Cardiolipin Polyspecific Autoreactivity in Two Broadly Neutralizing HIV-1 Antibodies

Abstract

The design of a human immunodeficiency virus-1 (HIV-1) immunogen that can induce broadly reactive neutralizing antibodies is a major goal of HIV-1 vaccine development. Although rare human monoclonal antibodies (mAbs) exist that broadly neutralize HIV-1, HIV-1 envelope immunogens do not induce these antibody specificities. Here we demonstrate that the two most broadly reactive HIV-1 envelope gp41 human mAbs, 2F5 and 4E10, are polyspecific autoantibodies reactive with the phospholipid cardiolipin. Thus, current HIV-1 vaccines may not induce these types of antibodies because of autoantigen mimicry of the conserved membrane-proximal epitopes of the virus. These results may have important implications for generating effective neutralizing antibody responses by using HIV-1 vaccines.

Monoclonal Antibodies to Phosphatidylinositol Phosphate Neutralize Human Immunodeficiency Virus Type 1: Role of Phosphate-Binding Subsites

“…Recently, an important observation was made that two of these neutralizing human gp41 MAbs, known as 4E10 and 2F5, cross-reacted with cardiolipin (CL) and are in the category of antibodies that have lupus anticoagulant-type anti-CL specificities (18,29). This observation is also consistent with a previous finding that HIV-1 could bind to, and fuse with, CL liposomes and that such binding inhibited infection of A3.01 cells by HIV-1 (20).…”

Immunogenicity of recombinant human immunodeficiency virus type 1-like particles expressing gp41 derivatives in a pre-fusion state

“…The poorly immunogenic nature of 2F5 and 4E10 epitopes was recently interpreted to be due to autoantigen mimicry of these conserved epitopes [78]. Haynes et al have noted that all of HIV-1 NAbs have extended CDRH3 loops, typical of autoantibodies, and that these mAbs cross-react with human antigens targeted during autoimmune responses [78]. On the other hand, our result is inconsistent with a recent observation employing a fluorescence-based binding assay to determine antigenic maps to gp41 among several seropositive individuals.…”

Lipidomics of host–pathogen interactions

“…apoptotic cells and mitochondria which expose/liberate cardiolipin and phosphatidylserine). Interestingly, rare human antibodies which neutralize HIV are also reactive against cardiolipin [61].…”