Complement Mediates the Binding of HIV to Erythrocytes

Abstract

A fraction of HIV is associated with erythrocytes even when the virus becomes undetectable in plasma under antiretroviral therapy. The aim of the present work was to further characterize this association in vitro. We developed an in vitro model to study the factors involved in the adherence of HIV-1 to erythrocytes. Radiolabeled HIV-1 (HIV) and preformed HIV-1/anti-HIV immune complexes (HIV-IC) were opsonized in various human sera, purified using sucrose density gradient ultracentrifugation, and incubated with human erythrocytes. We observed that, when opsonized in normal human serum, not only HIV-IC, but also HIV, bound to erythrocytes, although the adherence of HIV was lower than that of HIV-IC. The adherence was abolished when the complement system was blocked, but was maintained in hypogammaglobulinemic sera. Complement-deficient sera indicated that both pathways of complement were important for optimal adherence. No adherence was seen in C1q-deficient serum, and the adherence of HIV was reduced when the alternative pathway was blocked using anti-factor D Abs. The adherence could be inhibited by an mAb against complement receptor 1. At supraphysiological concentrations, purified C1q mediated the binding of a small fraction of HIV and HIV-IC to erythrocytes. In conclusion, HIV-IC bound to erythrocytes as other types of IC do when exposed to complement. Of particular interest was that HIV alone bound also to erythrocytes in a complement/complement receptor 1-dependent manner. Thus, erythrocytes may not only deliver HIV-IC to organs susceptible to infection, but free HIV as well. This may play a crucial role in the progression of the primary infection.

Factor I-Mediated Processing of Complement Fragments on HIV Immune Complexes Targets HIV to CR2-Expressing B Cells and Facilitates B Cell-Mediated Transmission of Opsonized HIV to T Cells

“…Shown is a representative result of three independent experiments. (11)(12)(13). The presence of HIV-specific Abs during the opsonization further triggers complement activation resulting in enhanced association of HIV-Ig-C with E. Under our experimental conditions, we determined a maximum binding capacity of HIV-Ig-C to E at 10 -15% of input virus (p24 Ag), which differed from the amount of E-associated HIV in previous reports.…”

“…Binding of such C3b-opsonized immune complexes (IC) to CR1 (CD35) on erythrocytes (E), a process referred to as immune adherence, has an important role in eliminating IC by transporting them to the liver and spleen, where they are cleared by phagocytes. Formation of HIV containing IC (HIV-Ig) in vitro by incubation of HIV in the presence of envelope-specific Abs and normal human serum (NHS) facilitates the binding of complement-opsonized HIV-Ig to the surface of E through CR1-C3b interactions (11,12). In addition, in the absence of HIV-specific Abs, complement opsonization of HIV was able to target HIV to E (11,12).…”

“…Formation of HIV containing IC (HIV-Ig) in vitro by incubation of HIV in the presence of envelope-specific Abs and normal human serum (NHS) facilitates the binding of complement-opsonized HIV-Ig to the surface of E through CR1-C3b interactions (11,12). In addition, in the absence of HIV-specific Abs, complement opsonization of HIV was able to target HIV to E (11,12). More importantly, an infectious pool of HIV associated with E was demonstrated in vivo in peripheral blood of HIV-infected individuals even with undetectable plasma viral load (13).…”

The good and evil of complement activation in HIV-1 infection

“…They may play a crucial role in the progression of the primary infection. 120 Factor I, in concert with CR1 on erythrocytes and factor H in serum, may be an important cofactor for the generation of C3d-opsonized infectious HIV-1 reservoirs on follicular dendritic cells and/or B cells in HIV-infected individuals. 121 Clinical evidence indicates that a pool of HIV-1 is associated with erythrocytes even after long-term suppression of viral RNA in plasma, which may play a role in HIV-1 replication or release in these individuals.…”

Interactions of Infectious HIV-1 Virions with Erythrocytes: Implications for HIV-1 Pathogenesis and Infectivity

“…In the course of HIV-1 infection circulating IC inevitably appear that consist of induced antibodies that are bound to infectious HIV-1 particles (Morrow et al, 1986). Many authors have analyzed the role of C in HIV-1 infection (Aasa-Chapman et al, 2005;Beck et al, 2008;Gras et al, 1997;Huber & www.intechopen.com Trkola, 2007;Legendre et al, 1996;Moir et al, 2000;Montefiori, 1997;Stoiber et al, 1997) and direct in vitro binding of HIV-1-erythrocyte IC to CR1 on erythrocytes, and even to recombinant CR1, has been demonstrated (Montefiori et al, 1994;Stoiber et al, 2008;Zhou & Montefiori, 1996) To illustrate C-dependent binding of HIV-1-IC to erythrocytes, Horakova et al (2004). used radiolabeled HIV-1, and also prepared preformed HIV-1/anti-HIV-1 immune complexes (HIV-IC) that were opsonized in various human sera.…”