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In a recent report [Haynes et al. Science 2005; 308:1906–1908], difficulties in eliciting broadly neutralizing antibodies to HIV were linked to the binding of prototypic broadly neutralizing monoclonal antibodies to autoantigens and in particular, to the binding of two antigp41 antibodies, 2F5 and 4E10, to the autoantigen cardiolipin. We used a number of assays to understand whether 2F5 and 4E10 are autoreactive, polyreactive, or have a generalized affinity for lipids that may facilitate recognition of their membrane proximal epitopes.2F5 and 4E10 were evaluated for autoreactivity using diagnostic assays developed to detect serum antibodies associated with antiphospholipid syndrome (APS). As an indication of polyreactivity, we measured the binding of 2F5 and 4E10 to liposomal bilayers of differing composition using surface plasmon resonance (SPR) spectroscopy and to protein microarrays using biochip technology.2F5 showed completely negative results in the APS and SPR studies, indicating that it is neither autoreactive nor absolutely requires phospholipid binding for epitope recognition. In contrast, 4E10 bound to more than one lipid and showed weak activity in the APS studies. The activity displayed by 4E10 more closely resembles that of antiphospholipid antibodies elicited during many infections than that of autoimmune APS antibodies, at variance with the notion that difficulites in eliciting 4E10-like antibodies can be attributed to tolerance mechanisms. The microarray studies further indicated that broadly neutralizing anti-HIV mAb are not exceptionally polyreactive.These results suggest that autoantigen mimicry cannot be reliably invoked as a general mechanism for HIV immune evasion.