A new paradigm about HERV-K102 particle production and blocked release to explain cortisol mediated immunosenescence and age-associated risk of chronic disease.

The majority of chronic diseases in the aging adult are thought to relate to immune aging characterized by dominant immunosuppression and paradoxically, concomitant inflammation. This is known collectively as immunosenescence. The main change thought to be controlling immune aging is the age-related decline in dehydroepiandrosterone (DHEA) and corresponding increase in cortisol; the net effect which decreases the DHEA/cortisol ratio. Exactly how this translates to immunosuppression and concomitant inflammation remains unclear. Recently a new component of the human innate immune system has been discovered. Human endogenous retrovirus K102 (HERV-K102) is a replication-competent foamy retrovirus unique to humans which has been implicated in chronic diseases. Accumulating evidence suggests that HERV-K102 may defend the host against viral infections, as well as against breast and other cancers. Particles are produced in activated monocytes and released into vacuoles but do not bud through the cell surface. This renders macrophages foamy, while the release of particles is only through cell lysis. New evidence presented here suggests DHEA but not DHEA-S may specifically bind and inactivate alpha-fetoprotein (AFP). AFP is a well-established immunosuppressive factor which importantly, also blocks cell lysis induction in macrophages through the 67 kilodalton (kD) AFP receptor (AFPr). Here, it is proposed that a decreased DHEA/cortisol ratio may favor the accumulation of foamy macrophages reflecting the cortisol induction of HERV-K102 particle production concomitant with the blocked release of particles by secreted AFP. This is a new paradigm to explain how cortisol-mediated immunosenescence can result in the persistence of foamy macrophages, and how this relates to risk of chronic disease.