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HIV-1 target cells in the CNS

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Abstract

HIV-1 replication in the central nervous system (CNS) is typically limited by the availability of target cells. HIV-1 variants that are transmitted and dominate the early stages of infection almost exclusively use the CCR5 coreceptor and are well adapted to entering, and thus infecting, cells expressing high CD4 densities similar to those found on CD4+ T cells. While the “immune privileged” CNS is largely devoid of CD4+ T cells, macrophage and microglia are abundant throughout the CNS. These cells likely express CD4 densities that are too low to facilitate efficient entry or allow sustained replication by most HIV-1 isolates. Examination of CNS viral populations reveals that late in disease the CNS of some individuals contains HIV-1 lineages that have evolved the ability to enter cells expressing low levels of CD4 and are well-adapted to entering macrophages. These macrophage-tropic (M-tropic) viruses are able to maintain sustained replication in the CNS for many generations, and their presence is associated with severe neurocognitive impairment. Whether conditions such as pleocytosis are necessary for macrophage-tropic viruses to emerge in the CNS is unknown, and extensive examinations of macrophage-tropic variants have not revealed a genetic signature of this phenotype. It is clear, however, that macrophage tropism is rare among HIV-1 isolates and is not transmitted, but is important due to its pathogenic effects on hosts. Prior to the evolution of macrophage-tropic variants, the viruses that are predominately infecting T cells (R5 T cell-tropic) may infect macrophages at a low level and inefficiently, but this could contribute to the reservoir.

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References

  • Albright AV, Shieh JTC, O’Connor MJ, Gonzalez-Scarano F (2000) Characterization of cultured microglia that can be infected by HIV-1. J Neurovirology 6:S53–S60

    Google Scholar 

  • Alexander M, Lynch R, Mulenga J, Allen S, Derdeyn CA, Hunter E (2010) Donor and recipient envs from heterosexual human immunodeficiency virus subtype C transmission pairs require high receptor levels for entry. J Virol 84:4100–4104

    PubMed Central  CAS  PubMed  Google Scholar 

  • Antinori A, Arendt G, Becker JT, Brew BJ, Byrd DA, Cherner M, Clifford DB, Cinque P, Epstein LG, Goodkin K, Gisslen M, Grant I, Heaton RK, Joseph J, Marder K, Marra CM, McArthur JC, Nunn M, Price RW, Pulliam L, Robertson KR, Sacktor N, Valcour V, Wojna VE (2007) Updated research nosology for HIV-associated neurocognitive disorders. Neurology 69:1789–1799

    CAS  PubMed  Google Scholar 

  • Archin NM, Margolis DM (2014) Emerging strategies to deplete the HIV reservoir. Curr Opin Infect Dis 27:29–35

    PubMed Central  CAS  PubMed  Google Scholar 

  • Archin NM, Liberty AL, Kashuba AD, Choudhary SK, Kuruc JD, Crooks AM, Parker DC, Anderson EM, Kearney MF, Strain MC, Richman DD, Hudgens MG, Bosch RJ, Coffin JM, Eron JJ, Hazuda DJ, Margolis DM (2012) Administration of vorinostat disrupts HIV-1 latency in patients on antiretroviral therapy. Nature 487:482–U1650

    PubMed Central  CAS  PubMed  Google Scholar 

  • Arima Y, Harada M, Kamimura D, Park JH, Kawano F, Yull FE, Kawamoto T, Iwakura Y, Betz UAK, Marquez G, Blackwell TS, Ohira Y, Hirano T, Murakami M (2012) Regional neural activation defines a gateway for autoreactive T cells to cross the blood–brain barrier. Cell 148:447–457

    CAS  PubMed  Google Scholar 

  • Arrildt K, Joseph SB, Swanstrom R (2012) The HIV-1 ENV protein: a coat of many colors. Curr HIV/AIDS Rep 9:52–63

  • Bagasra O, Lavi E, Bobroski L, Khalili K, Pestaner JP, Tawadros R, Pomerantz RJ (1996) Cellular reservoirs of HIV-1 in the central nervous system of infected individuals: Identification by the combination of in situ polymerase chain reaction and immunohistochemistry. Aids 10:573–585

  • Berger EA, Murphy PM, Farber JM (1999) Chemokine receptors as HIV-1 coreceptors: roles in viral entry, tropism, and disease. Annu Rev Immunol 17:657–700

    CAS  PubMed  Google Scholar 

  • Brenchley JM, Hill BJ, Ambrozak DR, Price DA, Guenaga FJ, Casazza JP, Kuruppu J, Yazdani J, Migueles SA, Connors M, Roederer M, Douek DC, Koup RA (2004) T-cell subsets that harbor human immunodeficiency virus (HIV) in vivo: implications for HIV pathogenesis. J Virol 78:1160–1168

    PubMed Central  CAS  PubMed  Google Scholar 

  • Brinchmann JE, Albert J, Vartdal F (1991) Few infected CD4+ T cells but a high proportion of replication-competent provirus copies in asymptomatic human immunodeficiency virus type 1 infection. J Virol 65:2019–2023

    PubMed Central  CAS  PubMed  Google Scholar 

  • Brown PD, Davies SL, Seake T, Millar ID (2004) Molecular mechanisms of cerebrospinal fluid production. Neuroscience 129:957–970

    PubMed Central  CAS  PubMed  Google Scholar 

  • Cahoy JD, Emery B, Kaushal A, Foo LC, Zamanian JL, Christopherson KS, Xing Y, Lubischer JL, Krieg PA, Krupenko SA, Thompson WJ, Barres BA (2008) A transcriptome database for astrocytes, neurons, and oligodendrocytes: A new resource for understanding brain development and function. Journal of Neuroscience 28:264–278

  • Carrithers MD, Visintin I, Viret C, Janeway CA (2002) Role of genetic background in P selectin-dependent immune surveillance of the central nervous system. J Neuroimmunol 129:51–57

    CAS  PubMed  Google Scholar 

  • Cashin K, Roche M, Sterjovski J, Ellett A, Gray LR, Cunningham AL, Ramsland PA, Churchill MJ, Gorry PR (2011) Alternative coreceptor requirements for efficient CCR5- and CXCR4-mediated HIV-1 entry into macrophages. J Virol 85:10699–709

