Role of Fc Receptor Polymorphisms in Antibody-Mediated Protection

Schmitz, Joern

Abstract

Recent investigations have suggested that efficient neutralization of AIDS viruses in vivo goes well beyond steric inhibition of the virus by antibodies. Efficient neutralization also depends on additional functional activities such as Fc? receptor-mediated deactivation of the virus. It is well established in humans that the action of antibodies depends on multiple pathways that enhance efficient extermination of its target. However, as the full potential of antibodies requires additional components of the host's immune system, antibody-mediated immune control gets more complex. In fact, the same potent monoclonal antibody may show a different in vivo efficacy depending on specific polymorphisms within the host's immune system. This has been demonstrated in detail for as Fc? receptor polymorphisms where a particular antibody treatment in some tumor patients has resulted in an inferior likelihood of clinical success because the downstream functional activities for the antibody were less efficient due to genetic variation between patients. In HIV infection, limited research has suggested that as Fc? receptor polymorphisms may also affect the progression to AIDS. However, until to date there is no published information available whether as Fc? receptor polymorphisms may affect SIV infection in rhesus macaques that are the most utilized animal model to study an AIDS-like disease in nonhuman primates. We have recently determined as Fc? receptor polymorphisms in rhesus macaques and have gained statistical evidence that as Fc? receptor polymorphisms also affect the in vivo efficacy of antibodies in this nonhuman primate species. Our preliminary data also suggest that as Fc? receptor polymorphisms may be correlated with a differential ability to contain SIV setpoint viremia. While these preliminary data are very encouraging, these observations need more scrutiny. Here we propose studies that (Aim 1) will determine the functional activity of different polymorphic forms of the as Fc? receptors in rhesus macaques. We will conduct (Aim 2) a prospective low dose neutralizing antibody administration and low dose mucosal challenge study to investigate whether as Fc? receptor polymorphisms may impact the efficacy of the neutralizing antibody b12 in protecting the animals from vaginal challenges.

Public Health Relevance

Recent investigations have suggested that efficient neutralization of AIDS viruses includes as Fc? receptor-mediated functions. We have recently determined that as Fc? receptor polymorphisms in rhesus macaques may affect SIV setpoint viremia. In our proposed studies we will determine the activity of as Fc? receptor polymorphisms by functional assays and evaluate whether genetic variability (i.e. as Fc? receptor polymorphisms) influence the efficacy of antibody-mediated protection against repeated low dose mucosal challenges.