Novel innate immune functions of the whey acidic protein family

Studies on the interaction of HIV with host factors have recently highlighted a potential role in the pathogenesis of AIDS for three distinct members of the whey acidic protein (WAP) family, secretory leukocyte protease inhibitor, Elafin, and ps20. Identified by an evolutionarily conserved canonical four-disulphide structural domain [whey four disulphide core domain (WFDC)], WAP proteins are increasingly being shown to display functions beyond both protease inhibition and anti-infective activity, to which they were originally ascribed. We propose novel mechanisms on why this might be the case based on an analysis of the structure-function of its human members. Our analysis suggests that the interaction of HIV with WAP proteins might unravel unknown functions of the ancient WFDC and inform novel immunotherapies for the treatment of HIV and broader virus infections.