Altered expression of fractalkine in HIV-1-infected astrocytes and consequences for the virus-related neurotoxicity.

HIV-1 infection in the central nervous system (CNS) causes the release of neurotoxic products from infected cells which trigger extensive neuronal loss. Clinically, this results in HIV-1-associated neurocognitive disorders (HAND). However, the effects on neuroprotective factors in the brain remain poorly understood and understudied in this situation. HAND is a multifactorial process involving several players, and the complex cellular mechanisms have not been fully elucidated yet. In this study, we reported that HIV-1 infection of astrocytes limits their potential to express the protective chemokine fractalkine in response to an inflammatory environment. We next confirmed that this effect was not due to a default in its shedding from the cell surface. We then investigated the biological mechanism responsible for this reduced fractalkine expression and found that HIV-1 infection specifically blocks the interaction of transcription factor NF-κB on its promoter with no effect on other cytokines. Moreover, we demonstrated that fractalkine production in astrocytes is regulated in response to immune factors secreted by infected/activated microglia and macrophages. In contrast, we observed that conditioned media from these infected cells also trigger neuronal apoptosis. At last, we demonstrated a strong neuroprotective action of fractalkine on human neurons by reducing neuronal damages. Taken together, our results indicate new relevant interactions between HIV-1 and fractalkine signaling in the CNS. This study provides new information to broaden the understanding of HAND and possibly foresee new therapeutic strategies. Considering its neuro-protective functions, reducing its production from astrocytes could have important outcomes in chronic neuroinflammation and in HIV-1 neuropathogenesis.

The delicate balance between neurotoxicity and neuroprotection in the context of HIV-1 infection.

Human immunodeficiency virus type-1 (HIV-1) causes a spectrum of neurological impairments, termed HIV-associated neurocognitive disorder (HAND), following the infiltration of infected cells into the brain. Even though the implementation of antiretroviral therapy reduced the systemic viral load, the prevalence of HAND remains unchanged and infected patients develop persisting neurological disturbances affecting their quality of life. As a result, HAND have gained importance in basic and clinical researches, warranting the need of developing new adjunctive treatments. Nonetheless, a better understanding of the molecular and cellular mechanisms remains necessary. Several studies consolidated their efforts into elucidating the neurotoxic signaling leading to HAND including the deleterious actions of HIV-1 viral proteins and inflammatory mediators. However, the scope of these studies is not sufficient to address all the complexity related to HAND development. Fewer studies focused on an altered neuroprotective capacity of the brain to respond to HIV-1 infection. Neurotrophic factors are endogenous polyproteins involved in neuronal survival, synaptic plasticity, and neurogenesis. Any defects in the processing or production of these crucial factors might compose a risk factor rendering the brain more vulnerable to neuronal damages. Due to their essential roles, they have been investigated for their diverse interplays with HIV-1 infection. In this review, we present a complete description of the neurotrophic factors involved in HAND. We discuss emerging concepts for their therapeutic applications and summarize the complex mechanisms that down-regulate their production in favor of a neurotoxic environment. For certain factors, we finally address opposing roles that rather lead to increased inflammation.

Production of IL-27 in multiple sclerosis lesions by astrocytes and myeloid cells: Modulation of local immune responses.

The mechanisms whereby human glial cells modulate local immune responses are not fully understood. Interleukin-27 (IL-27), a pleiotropic cytokine, has been shown to dampen the severity of experimental autoimmune encephalomyelitis, but it is still unresolved whether IL-27 plays a role in the human disease multiple sclerosis (MS). IL-27 contribution to local modulation of immune responses in the brain of MS patients was investigated. The expression of IL-27 subunits (EBI3 and p28) and its cognate receptor IL-27R (the gp130 and TCCR chains) was elevated within post-mortem MS brain lesions compared with normal control brains. Moreover, astrocytes (GFAP(+) cells) as well as microglia and macrophages (Iba1(+) cells) were important sources of IL-27. Brain-infiltrating CD4 and CD8 T lymphocytes expressed the IL-27R specific chain (TCCR) implying that these cells could respond to local IL-27 sources. In primary cultures of human astrocytes inflammatory cytokines increased IL-27 production, whereas myeloid cell inflammatory M1 polarization and inflammatory cytokines enhanced IL-27 expression in microglia and macrophages. Astrocytes in postmortem tissues and in vitro expressed IL-27R. Moreover, IL-27 triggered the phosphorylation of the transcription regulator STAT1, but not STAT3 in human astrocytes; indeed IL-27 up-regulated MHC class I expression on astrocytes in a STAT1-dependent manner. These findings demonstrated that IL-27 and its receptor were elevated in MS lesions and that local IL-27 can modulate immune properties of astrocytes and infiltrating immune cells. Thus, therapeutic strategies targeting IL-27 may influence not only peripheral but also local inflammatory responses within the brain of MS patients.