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01-02-2014

Giant cell encephalitis and microglial infection with mucosally transmitted simian-human immunodeficiency virus SHIV_SF162P3N in rhesus macaques

Authors: Carole Harbison, Ke Zhuang, Agegnehu Gettie, James Blanchard, Heather Knight, Peter Didier, Cecilia Cheng-Mayer, Susan Westmoreland

Published in: Journal of NeuroVirology | Issue 1/2014

Abstract

Neurocognitive disorders such as dementia and cognitive/motor impairments are among the most significant complications associated with human immunodeficiency virus (HIV) infection, especially in aging populations, yet the pathogenesis remains poorly understood. Activated macrophages and microglia in white matter along with the hallmark multinucleated giant cells are prominent features of HIV encephalitis (HIVE) and of several simian immunodeficiency virus (SIV) models. While infected microglia have been demonstrated in HIVE, this feature is not routinely seen in experimental infections in rhesus macaques using SIV or chimeric simian/HIV (SHIV) strains, limiting utility in HIV-1 pathogenesis and treatment studies. Here, 50 rhesus macaques were inoculated with the CCR5 (R5)-tropic SHIV_SF162P3N virus by one of three routes: intravenously (n = 9), intrarectally (n = 17), or intravaginally (n = 24). Forty-three monkeys became viremic, 26 developed AIDS, and 7 (7/26, 27 %) developed giant cell SIV encephalitis (SIVE). Rapid progressor phenotype was evident in five of seven (71 %) macaques with SIVE, and expansion to utilize the CXCR4 coreceptor (X4 coreceptor switch) was observed in four out of seven (57 %). SIVE lesions were present in gray and white matter in the cerebrum, cerebellum, thalamus, and brain stem of affected animals. Lesions were composed of virally infected CD68⁺, CD163⁺, and HLA-DR⁺ macrophages accompanied by white matter damage, necrosis, and astroglial and microglial activation. Importantly, microglial infection was observed, which makes R5 SHIV_SF162P3N infection of macaques an attractive animal model not only to study transmission and HIVE pathogenesis but also to conduct preclinical evaluation of therapeutic interventions aimed at eradicating HIV-1 from the central nervous system (CNS).

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Annamalai L, Bhaskar V, Pauley DR, Knight H, Williams K, Lentz M, Ratai E, Westmoreland SV, Gonzalez RG, O’Neil SP (2010) Impact of short-term combined antiretroviral therapy on brain virus burden in simian immunodeficiency virus-infected and CD8+ lymphocyte-depleted rhesus macaques. Am J Pathol 177:777–791PubMedCrossRef

Aquaro S, Calio R, Balzarini J, Bellocchi MC, Garaci E, Perno CF (2002) Macrophages and HIV infection: therapeutical approaches toward this strategic virus reservoir. Antivir Res 55:209–225PubMedCrossRef

Budka H, Costanzi G, Cristina S, Lechi A, Parravicini C, Trabattoni R, Vago L (1987) Brain pathology induced by infection with the human immunodeficiency virus (HIV). A histological, immunocytochemical, and electron microscopical study of 100 autopsy cases. Acta Neuropathol 75:185–198PubMedCrossRef

Cheng-Mayer C, Weiss C, Seto D, Levy JA (1989) Isolates of human immunodeficiency virus type 1 from the brain may constitute a special group of the AIDS virus. Proc Natl Acad Sci U S A 86:8575–8579PubMedCentralPubMedCrossRef

Churchill MJ, Wesselingh SL, Cowley D, Pardo CA, McArthur JC, Brew BJ, Gorry PR (2009) Extensive astrocyte infection is prominent in human immunodeficiency virus-associated dementia. Ann Neurol 66:253–258PubMedCrossRef

Deeks SG, Barre-Sinoussi F (2012) Public health: towards a cure for HIV. Nature 487:293–294PubMedCrossRef

Eden A, Price RW, Spudich S, Fuchs D, Hagberg L, Gisslen M (2007) Immune activation of the central nervous system is still present after >4 years of effective highly active antiretroviral therapy. J Infect Dis 196:1779–1783PubMedCrossRef

Gonzalez-Scarano F, Martin-Garcia J (2005) The neuropathogenesis of AIDS. Nat Rev Immunol 5:69–81PubMedCrossRef

Goulder PJ, Watkins DI (2008) Impact of MHC class I diversity on immune control of immunodeficiency virus replication. Nat Rev Immunol 8:619–630PubMedCentralPubMedCrossRef

Gray F, Adle-Biassette H, Brion F, Ereau T, le Maner I, Levy V, Corcket G (2000) Neuronal apoptosis in human immunodeficiency virus infection. J Neurovirol 6(Suppl 1):S38–S43PubMed

