The Role of Shed PrPc in the Neuropathogenesis of HIV Infection

Abstract

HIV-1 enters the CNS soon after peripheral infection and causes chronic neuroinflammation and neuronal damage that leads to cognitive impairment in 40-70% of HIV infected people. The non-pathogenic cellular isoform of the human prion protein (PrPc) is an adhesion molecule constitutively expressed in the CNS. Previously, our laboratory showed that shed PrPc (sPrPc) is increased in the CSF of HIV infected people with cognitive deficits as compared to infected people with no impairment. Here we demonstrate that CCL2 and TNF-α, inflammatory mediators that are elevated in the CNS of HIV infected people, increase shedding of PrPc from human astrocytes by increasing the active form of the metalloprotease ADAM10. We show that the consequence of this shedding can be the production of inflammatory mediators, as treatment of astrocytes with recombinant PrPc (recPrPc) increased secretion of CCL2, CXCL-12, and IL-8. Supernatants from recPrPc treated astrocytes containing factors produced in response to this treatment, but not recPrPc by itself, cause increased chemotaxis of both uninfected and HIV infected human monocytes, suggesting a role for sPrPc in monocyte recruitment into the brain. Furthermore, we examined whether PrPc participates in glutamate uptake, and found that recPrPc decreased uptake of this metabolite in astrocytes, that could lead to neurotoxicity and neuronal loss. Collectively, our data characterize mediators involved in PrPc shedding, and the effect of this sPrPc on monocyte chemotaxis and glutamate uptake from astrocytes. We propose that shedding of PrPc could be a potential target for therapeutics to limit the cognitive impairment characteristic of neuroAIDS.

Structural and mechanistic aspects influencing the ADAM10-mediated shedding of the prion protein

“…Though this could well be unrelated co-incidence, it might also be speculated that these pathophysiological roles are partially related to the production of shed PrP. Of note, it is precisely shed PrP that was causally linked with chronic inflammatory neuropathology in HIV patients [ 60 ] and development of tumours in the central nervous system [ 59 ] in two recent studies. This further supports the relevance of shed PrP in different pathophysiological conditions and highlights the need for further studies on the ADAM10-mediated shedding of PrP C .…”

“…Surprisingly, shed PrP has recently been associated with the development of specific tumours in the nervous system, where it correlates with increased cancer cell proliferation [ 59 ]. In addition, a recent report shows critical involvement of shed PrP in the neuropathogenesis of HIV/AIDS by recruiting monocytes and aggravating the inflammatory response and the associated cognitive impairment [ 60 ].…”

Chemokines and Chemokine Receptors: Accomplices for Human Immunodeficiency Virus Infection and Latency

“…As CCL2 is an inflammatory chemokine, the CCL2/CCR2 axis has been suggested to be involved in HIV-associated neurologic disorders ( 92 , 93 ). Several researchers have reported an upregulation of plasma CCL2 and its transcript levels in HIV infection ( 94 – 96 ).…”

GPI-anchor signal sequence influences PrPC sorting, shedding and signalling, and impacts on different pathomechanistic aspects of prion disease in mice

“…In the present study, a decreased amount of microglia in PrP C GPIThy-1 mice coincides with a delay to the terminal stage of prion disease, but further experiments would be needed to establish a direct correlation. Of note, a recent study has functionally linked ADAM10-mediated shedding of PrP C to inflammatory responses and monocyte recruitment to the brain [70]. So, it is conceivable that reduced levels of shed PrP (as a potential chemoattractant and activating factor) account for the impaired glial response in our mice.…”