    PubMed Central  CAS  PubMed  Google Scholar 

  • Cherner M, Masliah E, Ellis RJ, Marcotte TD, Moore DJ, Grant I, Heaton RK (2002) Neurocognitive dysfunction predicts postmortem findings of HIV encephalitis. Neurology 59:1563–1567

    CAS  PubMed  Google Scholar 

  • Chun TW, Stuyver L, Mizell SB, Ehler LA, Mican JAM, Baseler M, Lloyd AL, Nowak MA, Fauci AS (1997) Presence of an inducible HIV-1 latent reservoir during highly active antiretroviral therapy. Proc Natl Acad Sci U S A 94:13193–13197

    PubMed Central  CAS  PubMed  Google Scholar 

  • Chung WS, Clarke LE, Wang GX, Stafford BK, Sher A, Chakraborty C, Joung J, Foo LC, Thompson A, Chen CF, Smith SJ, Barres BA (2013) Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways. Nature 504:394–400

  • Churchill MJ, Gorry PR, Cowley D, Lal L, Sonza S, Purcell DFJ, Thompson KA, Gabuzda D, McArthur JC, Pardo CA, Wesselingh SL (2006) Use of laser capture microdissection to detect integrated HIV-1 DNA in macrophages and astrocytes from autopsy brain tissues. J Neurovirol 12:146–152

    PubMed  Google Scholar 

  • 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 66:253–258

    PubMed  Google Scholar 

  • Connor RI, Sheridan KE, Ceradini D, Choe S, Landau NR (1997) Change in coreceptor use correlates with disease progression in HIV-1-infected individuals. J Exp Med 185:621–628

    PubMed Central  CAS  PubMed  Google Scholar 

  • Cosenza MA, Zhao ML, Si QS, Lee SC (2002) Human brain parenchymal microglia express CD14 and CD45 and are productively infected by HIV-1 in HIV-1 encephalitis. Brain Pathol 12:442–455

    CAS  PubMed  Google Scholar 

  • Del Bigio MR (2010) Ependymal cells: biology and pathology. Acta Neuropathol 119:55–73

    PubMed  Google Scholar 

  • deVries HE, BlomRoosemalen MCM, vanOosten M, deBoer AG, vanBerkel TJC, Breimer DD, Kuiper J (1996) The influence of cytokines on the integrity of the blood–brain barrier in vitro. J Neuroimmunol 64:37–43

    CAS  Google Scholar 

  • Diamond TL, Roshal M, Jamburuthugoda VK, Reynolds HM, Merriam AR, Lee KY, Balakrishnan M, Bambara RA, Planelles V, Dewhurst S, Kim B (2004) Macrophage tropism of HIV-1 depends on efficient cellular dNTP utilization by reverse transcriptase. J Biol Chem 279:51545–51553

    PubMed Central  CAS  PubMed  Google Scholar 

  • Dick AD, Pell M, Brew BJ, Foulcher E, Sedgwick JD (1997) Direct ex vivo flow cytometric analysis of human microglial cell CD4 expression: examination of central nervous system biopsy specimens from HIV-seropositive patients and patients with other neurological disease. AIDS 11:1699–1708

    CAS  PubMed  Google Scholar 

  • Douek DC, Brenchley JM, Betts MR, Ambrozak DR, Hill BJ, Okamoto Y, Casazza JP, Kuruppu J, Kuntsman K, Wolinsky S, Grossman Z, Dybul M, Oxenius A, Price DA, Connors M, Koup RA (2002) HIV preferentially infects HIV-specific CD4(+) T cells. Nature 417:95–98

    CAS  PubMed  Google Scholar 

  • Duenas-Decamp MJ, Peters P, Burton D, Clapham PR (2008) Natural resistance of human immunodeficiency virus type 1 to the CD4bs antibody b12 conferred by a glycan and an arginine residue close to the CD4 binding loop. J Virol 82:5807–5814

    PubMed Central  CAS  PubMed  Google Scholar 

  • Duenas-Decamp MJ, Peters PJ, Burton D, Clapham PR (2009) Determinants flanking the CD4 binding loop modulate macrophage tropism of human immunodeficiency virus type 1 R5 envelopes. J Virol 83:2575–2583

    PubMed Central  CAS  PubMed  Google Scholar 

  • Dunfee RL, Thomas ER, Gorry PR, Wang J, Taylor J, Kunstman K, Wolinsky SM, Gabuzda D (2006) The HIV Env variant N283 enhances macrophage tropism and is associated with brain infection and dementia. Proc Natl Acad Sci U S A 103:15160–15165

    PubMed Central  CAS  PubMed  Google Scholar 

  • Dunfee RL, Thomas ER, Wang JB, Kunstman K, Wolinsky SM, Gabuzda D (2007) Loss of the N-linked glycosylation site at position 386 in the HIV envelope V4 region enhances macrophage tropism and is associated with dementia. Virology 367:222–234

    PubMed Central  CAS  PubMed  Google Scholar 

  • Fabriek BO, Van Haastert ES, Galea I, Polfliet MMJ, Dopp ED, Van den Heuvel MM, Van den Berg TK, De Groot CJA, Van der Valk P, Dijkstra CD (2005) CD163-positive perivascular macrophages in the human CNS express molecules for antigen recognition and presentation. Glia 51:297–305

    PubMed  Google Scholar 

  • Falangola MF, Hanly A, Galvaocastro B, Petito CK (1995) HIV-infection of human choroid-plexus—a possible mechanism of viral entry into the CNS. J Neuropathol Exp Neurol 54:497–503

    CAS  PubMed  Google Scholar 

  • Finzi D, Hermankova M, Pierson T, Carruth LM, Buck C, Chaisson RE, Quinn TC, Chadwick K, Margolick J, Brookmeyer R, Gallant J, Markowitz M, Ho DD, Richman DD, Siliciano RF (1997) Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy. Science 278:1295–1300

