CD4-Independent Infection of Astrocytes by Human Immunodeficiency Virus Type 1: Requirement for the Human Mannose Receptor

Abstract

Human immunodeficiency virus type 1 (HIV-1) infection occurs in the central nervous system and causes a variety of neurobehavioral and neuropathological disorders. Both microglia, the residential macrophages in the brain, and astrocytes are susceptible to HIV-1 infection. Unlike microglia that express and utilize CD4 and chemokine coreceptors CCR5 and CCR3 for HIV-1 infection, astrocytes fail to express CD4. Astrocytes express several chemokine coreceptors; however, the involvement of these receptors in astrocyte HIV-1 infection appears to be insignificant. In the present study using an expression cloning strategy, the cDNA for the human mannose receptor (hMR) was found to be essential for CD4-independent HIV-1 infectivity. Ectopic expression of functional hMR rendered U87.MG astrocytic cells susceptible to HIV-1 infection, whereas anti-hMR serum and hMR-specific siRNA blocked HIV-1 infection in human primary astrocytes. In agreement with these findings, hMR bound to HIV-1 virions via the abundant and highly mannosylated sugar moieties of HIV-1 envelope glycoprotein gp120 in a Ca 2؉ -dependent fashion. Moreover, hMR-mediated HIV-1 infection was dependent upon endocytic trafficking as assessed by transmission electron microscopy, as well as inhibition of viral entry by endosomo-and lysosomotropic drugs. Taken together, these results demonstrate the direct involvement of hMR in HIV-1 infection of astrocytes and suggest that HIV-1 interaction with hMR plays an important role in HIV-1 neuropathogenesis.Astrocytes, often identified by glial fibrillary acidic protein expression, constitute a majority of the cells in the brain and are essential for maintaining homeostasis in the brain and, hence, normal brain activities. A number of different and quite diverse functions have been attributed to astrocytes. These include secretion of neurotrophic factors, regulation of the interstitial pH, uptake and metabolism of neurotransmitters, antioxidant defense via scavenging and transforming oxygen free radicals into nontoxic species, modulation of neuronal signals, being an essential structural component of the bloodbrain barrier, and participating in immune responses through production and secretion of cytokines, proteases, protease inhibitors, adhesion molecules, and extracellular matrix components that are key mediators of immunity and inflammation (for recent reviews, see references 6, 13, and 58). Although it is important to note that several of the functions listed above are still controversial, the highly dynamic and reciprocal relationship between astrocytes and neurons suggests that dysfunction of astrocytes could contribute to the pathogenesis of neurological diseases.

Oligomerization of the Macrophage Mannose Receptor Enhances gp120-mediated Binding of HIV-1

“…The fate of HIV-1 upon binding to MR, as for other foreign antigens, is internalization and entry into the endocytic pathway of a variety of antigen-presenting cells as shown in immature MDDCs (43), dermal dendritic cells (24), MDMs (31,44), and astrocytes (45). Where DC-SIGN and MR are co-expressed on dermal DCs, HIV binding and entry probably occurs primarily via DC-SIGN.…”

Timing of Galectin-1 Exposure Differentially Modulates Nipah Virus Entry and Syncytium Formation in Endothelial Cells

“…For example, mannan-binding lectin, a soluble innate immune lectin, binds to influenza A virus and leads directly to virus inactivation (43). In contrast, another mannose-binding human lectin, macrophage mannose receptor (MMR) potentiates HIV binding to target cells (44)(45)(46), and MMR can also potentiate infection of macrophages by influenza virus (47), so that different mannose-binding lectins can bind to viruses to either reduce or potentiate infection. Considering the long-standing evolutionary relationship between virus and host, it is not entirely surprising that viruses have learned to co-opt host innate immune defenses for increased target cell entry and replication.…”

Astrocytes in the Rat Nucleus Tractus Solitarii Are Critical for Cardiovascular Reflex Control

“…Microinjections were made over 15 min in 25-50 nl increments until the total volume was injected. Doses and volumes of each agent were chosen according to previous publications (Itoh and Buñag, 1993;Madden et al, 1999;Nattie et al, 2004;Tsutsui et al, 2011;Wilkinson et al, 2011;Talman et al, 2012) and were confirmed in preliminary experiments to produce significant immunofluorescent changes for the targeted cell types over homologous regions of NTS. The pipette was left in the brainstem for an additional 15 min to reduce efflux of fluid from the pipette track.…”

“…The relative selectivity of SAP conjugates for specific neuronal types has been shown by others (Wiley andLappi, 1997, 1999;Madden et al, 1999) and was supported by our finding that treatment with SSP-SAP did not lead to loss of neurons with the biosynthetic enzyme, tyrosine hydroxylase (TH), which is essential for norepinephrine synthesis (Lin et al, 2012b). In contrast, injection into the NTS of anti-dopamine ␤-hydroxylase-SAP (anti-DBH-SAP), which led to a significant loss of TH and DBH neurons, while not affecting NTS neurons with the NK1R, also attenuated the arterial baroreflex and caused significant lability of arterial pressure (Talman et al, 2012).…”