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

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          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.

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          Most cited references 146

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          Identification of RANTES, MIP-1 alpha, and MIP-1 beta as the major HIV-suppressive factors produced by CD8+ T cells.

           R. S. Arya,  R Gallo,  P Lusso (1995)
          Evidence suggests that CD8+ T lymphocytes are involved in the control of human immunodeficiency virus (HIV) infection in vivo, either by cytolytic mechanisms or by the release of HIV-suppressive factors (HIV-SF). The chemokines RANTES, MIP-1 alpha, and MIP-1 beta were identified as the major HIV-SF produced by CD8+ T cells. Two active proteins purified from the culture supernatant of an immortalized CD8+ T cell clone revealed sequence identity with human RANTES and MIP-1 alpha. RANTES, MIP-1 alpha, and MIP-1 beta were released by both immortalized and primary CD8+ T cells. HIV-SF activity produced by these cells was completely blocked by a combination of neutralizing antibodies against RANTES, MIP-1 alpha, and MIP-1 beta. Recombinant human RANTES, MIP-1 alpha, and MIP-1 beta induced a dose-dependent inhibition of different strains of HIV-1, HIV-2, and simian immunodeficiency virus (SIV). These data may have relevance for the prevention and therapy of AIDS.
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            Change in Coreceptor Use Correlates with Disease Progression in HIV-1–Infected Individuals

            Recent studies have identified several coreceptors that are required for fusion and entry of Human Immunodeficiency Virus type 1 (HIV-1) into CD4+ cells. One of these receptors, CCR5, serves as a coreceptor for nonsyncytium inducing (NSI), macrophage-tropic strains of HIV-1, while another, fusin or CXCR-4, functions as a coreceptor for T cell line–adapted, syncytiuminducing (SI) strains. Using sequential primary isolates of HIV-1, we examined whether viruses using these coreceptors emerge in vivo and whether changes in coreceptor use are associated with disease progression. We found that isolates of HIV-1 from early in the course of infection predominantly used CCR5 for infection. However, in patients with disease progression, the virus expanded its coreceptor use to include CCR5, CCR3, CCR2b, and CXCR-4. Use of CXCR-4 as a coreceptor was only seen with primary viruses having an SI phenotype and was restricted by the env gene of the virus. The emergence of variants using this coreceptor was associated with a switch from NSI to SI phenotype, loss of sensitivity to chemokines, and decreasing CD4+ T cell counts. These results suggest that HIV-1 evolves during the course of infection to use an expanded range of coreceptors for infection, and that this adaptation is associated with progression to AIDS.
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              Emerging roles for lipids in shaping membrane-protein function.

              Studies of membrane proteins have revealed a direct link between the lipid environment and the structure and function of some of these proteins. Although some of these effects involve specific chemical interactions between lipids and protein residues, many can be understood in terms of protein-induced perturbations to the membrane shape. The free-energy cost of such perturbations can be estimated quantitatively, and measurements of channel gating in model systems of membrane proteins with their lipid partners are now confirming predictions of simple models.
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                Author and article information

                Journal
                Curr HIV Res
                Curr. HIV Res
                CHIVR
                Current HIV Research
                Bentham Science Publishers
                1570-162X
                1873-4251
                July 2018
                July 2018
                : 16
                : 4
                : 258-269
                Affiliations
                Department of Chemistry and Biochemistry, University of Alaska Fairbanks , Fairbanks, , AK , USA; Department of Biology and Wildlife, Institute of Arctic Biology, University of Alaska Fairbanks , Fairbanks, , AK , USA; Department of Biochemistry and Molecular Biology, Colorado State University , Fort Collins, , CO , USA
                Author notes
                [* ]Address correspondence to this author at the Department of Chemistry and Biochemistry, University of Alaska Fairbanks, Fairbanks, P.O. Box: 756160, Fairbanks, AK, USA; Tel/Fax: ++1-907-474-5752; E-mail: tbkuhn@ 123456alaska.edu
                Article
                CHIVR-16-258
                10.2174/1570162X16666181003144740
                6398609
                30280668
                © 2018 Bentham Science Publishers

                This is an open access article licensed under the terms of the Creative Commons Attribution-Non-Commercial 4.0 International Public License (CC BY-NC 4.0) ( https://creativecommons.org/licenses/by-nc/4.0/legalcode), which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.

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