    CAS  PubMed  Google Scholar 

  • Fischer-Smith T, Croul S, Sverstiuk AE, Capini C, L'Heureux D, Regulier EG, Richardson MW, Amini S, Morgello S, Khalili K, Rappaport J (2001) CNS invasion by CD14+/CD16+ peripheral blood-derived monocytes in HIV dementia: perivascular accumulation and reservoir of HIV infection. J Neurovirol 7:528–541

    CAS  PubMed  Google Scholar 

  • Fulcher JA, Hwangbo Y, Zioni R, Nickle D, Lin XD, Heath L, Mullins JI, Corey L, Zhu TF (2004) Compartmentalization of human immunodeficiency virus type 1 between blood monocytes and CD4(+) T cells during infection. J Virol 78:7883–7893

    PubMed Central  CAS  PubMed  Google Scholar 

  • Galea I, Palin K, Newman TA, Van Rooijen N, Perry VH, Boche D (2005) Mannose receptor expression specifically reveals perivascular macrophages in normal, injured, and diseased mouse brain. Glia 49:375–384

    PubMed  Google Scholar 

  • Galea I, Bechmann I, Perry VH (2007) What is immune privilege (not)? Trends Immunol 28:12–18

    CAS  PubMed  Google Scholar 

  • Goodenow MM, Collman RG (2006) HIV-1 coreceptor preference is distinct from target cell tropism: a dual-parameter nomenclature to define viral phenotypes. J Leukocyte Biol 80:965–972

    CAS  PubMed  Google Scholar 

  • Gorry PR, Bristol G, Zack JA, Ritola K, Swanstrom R, Birch CJ, Bell JE, Bannert N, Crawford K, Wang H, Schols D, De Clercq E, Kunstman K, Wolinsky SM, Gabuzda D (2001) Macrophage tropism of human immunodeficiency virus type 1 isolates from brain and lymphoid tissues predicts neurotropism independent of coreceptor specificity. J Virol 75:10073–10089

    PubMed Central  CAS  PubMed  Google Scholar 

  • Gorry PR, Taylor J, Holm GH, Mehle A, Morgan T, Cayabyab M, Farzan M, Wang H, Bell JE, Kunstman K, Moore JP, Wolinsky SM, Gabuzda D (2002) Increased CCR5 affinity and reduced CCR5/CD4 dependence of a neurovirulent primary human immunodeficiency virus type 1 isolate. J Virol 76:6277–6292

    PubMed Central  CAS  PubMed  Google Scholar 

  • Gorry PR, Ong C, Thorpe J, Bannwarth S, Thompson KA, Gatignol A, Wesselingh SL, Purcell DFJ (2003) Astrocyte infection by HIV-1: mechanisms of restricted virus replication, and role in the pathogenesis of HIV-1-associated dementia. Curr HIV Res 1:463–473

    CAS  PubMed  Google Scholar 

  • Harouse JM, Kunsch C, Hartle HT, Laughlin MA, Hoxie JA, Wigdahl B, Gonzalezscarano F (1989) CD4-independent infection of human neural cells by human immunodeficiency virus type 1. J Virol 63:2527–2533

    PubMed Central  CAS  PubMed  Google Scholar 

  • Harrington PR, Schnell G, Letendre SL, Ritola K, Robertson K, Hall C, Burch CL, Jabara CB, Moore DT, Ellis RJ, Price RW, Swanstrom R (2009) Cross-sectional characterization of HIV-1 env compartmentalization in cerebrospinal fluid over the full disease course. AIDS 23:907–915

    PubMed Central  PubMed  Google Scholar 

  • He J, Crews FT (2008) Increased MCP-1 and microglia in various regions of the human alcoholic brain. Exp Neurol 210:349–358

    PubMed Central  CAS  PubMed  Google Scholar 

  • Ho DD, Neumann AU, Perelson AS, Chen W, Leonard JM, Markowitz M (1995) Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature 373:123–126

    CAS  PubMed  Google Scholar 

  • Ho YC, Shan L, Hosmane NN, Wang J, Laskey SB, Rosenbloom DIS, Lai J, Blankson JN, Siliciano JD, Siliciano RF (2013) Replication-competent noninduced proviruses in the latent reservoir increase barrier to HIV-1 cure. Cell 155:540–551

    PubMed Central  CAS  PubMed  Google Scholar 

  • Hockly E, Richon VM, Woodman B, Smith DL, Zhou XB, Rosa E, Sathasivam K, Ghazi-Noori S, Mahal A, Lowden PAS, Steffan JS, Marsh JL, Thompson LM, Lewis CM, Marks PA, Bates GP (2003) Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, ameliorates motor deficits in a mouse model of Huntington’s disease. Proc Natl Acad Sci U S A 100:2041–2046

    PubMed Central  CAS  PubMed  Google Scholar 

  • Horikoshi Y, Sasaki A, Taguchi N, Maeda M, Tsukagoshi H, Sato K, Yamaguchi H (2003) Human GLUT5 immunolabeling is useful for evaluating microglial status in neuropathological study using paraffin sections. Acta Neuropathol 105:157–162

    CAS  PubMed  Google Scholar 

  • Ince WL, Harrington PR, Schnell GL, Patel-Chhabra M, Burch CL, Menezes P, Price RW, Eron JJ, Swanstrom RI (2009) Major coexisting human immunodeficiency virus type 1 env gene subpopulations in the peripheral blood are produced by cells with similar turnover rates and show little evidence of genetic compartmentalization. J Virol 83:4068–4080

    PubMed Central  CAS  PubMed  Google Scholar 

  • Ioannidis JPA, Reichlin S, Skolnik PR (1995) Long-term productive human immunodeficiency virus-1 infection in human infant microglia. Am J Pathol 147:1200–1206

    PubMed Central  CAS  PubMed  Google Scholar 

  • Isaacman-Beck J, Hermann EA, Yi YJ, Ratcliffe SJ, Mulenga J, Allen S, Hunter E, Derdeyn CA, Collman RG (2009) Heterosexual transmission of human immunodeficiency virus type 1 subtype C: macrophage tropism, alternative coreceptor use, and the molecular anatomy of CCR5 utilization. J Virol 83:8208–8220

    PubMed Central  CAS  PubMed  Google Scholar 

  • Joseph SB, Arrildt KT, Swanstrom AE, Schnell G, Lee B, Hoxie JA, Swanstrom R (2014) Quantification of entry phenotypes of macrophage-tropic HIV-1 across a wide range of CD4 densities. J Virol 88:1858–1869