Gunthard HF, Havlir DV, Fiscus S, Zhang ZQ, Eron J, Mellors J, Gulick R, Frost SD, Brown AJ, Schleif W, Valentine F, Jonas L, Meibohm A, Ignacio CC, Isaacs R, Gamagami R, Emini E, Haase A, Richman DD, Wong JK (2001) Residual human immunodeficiency virus (HIV) Type 1 RNA and DNA in lymph nodes and HIV RNA in genital secretions and in cerebrospinal fluid after suppression of viremia for 2 years. J Infect Dis 183:1318–1327PubMedCrossRef

Ho SH, Tasca S, Shek L, Li A, Gettie A, Blanchard J, Boden D, Cheng-Mayer C (2007) Coreceptor switch in R5-tropic simian/human immunodeficiency virus-infected macaques. J Virol 81:8621–8633PubMedCentralPubMedCrossRef

Keele BF, Giorgi EE, Salazar-Gonzalez JF, Decker JM, Pham KT, Salazar MG, Sun C, Grayson T, Wang S, Li H, Wei X, Jiang C, Kirchherr JL, Gao F, Anderson JA, Ping LH, Swanstrom R, Tomaras GD, Blattner WA, Goepfert PA, Kilby JM, Saag MS, Delwart EL, Busch MP, Cohen MS, Montefiori DC, Haynes BF, Gaschen B, Athreya GS, Lee HY, Wood N, Seoighe C, Perelson AS, Bhattacharya T, Korber BT, Hahn BH, Shaw GM (2008) Identification and characterization of transmitted and early founder virus envelopes in primary HIV-1 infection. Proc Natl Acad Sci U S A 105:7552–7557PubMedCentralPubMedCrossRef

Letendre S, Marquie-Beck J, Capparelli E, Best B, Clifford D, Collier AC, Gelman BB, McArthur JC, McCutchan JA, Morgello S, Simpson D, Grant I, Ellis RJ (2008) Validation of the CNS penetration-effectiveness rank for quantifying antiretroviral penetration into the central nervous system. Arch Neurol 65:65–70PubMedCentralPubMedCrossRef

Luciw PA, Pratt-Lowe E, Shaw KE, Levy JA, Cheng-Mayer C (1995) Persistent infection of rhesus macaques with T-cell-line-tropic and macrophage-tropic clones of simian/human immunodeficiency viruses (SHIV). Proc Natl Acad Sci U S A 92:7490–7494PubMedCentralPubMedCrossRef

Masliah E, Ge N, Mucke L (1996) Pathogenesis of HIV-1 associated neurodegeneration. Crit Rev Neurobiol 10:57–67PubMedCrossRef

McArthur JC (2004) HIV dementia: an evolving disease. J Neuroimmunol 157:3–10PubMedCrossRef

Michaels J, Sharer LR, Epstein LG (1988) Human immunodeficiency virus type 1 (HIV-1) infection of the nervous system: a review. Immunodefic Rev 1:71–104PubMed

Ohsawa K, Imai Y, Sasaki Y, Kohsaka S (2004) Microglia/macrophage-specific protein Iba1 binds to fimbrin and enhances its actin-bundling activity. J Neurochem 88:844–856PubMedCrossRef

Perno CF, Aquaro S, Rosenwirth B, Balestra E, Peichl P, Billich A, Villani N, Calio R (1994) In vitro activity of inhibitors of late stages of the replication of HIV in chronically infected macrophages. J Leukocyte Biol 56:381–386PubMed

Ren W, Tasca S, Zhuang K, Gettie A, Blanchard J, Cheng-Mayer C (2010) Different tempo and anatomic location of dual-tropic and X4 virus emergence in a model of R5 simian-human immunodeficiency virus infection. J Virol 84:340–351PubMedCentralPubMedCrossRef

Sacktor N, McDermott MP, Marder K, Schifitto G, Selnes OA, McArthur JC, Stern Y, Albert S, Palumbo D, Kieburtz K, De Marcaida JA, Cohen B, Epstein L (2002) HIV-associated cognitive impairment before and after the advent of combination therapy. J Neurovirol 8:136–142PubMedCrossRef

Salazar-Gonzalez JF, Salazar MG, Keele BF, Learn GH, Giorgi EE, Li H, Decker JM, Wang S, Baalwa J, Kraus MH, Parrish NF, Shaw KS, Guffey MB, Bar KJ, Davis KL, Ochsenbauer-Jambor C, Kappes JC, Saag MS, Cohen MS, Mulenga J, Derdeyn CA, Allen S, Hunter E, Markowitz M, Hraber P, Perelson AS, Bhattacharya T, Haynes BF, Korber BT, Hahn BH, Shaw GM (2009) Genetic identity, biological phenotype, and evolutionary pathways of transmitted/founder viruses in acute and early HIV-1 infection. J Exp Med 206:1273–1289PubMedCentralPubMedCrossRef

Schifitto G, Kieburtz K, McDermott MP, McArthur J, Marder K, Sacktor N, Palumbo D, Selnes O, Stern Y, Epstein L, Albert S (2001) Clinical trials in HIV-associated cognitive impairment: cognitive and functional outcomes. Neurology 56:415–418PubMedCrossRef

