specific complement-activating antibodies were measured as a function of C3d deposition on a panel of gp70-V1V2-coated beads. C3d was chosen for detection because it has been used previously to quantify complement activation [ 50 ], and because it is a dominant C3 cleavage fragment on complement-opsonized HIV-1 virions as determined in CD21-dependent binding experiments [ 42 , 43 ]. Carboxylated beads were coated with either gp70 as a control for nonspecific activity, or with gp70 scaffolds containing the V1V2 domains of the gp120 vaccine immunogens used in RV144 (92TH093, A244 and MN) ( Fig 1 ).…”

“…Additional soluble factors, such as complement factor H, may further contribute to the ability of HIV-1 to evade complement lysis [ 38 , 39 ]. In the absence of lysis, complement-opsonized HIV-1 is free to bind a variety of complement receptor-bearing cells, most notably cells expressing either CR1/CD35 [ 40 , 41 ] or CR2/CD21 [ 42 – 44 ]. Cellular interactions of complement-opsonized HIV-1 could have a number of consequences that may be either beneficial or harmful to the host [ 20 – 22 ].…”

Revisiting an IgG Fc Loss-of-Function Experiment: the Role of Complement in HIV Broadly Neutralizing Antibody b12 Activity

“…Early studies implicated complement activation in HIV-1 infection enhancement ( 23 – 29 ). More recently, it has been reported that complement-opsonized virus promotes viral establishment in colorectal mucosa ( 30 ) and infection of mucosa-resident Langerhans cells ( 31 ).…”

Structural biology of complement receptors

“…Another virus that exploits CR2 as a receptor for viral entry is the human immunodeficiency virus 1 (HIV-1) ( 84 ). HIV-1 can infect B cell lymphocytes in a complement/C3-dependent and CD4-independent manner, thus facilitating viral dispersion and access to lymphoid organs ( 85 ). Besides viruses, the pathogenic yeast Cryptococcus neoformans has been shown to use an extracellular factor, the antiphagocytic protein 1 (App1), to bind to CR2 (and also CR3) and avoid complement-mediated phagocytosis by alveolar macrophages ( 86 ).…”