    PubMed Central  PubMed  Google Scholar 

  • Keele BF, Giorgi EE, Salazar-Gonzalez JF, Decker JM, Pham KT, Salazar MG, Sun CX, Grayson T, Wang SY, Li H, Wei XP, Jiang CL, 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 characterisation of transmitted and early founder virus envelopes in primary HIV-1 infection. Proc Natl Acad Sci U S A 105:7552–7557

    PubMed Central  CAS  PubMed  Google Scholar 

  • Kettenmann H, Hanisch U-K, Noda M, Verkhratsky A (2011) Physiology of microglia. Physiol Rev 91:461–553

    CAS  PubMed  Google Scholar 

  • Kitamura O, Takeichi T, Wang EL, Tokunaga I, Ishigami A, S-i K (2010) Microglial and astrocytic changes in the striatum of methamphetamine abusers. Legal Med 12:57–62

    CAS  PubMed  Google Scholar 

  • Kivisakk P, Trebst C, Liu Z, Tucky BH, Sorensen TL, Rudick RA, Mack M, Ransohoff RM (2002) T-cells in the cerebrospinal fluid express a similar repertoire of inflammatory chemokine receptors in the absence or presence of CNS inflammation: implications for CNS trafficking. Clin Exp Immunol 129:510–518

    PubMed Central  CAS  PubMed  Google Scholar 

  • Kivisakk P, Mahad DJ, Callahan MK, Trebst C, Tucky B, Wei T, Wu LJ, Baekkevold ES, Lassmann H, Staugaitis SM, Campbell JJ, Ransohoff RM (2003) Human cerebrospinal fluid central memory CD4(+) T cells: evidence for trafficking through choroid plexus and meninges via P-selectin. Proc Natl Acad Sci U S A 100:8389–8394

    PubMed Central  PubMed  Google Scholar 

  • Koot M, Keet IPM, Vos AHV, Degoede REY, Roos MTL, Coutinho RA, Miedema F, Schellekens PTA, Tersmette M (1993) Prognostic value of HIV-1 syncytium-inducing phenotype for rate of CD4+ cell depletion and progression to AIDS. Ann Intern Med 118:681–688

    CAS  PubMed  Google Scholar 

  • Koyanagi Y, Miles S, Mitsuyasu RT, Merrill JE, Vinters HV, Chen ISY (1987) Dual infection of the central-nervous-system by AIDS viruses with distinct cellular tropisms. Science 236:819–822

    CAS  PubMed  Google Scholar 

  • Lambotte O, Taoufik Y, de Goer MG, Wallon C, Goujard C, Delfraissy JF (2000) Detection of infectious HIV in circulating monocytes from patients on prolonged highly active antiretroviral therapy. J Acquir Immune Defic Syndr 23:114–119

    CAS  PubMed  Google Scholar 

  • Lamers SL, Gray RR, Salemi M, Huysentruyt LC, McGrath MS (2011) HIV-1 phylogenetic analysis shows HIV-1 transits through the meninges to brain and peripheral tissues. Infect Genet Evol 11:31–37

    PubMed Central  PubMed  Google Scholar 

  • Lawn SD, Pisell TL, Hirsch CS, Wu M, Butera ST, Toossi Z (2001) Anatomically compartmentalized human immunodeficiency virus replication in HLA-DR(+) cells and CD14(+) macrophages at the site of pleural tuberculosis coinfection. J Infect Dis 184:1127–1133

    CAS  PubMed  Google Scholar 

  • Lee B, Sharron M, Montaner LJ, Weissman D, Doms RW (1999) Quantification of CD4, CCR5, and CXCR4 levels on lymphocyte subsets, dendritic cells, and differentially conditioned monocyte-derived macrophages. Proc Natl Acad Sci U S A 96:5215–5220

    PubMed Central  CAS  PubMed  Google Scholar 

  • Li S, Juarez J, Alali M, Dwyer D, Collman R, Cunningham A, Naif HM (1999) Persistent CCR5 utilization and enhanced macrophage tropism by primary blood human immunodeficiency virus type 1 isolates from advanced stages of disease and comparison to tissue-derived isolates. J Virol 73:9741–9755

    PubMed Central  CAS  PubMed  Google Scholar 

  • Li H, Bar KJ, Wang S, Decker JM, Chen Y, Sun C, Salazar-Gonzalez JF, Salazar MG, Learn GH, Morgan CJ, Schumacher JE, Hraber P, Giorgi EE, Bhattacharya T, Korber BT, Perelson AS, Eron JJ, Cohen MS, Hicks CB, Haynes BF, Markowitz M, Keele BF, Hahn BH, Shaw GM (2010) High multiplicity infection by HIV-1 in men who have sex with men. PLoS Pathog 6:e1000890

    PubMed Central  PubMed  Google Scholar 

  • Liu Y, Liu H, Kim BO, Gattone VH, Li JL, Nath A, Blum J, He JJ (2004) CD4-independent infection of astrocytes by human immunodeficiency virus type 1: requirement for the human mannose receptor. J Virol 78:4120–4133

    PubMed Central  CAS  PubMed  Google Scholar 

  • Maher F, Vannucci SJ, Simpson IA (1994) Glucose transporter proteins in brain. FASEB J 8:1003–1011

    CAS  PubMed  Google Scholar 

  • Matsuda K, Brown CR, Foley B, Goeken R, Whitted S, Dang Q, Wu F, Plishka R, Buckler-White A, Hirscha VM (2013) Laser capture microdissection assessment of virus compartmentalization in the central nervous systems of macaques infected with neurovirulent simian immunodeficiency virus. J Virol 87:8896–8908

    PubMed Central  CAS  PubMed  Google Scholar 

  • McCarthy M, He J, Wood C (1998) HIV-1 strain-associated variability in infection of primary neuroglia. J Neurovirol 4:80–89

    CAS  PubMed  Google Scholar 

  • Mefford ME, Gorry PR, Kunstman K, Wolinsky SM, Gabuzda D (2008) Bioinformatic prediction programs underestimate the frequency of CXCR4 usage by R5X4 HIV type 1 in brain and other tissues. Aids Res Hum Retroviruses 24:1215–1220

