Anti-phospholipid human monoclonal antibodies inhibit CCR5-tropic HIV-1 and induce β-chemokines

Abstract

Traditional antibody-mediated neutralization of HIV-1 infection is thought to result from the binding of antibodies to virions, thus preventing virus entry. However, antibodies that broadly neutralize HIV-1 are rare and are not induced by current vaccines. We report that four human anti-phospholipid monoclonal antibodies (mAbs) (PGN632, P1, IS4, and CL1) inhibit HIV-1 CCR5-tropic (R5) primary isolate infection of peripheral blood mononuclear cells (PBMCs) with 80% inhibitory concentrations of <0.02 to ∼10 µg/ml. Anti-phospholipid mAbs inhibited PBMC HIV-1 infection in vitro by mechanisms involving binding to monocytes and triggering the release of MIP-1α and MIP-1β. The release of these β-chemokines explains both the specificity for R5 HIV-1 and the activity of these mAbs in PBMC cultures containing both primary lymphocytes and monocytes.

Immunologic characteristics of HIV‐infected individuals who make broadly neutralizing antibodies

“…It was suggested that SLE and other autoimmune diseases might provide protection against infection,75 but to date no study has isolated the protective factor. One candidate antibody class, antiphospholipid antibodies that can be found in autoimmune disease, was shown to block infection in vitro but testing of patient samples gave inconclusive results 15. Thus, whether SLE or other autoimmune diseases are protective against HIV‐1 infection remains an open question.…”

“…A number of antibody‐mediated functions against HIV‐1 have been studied, including virus capture and phagocytosis,9, 10 antibody‐dependent cell‐mediated virus inhibition,11, 12 antibody‐dependent cell‐mediated cytotoxicity (ADCC),13, 14 chemokine secretion of monocytes stimulated by antibodies,15 and virus neutralization 16, 17, 18. Neutralization has been shown to exert immune pressure on HIV‐1,19, 20 while the role of other antibody‐mediated functions in exerting immune pressure is unclear, primarily because antibodies that mediate ADCC and other activities often also neutralize 21.…”

Les anticorps anti-VIH

“…Le mécanisme d'inhibition n'a pas encore été clairement identifié même s'il a été proposé que les complexes immuns, fixés aux cellules effectrices par l'intermédiaire des RFcγ, seraient phagocytés puis dégradés dans des lysosomes spécifiques. La fixation des anticorps sur les RFc de cellules effectrices peut aussi déclencher l'activation d'autres mécanismes fonctionnels qui pourraient conduire à une diminution de la réplication virale, comme : -l'induction de cytokines et/ou de chimiokines antivirales [15] ; -la maturation des cellules présentatrices d'antigènes qui favoriserait la restriction virale par des mécanismes postfusion [16]. …”

Lipid Involvement in Viral Infections: Present and Future Perspectives for the Design of Antiviral Strategies

“…As a first approach to inhibit enveloped virus multiplication, the functions of lipids incorporated into the viral particle can be targeted by chemical compounds or even by antibodies [161]. This is the case of broad-spectrum antivirals, − some of them already licensed for human use, such as arbidol [162][163][164] −, or inhibitors of membrane fusion [3].…”

“…The safety and pharmacokinetics of this antibody have been already evaluated in clinical trials for treatment of other human disorders [201]. Another example of the use of antiphospholipidantibodies to combat a viral disease is provided by HIV, since different antiphospholipid antibodies have shown a broad neutralizing activity against this virus [161].…”