HIV infection of fetal human astrocytes: the potential role of a receptor-mediated endocytic pathway

Hao, Hsiao Nan; Lyman, William D.

doi:10.1016/s0006-8993(98)01371-7

Cited by 52 publications

(32 citation statements)

References 26 publications

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“…Uptake by immature DC would then make possible a "second round" of transduction if vector cores could escape from the endosome to transduce the engulfing cell. This has been demonstrated to be a pathway for HIV infection in multiple cell types [37][38][39][40][41][42]. Figure 8 illustrates this hypothesis in the context of our experiments.…”

Section: Discussionsupporting

confidence: 60%

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Induction of HIV‐specific T and B cell responses with a replicating and conditionally infectious lentiviral vaccine

2008

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The development of an HIV vaccine that induces broad and potent immunity is critically needed. Viruses, including lentiviruses, have been used as vectors for ex vivo transduction of antigens into dendritic cells (DC). We hypothesized that DC transduced with a vector that allows selective infection of DC could induce potent immunity by continually priming DC. A lentiviral vector encoding HIV gag-pol without env would form viral cores in transduced DC, but would release non-infectious particles by budding into endosomes and releasing apoptotic bodies or exosomes containing viral cores. DC function by endocytosing DCderived apoptotic bodies, and they are specialized in their ability to move endocytic contents into the cytoplasm. We postulated that endocytosis of vector cores could lead to transduction of a second round of DC. In this report, we demonstrate accumulation of viral cores inside transduced DC and show second-round transduction of immature DC that endocytose transduced DC in vitro. The effectiveness of immunization of mice with transduced DC to induce specific lymphocyte activation was assessed. Mice developed antigen-specific T cell responses and specific antibodies after immunization. Transduction of DC with a replication-competent but conditionally infectious lentivirus could be a novel vaccine strategy for HIV.Key words: Dendritic cell Á HIV Á Immune response Á Lentiviral vector Introduction A safe and effective vaccine for HIV is critically needed to combat the worldwide scourge of AIDS. While the correlates of immune protection have yet to be clearly defined, either for protective or therapeutic vaccines, it is widely believed that both CD4 + and CD8 + T cell as well as humoral immunity are important. How sufficiently broad, potent, and sustained responses can be elicited has yet to be determined, and this represents a critical gap in our understanding of how to generate an effective vaccine such that protective or therapeutic immunity can be achieved. Selection and activation of lymphocytes is a function of antigen presentation by dendritic cells (DC), making DC a logical vehicle for immunotherapy [1]. Early studies showed that DC loaded with tumor extracts [2,3] or antigenic peptides [2][3][4][5] induced anti-tumor immunity in both laboratory mice [2,4,5] and human melanoma patients [3]. More recently, viruses have been used as gene transfer vectors for the ex vivo transduction of DC with selected antigens. Lentiviral vectors have a number of advantages over adenoviruses, adeno-associated viruses, poxviruses, and alphaviruses. Transduction is stable due to chromosomal integration and non-dividing cells are efficiently transduced [6]. Lentivirally transduced DC have been studied for their ability to induce anti-tumor immunity. Breckpot et al. [7] demonstrated that murine DC transduced with a lentivirus encoding a truncated variant of ovalbumin (OVA) protected against tumor challenge with OVA-expressing cells. He et al. [8] recently described the transduction of murine DC with a lentiviral vector...