    PubMed Central  CAS  PubMed  Google Scholar 

  • Musich T, Peters PJ, Duenas-Decamp MJ, Gonzalez-Perez MP, Robinson J, Zolla-Pazner S, Ball JK, Luzuriaga K, Clapham PR (2011) A conserved determinant in the V1 loop of HIV-1 modulates the V3 loop to prime low CD4 use and macrophage infection. J Virol 85:2397–2405

    PubMed Central  CAS  PubMed  Google Scholar 

  • Nag S, Begley DJ (2005) Blood–brain barrier, exchange of metabolites and gases. In: Kalimo H (ed) Pathology and genetics: cerebrovascular diseases. Neuropath, Basel, pp 22–29

    Google Scholar 

  • Naif HM, Li S, Alali M, Sloane A, Wu LJ, Kelly M, Lynch G, Lloyd A, Cunningham AL (1998) CCR5 expression correlates with susceptibility of maturing monocytes to human immunodeficiency virus type 1 infection. J Virol 72:830–836

    PubMed Central  CAS  PubMed  Google Scholar 

  • Nedergaard M, Ransom B, Goldman SA (2003) New roles for astrocytes: redefining the functional architecture of the brain. Trends Neurosci 26:523–530

    CAS  PubMed  Google Scholar 

  • Neuenjacob E, Arendt G, Wendtland B, Jacob B, Schneeweis M, Wechsler W (1993) Frequency and topographical distribution of CD68-positive macrophages and HIV-1 core proteins in HIV-associated brain lesions. Clin Neuropathol 12:315–324

    CAS  Google Scholar 

  • Nuovo GJ, Alfieri ML (1996) AIDS dementia is associated with massive, activated HIV-1 infection and concomitant expression of several cytokines. Mol Med 2:358–366

  • Nuutinen T, Suuronen T, Kauppinen A, Salminen A (2010) Valproic acid stimulates clusterin expression in human astrocytes: implications for Alzheimer’s disease. Neurosci Lett 475:64–68

    CAS  PubMed  Google Scholar 

  • Ochsenbauer C, Edmonds TG, Ding HT, Keele BF, Decker J, Salazar MG, Salazar-Gonzalez JF, Shattock R, Haynes BF, Shaw GM, Hahn BH, Kappes JC (2012) Generation of transmitted/founder HIV-1 infectious molecular clones and characterization of their replication capacity in CD4 T lymphocytes and monocyte-derived macrophages. J Virol 86:2715–2728

    PubMed Central  CAS  PubMed  Google Scholar 

  • Ohagen A, Devitt A, Kunstman KJ, Gorry PR, Rose PP, Korber B, Taylor J, Levy R, Murphy RL, Wolinsky SM, Gabuzda D (2003) Genetic and functional analysis of full-length human immunodeficiency virus type 1 env genes derived from brain and blood of patients with AIDS. J Virol 77:12336–12345

    PubMed Central  CAS  PubMed  Google Scholar 

  • Orenstein JM, Fox C, Wahl SM (1997) Macrophages as a source of HIV during opportunistic infections. Science 276:1857–1861

    CAS  PubMed  Google Scholar 

  • Ousman SS, Kubes P (2012) Immune surveillance in the central nervous system. Nat Neurosci 15:1096–1101

    CAS  PubMed  Google Scholar 

  • Ouyang Y, Liu L, Zhang Y, Yuan L, Liu Z, Yang S, Wei F, Qiao L, Chen D (2014) Discordant patterns of tissue-specific genetic characteristics in the HIV-1 env gene from HIV-associated neurocognitive disorder (HAND) and non-HAND patients. J Neurovirol 20:332–340

  • Palmieri D, Lockman PR, Thomas FC, Hua E, Herring J, Hargrave E, Johnson M, Flores N, Qian YZ, Vega-Valle E, Taskar KS, Rudraraju V, Mittapalli RK, Gaasch JA, Bohn KA, Thorsheim HR, Liewehr DJ, Davis S, Reilly JF, Walker R, Bronder JL, Feigenbaum L, Steinberg SM, Camphausen K, Meltzer PS, Richon VM, Smith QR, Steeg PS (2009) Vorinostat inhibits brain metastatic colonization in a model of triple-negative breast cancer and induces DNA double-strand breaks. Clin Cancer Res 15:6148–6157

    CAS  PubMed  Google Scholar 

  • Parrish NF, Wilen CB, Banks LB, Iyer SS, Pfaff JM, Salazar-Gonzalez JF, Salazar MG, Decker JM, Parrish EH, Berg A, Hopper J, Hora B, Kumar A, Mahlokozera T, Yuan S, Coleman C, Vermeulen M, Ding H, Ochsenbauer C, Tilton JC, Permar SR, Kappes JC, Betts MR, Busch MP, Gao F, Montefiori D, Haynes BF, Shaw GM, Hahn BH, Doms RW (2012) Transmitted/founder and chronic subtype C HIV-1 use CD4 and CCR5 receptors with equal efficiency and are not inhibited by blocking the integrin α4β7. PLoS Pathog 8:e1002686

    PubMed Central  CAS  PubMed  Google Scholar 

  • Perdiguero EG, Schulz C, Geissmann F (2013) Development and homeostasis of “resident” myeloid cells: the case of the microglia. Glia 61:112–120

    Google Scholar 

  • Perelson AS, Neumann AU, Markowitz M, Leonard JM, Ho DD (1996) HIV-1 dynamics in vivo: virion clearance rate, infected cell life-span, and viral generation time. Science 271:1582–1586

    CAS  PubMed  Google Scholar 

  • Perelson AS, Essunger P, Cao YZ, Vesanen M, Hurley A, Saksela K, Markowitz M, Ho DD (1997) Decay characteristics of HIV-1-infected compartments during combination therapy. Nature 387:188–191

