HIV Associated Neurodegenerative Disorders: A New Perspective on the Role of Lipid Rafts in Gp120-Mediated Neurotoxicity

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 reduced incidence of severe forms of HIV-associated neurocognitive disorders (HAND) in infected individuals. 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 enters 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 review 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 participant in gp120-mediated neurodegeneration underlying HIV induced CNS pathology.

Direct interaction of HIV gp120 with neuronal CXCR4 and CCR5 receptors induces cofilin-actin rod pathology via a cellular prion protein- and NOX-dependent mechanism

“…Productive infection by HIV in the CNS is restricted primarily to microglia and, to lesser extent astrocytes with subsequent injury and apoptotic death in neurons [ 2 , 31 , 32 ]. Hence, there has been some debate whether gp120-associated neuronal injury observed in HAND is the result of indirect effects mediated by the release of neurotoxic, proinflammatory host factors from infected or activated glial cells, or rather the result of a direct neurotoxic effect of soluble HIV proteins shed from infected host cells and virus [ 12 , 33 , 34 ]. For that reason, we examined the presence of microglia cells and/or astrocytes in our neuronal cultures by immunocytochemistry ( Fig 3 ).…”

“…Neuronal injury observed in HAND occurs indirectly through the release of neurotoxic, proinflammatory host factors predominantly from microglia and astrocytes, which are productively infected by HIV [ 2 , 31 , 32 ], or as a direct neurotoxic effect of soluble HIV proteins shed from infected host cells and virus such as gp120 [ 12 , 33 , 34 , 81 ]. Pertinent to our studies, gp120 stimulates the release of pro-inflammatory and pro-apoptotic cytokines such as TNFα [ 82 – 84 ].…”

“…Synaptopathy has emerged as a hallmark of HIV-mediated neurotoxicity of HAND in the post-cART era [74] and impairments in neuronal cytoskeleton are highly relevant driven by neurotoxic HIV proteins [93][94][95]. Synaptic dysfunction and dendritic simplification are linked to gp120 neurotoxicity and underlie cognitive impairments observed in HAND yet the mechanisms are poorly understood [12,96,97]. The activation of a PrP C /NOX-mediated pathway of rod induction is one potential mechanism for gp120-induced synaptic dysfunction involving the perturbation of neuronal cytoskeleton dynamics.…”

“…Gp120 co-receptor preference categorizes distinct strains of HIV on the basis of cellular tropism, with macrophage or R5-tropic strains binding CCR5 receptors, T-cell or X4-tropic strains preferentially binding CXCR4 receptors, and dual-tropic strains binding both co-receptors [8]. Coalescence of lipid raft domains into large, stable platforms supports clustering of receptors and components of receptor-activated signaling cascades observed in a number of CNS dysfunctions, including CNS aging and trauma, as well as Alzheimer's disease (AD) [9][10][11][12]. Indeed, gp120 was found to enlarge and stabilize raft domains in a CXCR4-dependent pathway involving the redox-sensitive translocation of neutral sphingomyelinase 2 (nSmase2) to the membrane and the forward trafficking, surface expression, and clustering of NMDA receptors to enlarged raft domains [13][14][15][16].…”

Co-morbilidad neuro-psiquiátrica en infección por VIH

“…Respecto a la respuesta del hospedero, la infección por VIH incentiva la producción de una serie de mediadores pro-inflamatorios sistémicos y en el SNC. Sobre el tejido neural, estos procesos estarían mediados principalmente por la activación y entrada al SNC de monocitos CD16 + y el aumento en la expresión de receptores quemotácticos como el CCL2 en astrocitos 28,29 . Estos mediadores producen un aumento en la actividad de las microglías, las que junto a células T activadas liberan sustancias como FNT, IL-1, IFN-y glutamato, generando apoptosis y daño VIH / SIDA Artículo de Revisión axonal 30 .…”