Abstract
The implementation of combination antiretroviral therapy (cART) as the primary means of treatment for HIV infection has achieved a dramatic decline in deaths attributed to AIDS and the re-duced incidence of severe forms of HIV-associated neurocognitive disorders (HAND) in infected in-dividuals. Despite these advances, milder forms of HAND persist and prevalence of these forms of neurocognitive impairment are rising with the aging population of HIV infected individuals. HIV en-ters the CNS early in the pathophysiology establishing persistent infection in resident macrophages and glial cells. These infected cells, in turn, secrete neurotoxic viral proteins, inflammatory cytokines, and small metabolites thought to contribute to neurodegenerative processes. The viral envelope protein gp120 has been identified as a potent neurotoxin affecting neurodegeneration via indirect and direct mechanisms involving interactions with chemokine co-receptors CCR5 and CXCR4. This short re-view focuses on gp120 neurotropism and associated mechanisms of neurotoxicity linked to chemokine receptors CCR5 and CXCR4 with a new perspective on plasma membrane lipid rafts as an active par-ticipant in gp120-mediated neurodegeneration underlying HIV induced CNS pathology.
Highlights
Human immunodeficiency virus (HIV), a member of the lentivirus genus of the Retroviridae family of RNA viruses, is the etiologic agent responsible for acquired immune deficiency syndrome (AIDS) and its associated complications, which has been responsible for 35 million deaths and more than 70 million infections worldwide since first emerging in the early 1980s [1]
The use of HIV antiretroviral drugs on Feline immunodeficiency virus (FIV) infected cats has been demonstrated to significantly reduce viral load, which may be suggestive of a similar mechanism for neuropathogenesis between the two lentiviruses, lending further support to a role for CXCR4 signaling in HIV neurotoxicity [77, 78]
In these indirect models of gp120 neurotoxicity, the release of excitotoxic mediators from surrounding macrophages and glial cells induces neuronal apoptosis via disruption of neuronal homeostasis. These results suggest that mitigating oxidative stress in HIV-associated neurocognitive disorders (HAND) through the use of antioxidants to protect against neuronal apoptosis arising from indirect insults mediated by gp120 might be an effective therapy, and several studies have investigated this approach with varying degrees of success [118, 119]
Summary
Human immunodeficiency virus (HIV), a member of the lentivirus genus of the Retroviridae family of RNA viruses, is the etiologic agent responsible for acquired immune deficiency syndrome (AIDS) and its associated complications, which has been responsible for 35 million deaths and more than 70 million infections worldwide since first emerging in the early 1980s [1]. HIV causes chronic disease in infected individuals with a characteristic period of clinical latency and persistent viral replication. Advances in understanding the virus and improvements in diagnosis, treatment, and outcomes of the disease have led to a substantial reduction in HIV-related mortality. As the epidemiology of HIV/AIDS shifts from an acute infection to chronic disease, new challenges emerge in terms of management of long-term infection and associated comorbidities that can have profound impacts on quality of life for infected individuals. HIV isolates are grouped into two types of which HIV-type 1 (HIV-1) is the strain responsible for the present worldwide epidemic of AIDS and is the principal subject of this review
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