    CAS  PubMed  Google Scholar 

  • Peters PJ, Bhattacharya J, Hibbitts S, Dittmar MT, Simmons G, Bell J, Simmonds P, Clapham PR (2004) Biological analysis of human immunodeficiency virus type 1 R5 envelopes amplified from brain and lymph node tissues of AIDS patients with neuropathology reveals two distinct tropism phenotypes and identifies envelopes in the brain that confer an enhanced tropism and fusigenicity for macrophages. J Virol 78:6915–6926

    PubMed Central  CAS  PubMed  Google Scholar 

  • Peters PJ, Sullivan WM, Duenas-Decamp MJ, Bhattacharya J, Ankghuambom C, Brown R, Luzuriaga K, Bell J, Simmonds P, Ball J, Clapham PR (2006) Non-macrophage-tropic human immunodeficiency virus type 1 R5 envelopes predominate in blood, lymph nodes, and semen: implications for transmission and pathogenesis. J Virol 80:6324–6332

    PubMed Central  CAS  PubMed  Google Scholar 

  • Petito CK, Chen HX, Mastri AR, Torres-Munoz J, Roberts B, Wood C (1999) HIV infection of choroid plexus in AIDS and asymptomatic HIV-infected patients suggests that the choroid plexus may be a reservoir of productive infection. J Neurovirol 5:670–677

    CAS  PubMed  Google Scholar 

  • Pilcher CD, Shugars DC, Fiscus SA, Miller WC, Menezes P, Giner J, Dean B, Robertson K, Hart CE, Lennox JL, Eron JJ Jr, Hicks CB (2001) HIV in body fluids during primary HIV infection: implications for pathogenesis, treatment and public health. AIDS 15:837–45

    CAS  PubMed  Google Scholar 

  • Ping LH, Joseph SB, Anderson JA, Abrahams MR, Salazar-Gonzalez JF, Kincer LP, Treurnicht FK, Arney L, Ojeda S, Zhang M, Keys J, Potter EL, Chu H, Moore P, Salazar MG, Iyer S, Jabara C, Kirchherr J, Mapanje C, Ngandu N, Seoighe C, Hoffman I, Gao F, Tang Y, Labranche C, Lee B, Saville A, Vermeulen M, Fiscus S, Morris L, Karim SA, Haynes BF, Shaw GM, Korber BT, Hahn BH, Cohen MS, Montefiori D, Williamson C, Swanstrom R (2013) Comparison of viral Env proteins from acute and chronic infections with subtype C human immunodeficiency virus type 1 identifies differences in glycosylation and CCR5 utilization and suggests a new strategy for immunogen design. J Virol 87:7218–7233

    PubMed Central  CAS  PubMed  Google Scholar 

  • Polazzi E, Monti B (2010) Microglia and neuroprotection: from in vitro studies to therapeutic applications. Prog Neurobiol 92:293–315

    PubMed  Google Scholar 

  • Psallidopoulos MC, Schnittman SM, Thompson LM, Baseler M, Fauci AS, Lane HC, Salzman NP (1989) Integrated proviral human immunodeficiency virus type 1 is present in CD4+ peripheral blood lymphocytes in healthy seropositive individuals. J Virol 63:4626–4631

    PubMed Central  CAS  PubMed  Google Scholar 

  • Ransohoff RM, Cardona AE (2010) The myeloid cells of the central nervous system parenchyma. Nature 468:253–262

    CAS  PubMed  Google Scholar 

  • Ransohoff RM, Engelhardt B (2012) The anatomical and cellular basis of immune surveillance in the central nervous system. Nat Rev Immunol 12:623–635

    CAS  PubMed  Google Scholar 

  • Ransohoff RM, Kivisakk P, Kidd G (2003) Three or more routes for leukocyte migration into the central nervous system. Nat Rev Immunol 3:569–81

    CAS  PubMed  Google Scholar 

  • Rossi F, Querido B, Nimmagadda M, Cocklin S, Navas-Martin S, Martin-Garcia J (2008) The V1–V3 region of a brain-derived HIV-1 envelope glycoprotein determines macrophage tropism, low CD4 dependence, increased fusogenicity and altered sensitivity to entry inhibitors. Retrovirology 5:89

    PubMed Central  PubMed  Google Scholar 

  • Salazar-Gonzalez JF, Salazar MG, Keele BF, Learn GH, Giorgi EE, Li H, Decker JM, Wang SY, 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 206:1273–1289

    PubMed Central  CAS  PubMed  Google Scholar 

  • Salimi H, Roche M, Webb N, Gray LR, Chikere K, Sterjovski J, Ellett A, Wesselingh SL, Ramsland PA, Lee B, Churchill MJ, Gorry PR (2013) Macrophage-tropic HIV-1 variants from brain demonstrate alterations in the way gp120 engages both CD4 and CCR5. J Leukocyte Biol 93:113–126

    PubMed Central  CAS  PubMed  Google Scholar 

  • Sasaki A, Yamaguchi H, Horikoshi Y, Tanaka G, Nakazato Y (2004) Expression of glucose transporter 5 by microglia in human gliomas. Neuropathol Appl Neurobiol 30:447–455

    CAS  PubMed  Google Scholar 

  • Schnell G, Spudich S, Harrington P, Price RW, Swanstrom R (2009) Compartmentalized human immunodeficiency virus type 1 originates from long-lived cells in some subjects with HIV-1-associated dementia. PLoS Pathog 5:e1000395

    PubMed Central  PubMed  Google Scholar 

  • Schnell G, Price RW, Swanstrom R, Spudich S (2010) Compartmentalization and clonal amplification of HIV-1 variants in the cerebrospinal fluid during primary infection. J Virol 84:2395–2407

    PubMed Central  CAS  PubMed  Google Scholar 

  • 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:e1002286

    PubMed Central  CAS  PubMed  Google Scholar 

  • Schnittman SM, Psallidopoulos MC, Lane HC, Thompson L, Baseler M, Massari F, Fox CH, Salzman NP, Fauci AS (1989) The reservoir for HIV-1 in human peripheral blood is a T cell that maintains expression of CD4. Science 245:305–308

    CAS  PubMed  Google Scholar 

  • Shirai Y (1921) On the transplantation of the rat sarcoma in adult heterogeneous animals. Jpn Med World 1:14–15

    Google Scholar 

  • Simon V, Ho DD (2003) HIV-1 dynamics in vivo: implications for therapy. Nat Rev Microbiol 1:181–190

