Lack of Evidence for Molecular Mimicry in HIV-Infected Subjects

Abstract

Previous studies in HIV patients have reported autoantibodies to several human proteins, including erythropoietin (EPO), interferon-α (IFN-α), interleukin-2 (IL-2), and HLA-DR, as potential mediators of anemia or immunosuppression. The etiology of these autoantibodies has been attributed to molecular mimicry between HIV epitopes and self-proteins. Here, the Luciferase Immunoprecipitation System (LIPS) was used to investigate the presence of such autoantibodies in HIV-infected adults. High levels of antibodies to HIV proteins such as capsid (p24), matrix (p17), envelope (gp41), and reverse transcriptase (RT) were detected using LIPS in both untreated and anti-retroviral-treated HIV-infected individuals but not in uninfected controls. LIPS readily detected anti-EPO autoantibodies in serum samples from subjects with presumptive pure red cell aplasia but not in any of the samples from HIV-infected or uninfected individuals. Similarly, subjects with HIV lacked autoantibodies to IFN-α, IL-2, HLA-DR and the immunoglobulin lambda light chain; all purported targets of molecular mimicry. While molecular mimicry between pathogen proteins and self-proteins is a commonly proposed mechanism for autoantibody production, the findings presented here indicate such a process is not common in HIV disease.

Fig 1. Antibody responses to HIV proteins.

LIPS was used to detect antibodies against four HIV proteins in eight healthy controls (HC), HIV-infected subjects before ART (n = 60), and after ART (n = 27). The level of antibody (in LU) against the HIV proteins p24 (A), p17 (B), gp41 (C), and RT (D) is plotted on the y-axis using a log₁₀ scale. Each symbol in the graph represents one sample from one subject. The horizontal line represents the median LU value in each group. Statistically significant differences were calculated with the Mann-Whitney U test and only statistically significant values are shown.

Fig 2. No evidence of anti-EPO autoantibodies in HIV patients.

Negative (Neg) and positive (Pos) control (CTRL) monoclonal antibodies (MAB) to EPO, as well as anti-EPO Neg and Pos CTRL clinical sera were assayed using LIPS. Two of the anti-EPO monoclonal antibodies were of the IgM isotype (marked by stars), which is an immunoglobulin isotype that binds poorly to protein A/G beads. Anti-EPO antibody levels were also measured in eight healthy controls (HC), HIV patients before ART (n = 60), and after 3–7 years of ART (n = 27). The anti-EPO antibody levels in LU are plotted on the y-axis using a log₁₀ scale. The median anti-EPO antibody level in the healthy controls and HIV patient groups are shown by the horizontal line. The dotted line represents the cut-off value for determining seropositivity for EPO.

Fig 3. Lack of autoantibodies against IFN-α, IL-2, HLA-DR, and λ-LC in HIV-infected subjects.

Autoantibody levels in LU as determined by LIPS are shown for (A) IFN-α, (B) IL-2, (C) HLA-DR, and (D) λ-LC on the y-axis using a log₁₀ scale. The LU value for each of the positive control antibodies (closed squares) used to validate the assays is shown in its respective plot. The dotted line represents the cut-off value for determining seropositivity.