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Section: Discussionsupporting

confidence: 60%

“…No mouse developed a population of IL-4 + CD4 + T cells, arguing that a Th1 response was induced. Serum was collected from each of the animals before each injection (days 0, 14, and 28) and at sacrifice (days [35][36][37][38][39][40]. A p24-binding antibody ELISA was performed and the results are shown in Fig.…”

Section: T and B Cell Responses To Vaccinationmentioning

confidence: 99%

Induction of HIV‐specific T and B cell responses with a replicating and conditionally infectious lentiviral vaccine

2008

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“…Although MR has been shown to be expressed in murine astrocytes (10), no direct evidence is available as to whether hMR is expressed on human astrocytes. Thus, we first determined hMR expression in human primary astrocytes, which have been shown to be susceptible to HIV-1 infection (25,29,63,76,81). Double immunofluorescence staining showed that hMR was expressed in human primary astrocytes ( Fig.…”

Section: Resultsmentioning

confidence: 99%

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

Liu

Kim

et al. 2004

J Virol

181

130

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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.

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“…Gp120 is a structural HIV-1 envelope protein that is crucial for viral entry into the CNS (Hao and Lyman, 1999). In vitro and in vivo studies have reported that gp120-induced neurotoxicity is mediated through different cell surface receptors, such as CCR5 and CXCR4 chemokine receptors and N-methyl-d-aspartate receptor mechanisms (Lipton et al, 1995;Barks et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

“…In vitro and in vivo studies have reported that gp120-induced neurotoxicity is mediated through different cell surface receptors, such as CCR5 and CXCR4 chemokine receptors and N-methyl-d-aspartate receptor mechanisms (Lipton et al, 1995;Barks et al, 1997). A study examining human astrocyte cultures exposed to HIV-1 and gp120 indicated that gp120 is likely responsible for HIV-1 binding to astrocytes (Hao and Lyman, 1999). By binding to these cell surface receptors, gp120 may trigger neuronal apoptosis and excitotoxicity as a result of oxidative stress, perturbed cellular calcium homeostasis and mitochondrial alterations, leading to neuronal death (Lipton, 1991;Corasaniti et al, 2001b;Haughey and Mattson, 2002).…”

Section: Introductionmentioning

confidence: 99%

Differential long‐term neurotoxicity of HIV‐1 proteins in the rat hippocampal formation: A design‐based stereological study

et al. 2007

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The human immunodeficiency virus type 1 (HIV-1) proteins, gp120 and Tat, are believed to play a role in mediating central nervous system (CNS) pathology in HIV-1 infected patients. Using design-based stereology, we examined the role of neonatal intrahippocampal injections of gp120 and Tat on the adult hippocampus (~7½ month). Postnatal day (P)1-treated Sprague-Dawley rats were bilaterally injected with vehicle (VEH, 0.5 μl sterile buffer), gp120 (100 ng), Tat (25 μg) or combined gp120 + Tat (100 ng + 25 μg). Using Nissl-stained tissue sections, we quantified total neurons in five subregions of the rat hippocampus [granual layer (GL), hilus of the dentate gyrus (DGH), cornu ammonis fields (CA)2/3, CA1, and subiculum (SUB)], and total glial cells (astrocytes and oligodendrocytes) in two subregions (DGH and SUB). Estimates of cell area and cell volume were taken in the DGH. There was a significant reduction of neuron number in the CA2/3 subfield by Tat and gp120, and a significant reduction in the DGH by Tat only. For glial cells, numbers of astrocytes in the DGH and SUB were increased by the Tat protein, whereas no effects were noted for gp120. Finally, for oligodendrocytes Tat increased cell number in the DGH but not in any other region; gp120 had no detectable effect in any brain region. Estimates of cell area and cell volume of the three different cell types revealed no significant differences between treatments. Collectively, these results suggest differential effects of gp120 and Tat on the estimated total number of neurons, as well as on the number of glial cells.

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HIV infection of fetal human astrocytes: the potential role of a receptor-mediated endocytic pathway

Cited by 52 publications

References 26 publications

Induction of HIV‐specific T and B cell responses with a replicating and conditionally infectious lentiviral vaccine

Induction of HIV‐specific T and B cell responses with a replicating and conditionally infectious lentiviral vaccine

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

Differential long‐term neurotoxicity of HIV‐1 proteins in the rat hippocampal formation: A design‐based stereological study

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