    CAS  PubMed  Google Scholar 

  • Sleasman JW, Aleixo LF, Morton A, SkodaSmith S, Goodenow MM (1996) CD4+ memory T cells are the predominant population of HIV-1-infected lymphocytes in neonates and children. AIDS 10:1477–1484

    CAS  PubMed  Google Scholar 

  • Sonza S, Maerz A, Uren S, Violo A, Hunter S, Boyle W, Crowe S (1995) Susceptibility of human monocytes to HIV type 1 infection in vitro is not dependent on their level of CD4 expression. Aids Res Hum Retroviruses 11:769–776

    CAS  PubMed  Google Scholar 

  • Sonza S, Mutimer HP, Oelrichs R, Jardine D, Harvey K, Dunne A, Purcell DF, Birch C, Crowe SM (2001) Monocytes harbour replication-competent, non-latent HIV-1 in patients on highly active antiretroviral therapy. AIDS 15:17–22

    CAS  PubMed  Google Scholar 

  • Spivak AM, Salgado M, Rabi SA, O'Connell KA, Blankson JN (2011) Circulating monocytes are not a major reservoir of HIV-1 in elite suppressors. J Virol 85:10399–403

    PubMed Central  PubMed  Google Scholar 

  • Spudich S, Gisslen M, Hagberg L, Lee E, Liegler T, Brew B, Fuchs D, Tambussi G, Cinque P, Hecht FM, Price RW (2011) Central nervous system immune activation characterizes primary human immunodeficiency virus 1 infection even in participants with minimal cerebrospinal fluid viral burden. J Infect Dis 204:753–60

    PubMed Central  CAS  PubMed  Google Scholar 

  • Stoler MH, Eskin TA, Benn S, Angerer RC, Angerer LM (1986) Human T-cell lymphotropic virus type III infection of the central nervous system. A preliminary in situ analysis. JAMA 256:2360–2364

    CAS  PubMed  Google Scholar 

  • Sturdevant CB, Dow A, Jabara CB, Joseph SB, Schnell G, Takamune N, Mallewa M, Heyderman RS, Van Rie A, Swanstrom R (2012) Central nervous system compartmentalization of HIV-1 subtype C variants early and late in infection in young children. PLoS Pathog 8:e1003094

    PubMed Central  CAS  PubMed  Google Scholar 

  • Takahashi K, Wesselingh SL, Griffin DE, McArthur JC, Johnson RT, Glass JD (1996) Localization of HIV-1 in human brain using polymerase chain reaction in situ hybridization and immunocytochemistry. Ann Neurol 39:705–711

  • Tasdemir-Yilmaz OE, Freeman MR (2014) Astrocytes engage unique molecular programs to engulf pruned neuronal debris from distinct subsets of neurons. Gene Dev 28:20–33

  • Thomas ER, Dunfee RL, Stanton J, Bogdan D, Taylor J, Kunstman K, Bell JE, Wolinsky SM, Gabuzda D (2007) Macrophage entry mediated by HIV Envs from brain and lymphoid tissues is determined by the capacity to use low CD4 levels and overall efficiency of fusion. Virology 360:105–119

    PubMed Central  CAS  PubMed  Google Scholar 

  • Thompson KA, Churchill MJ, Gorry PR, Sterjovski J, Oelrichs RB, Wesselingh SL, McLean CA (2004) Astrocyte specific viral strains in HIV dementia. Ann Neurol 56:873–877

    CAS  PubMed  Google Scholar 

  • Toma J, Whitcomb JM, Petropoulos CJ, Huang W (2010) Dual-tropic HIV type 1 isolates vary dramatically in their utilization of CCR5 and CXCR4 coreceptors. Aids 24:2181–2186

    CAS  PubMed  Google Scholar 

  • Tremblay ME, Stevens B, Sierra A, Wake H, Bessis A, Nimmerjahn A (2011) The role of microglia in the healthy brain. J Neurosci 31:16064–16069

    CAS  PubMed  Google Scholar 

  • Valcour V, Chalermchai T, Sailasuta N, Marovich M, Lerdlum S, Suttichom D, Suwanwela NC, Jagodzinski L, Michael N, Spudich S, van Griensven F, de Souza M, Kim J, Ananworanich J (2012) Central nervous system viral invasion and inflammation during acute HIV infection. J Infect Dis 206:275–282

    PubMed Central  CAS  PubMed  Google Scholar 

  • Vannucci SJ, Maher F, Simpson IA (1997) Glucose transporter proteins in brain: delivery of glucose to neurons and glia. Glia 21:2–21

    CAS  PubMed  Google Scholar 

  • Verkhratsky A, Orkand RK, Kettenmann H (1998) Glial calcium: homeostasis and signaling function. Physiol Rev 78:99–141

    CAS  PubMed  Google Scholar 

  • Wang JB, Crawford K, Yuan ML, Wang H, Gorry PR, Gabuzda D (2002) Regulation of CC chemokine receptor 5 and CD4 expression and human immunodeficiency virus type 1 replication in human macrophages and microglia by T helper type 2 cytokines. J Infect Dis 185:885–897

    CAS  PubMed  Google Scholar 

  • Wang T, Xu YN, Zhu HY, Andrus T, Ivanov SB, Pan C, Dolores J, Dann GC, Zhou M, Forte D, Yang ZH, Holte S, Corey L, Zhu TF (2013) Successful isolation of infectious and high titer human monocyte-derived HIV-1 from two subjects with discontinued therapy. Plos One 8:e65071

    PubMed Central  CAS  PubMed  Google Scholar 

  • Warren KE, McCully C, Dvinge H, Tjornelund J, Sehested M, Lichenstein HS, Balis FM (2008) Plasma and cerebrospinal fluid pharmacokinetics of the histone deacetylase inhibitor, belinostat (PXD101), in non-human primates. Cancer Chemother Pharmacol 62:433–437

    CAS  PubMed  Google Scholar 

  • Watkins BA, Dorn HH, Kelly WB, Armstrong RC, Potts BJ, Michaels F, Kufta CV, Duboisdalcq M (1990) Specific tropism of HIV-1 for microglial cells in primary human brain cultures. Science 249:549–553

