The AIR-1 gene product CIITA is the master regulator of MHC class II gene expression. This makes CIITA a crucial element for triggering antigen presentation to CD4+ T cells and thus the cascade of events leading to an efficient adaptive immune response. Recently we discovered that CIITA is also endowed with the capacity to directly inhibit both HIV-1 and HTLV retroviruses in infected cells by blocking the function of the viral transactivators Tat and Tax. Thus CIITA exerts a dual role against human retroviruses. The first, classical role is the upregulation of MHC class II expression and thus the capacity to present viral antigens to CD4+ T cells. The other, evolutionary new and fundamental role is to inhibit directly viral replication and spreading. We will discuss the molecular mechanisms by which CIITA counteracts specifically viral transactivators. These distinct properties of CIITA will shed new light on the molecular mechanisms of adaptive coevolution of hosts and pathogens and may be exploited to envisage novel therapeutic strategies aimed at counteracting retroviral infections and thus their oncogenic potential.