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July 11, 2017

HIV's Molecular Mimicry Exploits Immune Tolerance to Halt Antibody Attack

  • The human immune system has a built in failsafe to ensure that we don’t normally produce antibodies that attack our own tissues. The failsafe, known as immune tolerance, ensures that any B cells that might produce self-reactive broadly neutralizing antibodies (bnAbs) are eliminated in the bone marrow, or if the B cells do reach the circulation they are suppressed so that they can’t mature into antibody-secreting plasma cells.

    Work in mice by a team at the University of Colorado School of Medicine now suggests that human immunodeficiency virus 1 (HIV-1) exploits immune tolerance to prevent the production of broadly neutralizing antibodies (bnAbs) that can target the viral Env protein and destroy the virus, because the same antibodies would also recognize epitopes on the body’s own histone H2A. The team, led by Raul M. Torres, Ph.D., professor of immunology and microbiology at the University of Colorado School of Medicine, has found that mice with weakened immune tolerance due genetic defects or drug treatment readily produce broadly neutralizing antibodies that can eliminate multiple strains of HIV-1.

    “We think this may reflect an example of molecular mimicry where HIV-1 Env has evolved to mimic an epitope on histone H2A as a mechanism of immune camouflage," Prof. Torres suggests.

    Human patients with the autoimmune disorder systemic lupus erythematosus (SLE) are known to demonstrate a lower incidence of HIV-1 infection, and this is thought to be because they produce self-reactive antibodies that can also neutralize HIV-1. To investigate this a bit further in a mouse model, Dr. Torres’ team looked first at animals with a genetic defect that causes symptoms similar to SLE. When the animals were injected with alum, an adjuvant used in vaccines to trigger antibody secretion, they started to produce antibodies that neutralize HIV-1.

    Production of antibodies that could neutralize HIV-1 was also associated with increased levels of a self-reactive antibody targeting histone H2A. “ … autoimmune-prone strains of mice treated with alum produce HIV-1–neutralizing anti-bodies, and this activity correlates with increased anti-H2A IgM autoantibody titers,” the authors note in their published paper in the Journal of Experimental Medicine, which is titled “Breaching Peripheral Tolerance Promotes the Production of HIV-1–Neutralizing Antibodies.”

    The researchers then treated normal mice using pristane, a drug that impairs immunological tolerance. The pristane-treated animals also started to produce antibodies that could neutralize some strains of HIV-1. Production of these antibodies was increased further when the pristine-treated mice were injected with the alum adjuvant. And when the animals were then injected with the HIV-1 protein Env, they started to produce potent bnAbs that were able to neutralize a broad range of HIV-1 strains.

    Again, the production of HIV-1 neutralizing antibodies correlated with increased levels of the self-reactive anti-histone H2A antibodies, which the researchers purified, and confirmed were able to neutralize HIV-1.

    “Here, using lupus prone mouse models, we confirm that immunological tolerance indeed limits wild-type B cells from producing Env-specific antibodies able to neutralize tier 2 HIV-1 strains,” the authors conclude. “We extend these findings by further formally demonstrating that a breach in peripheral tolerance can lead to the production of HIV-1–neutralizing antibodies in mice with wild-type immune systems.”

    Prof. Torres stresses that his team’s work was carried out in an animal model, and more research will need to investigate whether the findings are relevant to HIV immunity in humans. Studies will need to determine whether it is possible to transiently relax immunological tolerance so that HIV-1 bnAb production can be triggered through vaccination, but without causing autoimmune side effects. “It is not clear that relaxing tolerance is a path for promoting humoral immunity to HIV,” Dr. Torres told GEN. “Ongoing work in the lab is to attempt to transiently break peripheral tolerance in mouse models and to monitor autoantibody production, the ability of treated mice to mount a neutralizing HIV antibody response, and whether tolerance is reinstated after treatment.”

    It has been more commonly thought that similarities between a pathogen and a cross-reactive self-antigen represent the basis for certain autoimmune diseases, Dr. Torres further points out. “That is, upon infection, the immune response generates antibodies against the pathogen but that these can also recognize self-antigens and ultimately may lead to autoimmunity. However, there are a number of examples in which an antibody against a particular pathogen also cross-reacts with a self-antigen and, thus, in these cases it may very well be that these represent examples of ‘immune camouflage’ by the pathogen. Whether this similarity represents evolution by the pathogen to escape tolerance is difficult to determine.”

    Dr. Torres cites examples, including infections by Streptococcus pyogenes, in which antibodies against two strep antigens, M protein and N-acetyl-D-glucosamine (GlcNAc), also cross-react with a cardiac protein, host myosin. And in Epstein–Barr virus (EBV) infection, antibodies against the viral Epstein–Barr nuclear antigen 1 (EBNA-1) antigen also cross-react with Smith self-antigen, a nuclear protein.

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