    CAS  PubMed  Google Scholar 

  • Wei XP, Ghosh SK, Taylor ME, Johnson VA, Emini EA, Deutsch P, Lifson JD, Bonhoeffer S, Nowak MA, Hahn BH, Saag MS, Shaw GM (1995) Viral dynamics in human immunodeficiency virus type 1 infection. Nature 373:117–122

    CAS  PubMed  Google Scholar 

  • Wightman F, Ellenberg P, Churchill M, Lewin SR (2012) HDAC inhibitors in HIV. Immunol Cell Biol 90:47–54

    CAS  PubMed  Google Scholar 

  • Wilen CB, Parrish NF, Pfaff JM, Decker JM, Henning EA, Haim H, Petersen JE, Wojcechowskyj JA, Sodroski J, Haynes BF, Montefiori DC, Tilton JC, Shaw GM, Hahn BH, Doms RW (2011) Phenotypic and immunologic comparison of clade B transmitted/founder and chronic HIV-1 envelope glycoproteins. J Virol 85:8514–8527

    PubMed Central  CAS  PubMed  Google Scholar 

  • Wilen CB, Tilton JC, Doms RW (2012) HIV: Cell binding and Entry. In: Bushman FD, Nabel GJ, Swanstrom R (eds) HIV: from biology to prevention to treatment. Cold Spring Harbor Laboratory Press, Cold Spring Harbor

    Google Scholar 

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

    PubMed Central  CAS  PubMed  Google Scholar 

  • Williams KC, Corey S, Westmoreland SV, Pauley D, Knight H, deBakker C, Alvarez X, Lackner AA (2001) Perivascular macrophages are the primary cell type productively infected by simian immunodeficiency virus in the brains of macaques: implications for the neuropathogenesis of AIDS. J Exp Med 193:905–915

    PubMed Central  CAS  PubMed  Google Scholar 

  • Wong JK, Hezareh M, Gunthard HF, Havlir DV, Ignacio CC, Spina CA, Richman DD (1997) Recovery of replication-competent HIV despite prolonged suppression of plasma viremia. Science 278:1291–1295

    CAS  PubMed  Google Scholar 

  • Xu YN, Zhu HY, Wilcox CK, van't Wout A, Andrus T, Llewellyn N, Stamatatos L, Mullins JI, Corey L, Zhu TF (2008) Blood monocytes harbor HIV type 1 strains with diversified phenotypes including macrophage-specific CCR5 virus. J Infect Dis 197:309–318

    CAS  PubMed  Google Scholar 

  • Yi YJ, Chen W, Frank I, Cutilli J, Singh A, Starr-Spires L, Sulcove J, Kolson DL, Collman RG (2003) An unusual syncytia-inducing human immunodeficiency virus type 1 primary isolate from the central nervous system that is restricted to CXCR4, replicates efficiently in macrophages, and induces neuronal apoptosis. J Neurovirol 9:432–441

    CAS  PubMed  Google Scholar 

  • Yukl SA, Shergill AK, Ho T, Killian M, Girling V, Epling L, Li PL, Wong LK, Crouch P, Deeks SG, Havlir DV, McQuaid K, Sinclair E, Wong JK (2013) The distribution of HIV DNA and RNA in cell subsets differs in gut and blood of HIV-positive patients on ART: implications for viral persistence. J Infect Dis 208:1212–1220

    PubMed Central  CAS  PubMed  Google Scholar 

  • Zamarchi R, Allavena P, Borsetti A, Stievano L, Tosello V, Marcato N, Esposito G, Roni V, Paganin C, Bianchi G, Titti F, Verani P, Gerosa G, Amadori A (2002) Expression and functional activity of CXCR-4 and CCR-5 chemokine receptors in human thymocytes. Clin Exp Immunol 127:321–330

    PubMed Central  CAS  PubMed  Google Scholar 

  • Zhou L, Ng T, Yuksel A, Wang B, Dwyer DE, Saksena NK (2008) Absence of HIV infection in the choroid plexus of two patients who died rapidly with HIV-associated dementia. Aids Res Hum Retroviruses 24:839–843

    CAS  PubMed  Google Scholar 

  • Zhu TF, Muthui D, Holte S, Nickle D, Feng F, Brodie S, Hwangbo Y, Mullins JI, Corey L (2002) Evidence for human immunodeficiency virus type 1 replication in vivo in CD14(+) monocytes and its potential role as a source of virus in patients on highly active antiretroviral therapy. J Virol 76:707–716

    PubMed Central  CAS  PubMed  Google Scholar 

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Acknowledgments

We thank all of those who contributed in the collection of these samples and all of the subjects who provided the samples. We are especially grateful to our UNC CFAR colleagues and especially the UNC CFAR Clinical Core led by Dr. Joseph Eron. In addition, Drs. Richard Price and Serena Spudich have been essential collaborators on many of our studies of HIV-1 in the CNS/CSF.

This work was funded by awards from the National Institutes of Health R37 AI44667 and P01 MH094177 to R.S. K.T.A. was supported by T32 AI07419. We also received support from the UNC Center for AIDS Research (P30 AI50410) and the Lineberger Comprehensive Cancer Center (P30 CA16086).

Conflict of interest statement

The authors declare that they have no conflict of interest.

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  1. Christa B. Sturdevant

    Present address: Department of Surgery, Duke University Medical Center, Durham, NC, 27710, USA

Authors and Affiliations

  1. Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA

    Sarah B. Joseph & Ronald Swanstrom

  2. Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA

    Kathryn T. Arrildt, Christa B. Sturdevant & Ronald Swanstrom

  3. Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA

    Ronald Swanstrom

  4. UNC Center for AIDS Research, University of North Carolina at Chapel Hill, School of Medicine, Chapel Hill, NC, 27599, USA

    Ronald Swanstrom

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  1. Sarah B. Joseph
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Correspondence to Sarah B. Joseph.

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Joseph, S.B., Arrildt, K.T., Sturdevant, C.B. et al. HIV-1 target cells in the CNS. J. Neurovirol. 21, 276–289 (2015). https://doi.org/10.1007/s13365-014-0287-x

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