Inhibition of HIV-1 Infectivity through an Innate Mechanism Involving Naturally Occurring IgM Anti-Leukocyte Autoantibodies

Abstract

In prior studies, we show that naturally occurring IgM anti-leukocyte autoantibodies (IgM-ALA) bind to CD3, CD4, CCR5, and CXCR4 receptors. These observations prompted us to determine whether IgM-ALA have a role in inhibiting HIV-1 infectivity by inhibiting viral entry into cells. We show that purified IgM, but not IgG, from individual sera of both normal and HIV-1 infected individuals is highly inhibitory (>95%) to HIV-1 viral infectivity both in vitro using PHA plus IL-2 activated PBL and in vivo using the human PBL-SCID mouse. Inhibition was observed with physiological doses of purified serum IgM and even after IgM was added 3 days postinfection in the in vitro assays. Absorbing purified serum IgM either with leukocytes or immobilized recombinant CD4 significantly decreased (>80%) the inhibitory effect on HIV-1 infectivity. IgM inhibited by >90% syncytia formation with the X4-IIIB infected SupT-1 cells indicating therefore that IgM inhibits viral attachment to core-receptors. IgM mediated anti-HIV-1 activity was highly specific as only certain IgM-ALA, obtained from human B cell clones inhibited HIV-1. IgM from certain HIV-1 infected individuals were not inhibitory to some R5-HIV-1 viral strains indicating that certain HIV-IgM may lack Abs reactive to strain specific coreceptor epitopes. These data indicate that an innate immune mechanism which is present from birth i.e., IgM-ALA, has a role in inhibiting HIV-1 viral entry into cells. Validation of this data with other in vivo models will be needed to determine whether in vivo administration or enhancement of IgM-ALA, e.g., through a vaccine, could prolong the asymptomatic state in HIV-1 infected individuals.

Natural IgM Anti-Leukocyte Autoantibodies Attenuate Excess Inflammation Mediated by Innate and Adaptive Immune Mechanisms Involving Th-17

“…Additionally, we showed that human IgM immunoprecipitated chemokine receptors, e.g. CXCR4 and CCR5, and inhibited the binding of chemokines (and HIV-1) to these receptors, as well as inhibited chemotaxis induced by chemokines (1,7). …”

Naturally occurring auto-antibodies in homeostasis and disease

“…IgM-ALA NAbs have yet another beneficial effect because their binding to CD4 prevents HIV-1 virus from attaching to leukocytes and reduces infectivity by 95% in vitro and in severe combined immunodeficiency mice containing human peripheral lymphocytes [50]. The IgM-ALA NAbs as characterized so far are a heterogenous group of NAbs, which can vary in their receptor specificity and concentration.…”

Natural Autoantibodies—Homeostasis, Autoimmunity, and Therapeutic Potential

“…An example of this principle is depicted by the important contribution NAbs have against many pathogens, both bacterial and viral, among which are pneumococcus, Salmonella typhimurium, influenza, lymphocytic choriomeningitis virus, and human immunodeficiency virus (HIV) [46,[82][83][84]. It has been shown in murine models that NAbs-deficient and IgM-negative mice are more vulnerable to viral infections than normal mice [46].…”

“…As a group of antibodies they comprise several different IgM, each with specificities for a different leukocyte receptor. ALA antibodies bind to CD4+ T cells, inhibit their activation, and by that disable the HIV-1 virus from attaching to leukocytes and reduce the viruses infectivity by 95% [83]. Phosphatidylcholine (PC) is a major constituent of most cell membranes, which exist on the cell's outer layer.…”