Schnell G, Joseph S, Spudich S, Price RW, Swanstrom R (2011) HIV-1 replication in the central nervous system occurs in two distinct cell types. PLoS Pathog 7:e1002286PubMedCentralPubMedCrossRef

Shakirzyanova M, Tsai L, Ren W, Gettie A, Blanchard J, Cheng-Mayer C (2012) Pathogenic consequences of vaginal infection with CCR5-tropic simian-human immunodeficiency virus SHIV_SF162P3N. J Virol 86:9432–9442PubMedCentralPubMedCrossRef

Sharer LR (1992) Pathology of HIV-1 infection of the central nervous system. A review. J Neuropathol Exp Neurol 51:3–11PubMedCrossRef

Soulas C, Conerly C, Kim WK, Burdo TH, Alvarez X, Lackner AA, Williams KC (2011) Recently infiltrating MAC387(+) monocytes/macrophages a third macrophage population involved in SIV and HIV encephalitic lesion formation. Am J Pathol 178:2121–2135PubMedCrossRef

Soulas C, Donahue RE, Dunbar CE, Persons DA, Alvarez X, Williams KC (2009) Genetically modified CD34+ hematopoietic stem cells contribute to turnover of brain perivascular macrophages in long-term repopulated primates. Am J Pathol 174:1808–1817PubMedCrossRef

Staprans S, Marlowe N, Glidden D, Novakovic-Agopian T, Grant RM, Heyes M, Aweeka F, Deeks S, Price RW (1999) Time course of cerebrospinal fluid responses to antiretroviral therapy: evidence for variable compartmentalization of infection. AIDS 13:1051–1061PubMedCrossRef

Trillo-Pazos G, Diamanturos A, Rislove L, Menza T, Chao W, Belem P, Sadiq S, Morgello S, Sharer L, Volsky DJ (2003) Detection of HIV-1 DNA in microglia/macrophages, astrocytes and neurons isolated from brain tissue with HIV-1 encephalitis by laser capture microdissection. Brain Pathol 13:144–154PubMedCrossRef

Wiley CA, Schrier RD, Nelson JA, Lampert PW, Oldstone MB (1986) Cellular localization of human immunodeficiency virus infection within the brains of acquired immune deficiency syndrome patients. Proc Natl Acad Sci U S A 83:7089–7093PubMedCentralPubMedCrossRef

Wiley CA, Soontornniyomkij V, Radhakrishnan L, Masliah E, Mellors J, Hermann SA, Dailey P, Achim CL (1998) Distribution of brain HIV load in AIDS. Brain Pathol 8:277–284PubMedCrossRef

Wynn HE, Brundage RC, Fletcher CV (2002) Clinical implications of CNS penetration of antiretroviral drugs. CNS Drugs 16:595–609PubMedCrossRef

Yadav A, Collman RG (2009) CNS inflammation and macrophage/microglial biology associated with HIV-1 infection. J Neuroimmune Pharmacol 4:430–447PubMedCrossRef

Yilmaz A, Price RW, Spudich S, Fuchs D, Hagberg L, Gisslen M (2008) Persistent intrathecal immune activation in HIV-1-infected individuals on antiretroviral therapy. J Acquir Immune Defic Syndr 47:168–173PubMedCentralPubMedCrossRef

Zink MC, Amedee AM, Mankowski JL, Craig L, Didier P, Carter DL, Munoz A, Murphey-Corb M, Clements JE (1997) Pathogenesis of SIV encephalitis. Selection and replication of neurovirulent SIV. Am J Pathol 151:793–803PubMed

Zink MC, Brice AK, Kelly KM, Queen SE, Gama L, Li M, Adams RJ, Bartizal C, Varrone J, Rabi SA, Graham DR, Tarwater PM, Mankowski JL, Clements JE (2010) Simian immunodeficiency virus-infected macaques treated with highly active antiretroviral therapy have reduced central nervous system viral replication and inflammation but persistence of viral DNA. J Infect Dis 202:161–170PubMedCentralPubMedCrossRef

Title: Giant cell encephalitis and microglial infection with mucosally transmitted simian-human immunodeficiency virus SHIVSF162P3N in rhesus macaques
Authors: Carole Harbison
Ke Zhuang
Agegnehu Gettie
James Blanchard
Heather Knight
Peter Didier
Cecilia Cheng-Mayer
Susan Westmoreland
Publication date: 01-02-2014
Publisher: Springer US
Published in: Journal of NeuroVirology / Issue 1/2014
Print ISSN: 1355-0284
Electronic ISSN: 1538-2443
DOI: https://doi.org/10.1007/s13365-013-0229-z

At a glance: The STEP trials

Springer Medicine

Giant cell encephalitis and microglial infection with mucosally transmitted simian-human immunodeficiency virus SHIV_SF162P3N in rhesus macaques

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

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