Complement-activating antibodies in sera from infected individuals and vaccinated volunteers that target human immunodeficiency virus type 1 to complement receptor type 1 (CR1, CD35)

Abstract

Complement receptor type 1 (CR1) plays a central role in clearing immune complexes from the circulation and probably contributes to the retention of immune complexes on the surface of follicular dendritic cells. Virus-specific, complement-activating antibodies can target human immunodeficiency virus type 1 (HIV-1) to CR1-bearing cells but the potential impact that these antibodies have on HIV-1 pathogenesis is unknown. To study these antibodies, an assay was developed in which immune complexes containing HIV-1, antibody, and complement were formed in vitro and captured on the surface of 96-well immunoplates coated with recombinant soluble human CR1 (rsCR1). Captured virus was detected by p24 immunoassay or by infection of human CD4+ lymphocytes. Two laboratory strains of HIV-1 (IIIB and MN) and primary isolates could be captured using sera from infected individuals or vaccinated volunteers as a source of complement-activating antibodies. HIV-1 immune complexes captured by solid-phase rsCR1 could be transferred to MT-2 cells for productive infection. Antibodies had no activity in this assay when the normal human serum used as a source of complement had been heat-inactivated or depleted of complement component C3, confirming a requirement for complement. These complement-activating antibodies in sera from infected individuals showed strong cross-reactivity with HIV-1 IIIB, MN, and a heterologous primary isolate, but reacted poorly with the autologous isolate obtained at the time of serum collection. Average titers of these antibodies measured with HIV-1 IIIB were moderately lower in HIV-1-infected progressors compared to nonprogressors. In contrast to sera from infected individuals, sera from gp160IIIB-vaccinated volunteers showed specificity for the vaccine strain of virus. These results provide supporting evidence that envelope-specific, complement-activating antibodies induced by infection or gp160 immunization can target HIV-1 immune complexes to CR1. In addition, they demonstrate that such antibodies may sometimes be type-specific and that HIV-1 immune complexes bound to CR1 are infectious.