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Evidence for cFMS signaling in HIV production by brain macrophages and microglia

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Abstract

Combination antiretroviral therapy (cART) has improved the longevity and quality of life for people living with HIV; however, it does not target virus that persists in long-lived cells, such as macrophages (MΦs). This allows for the development of viral reservoirs in various anatomical compartments where these cells reside, including the central nervous system (CNS), where perivascular MΦs and resident microglia constitute the principle cellular reservoir of HIV. How HIV persists in MΦs/microglia is not completely understood; however, prosurvival signaling that protects infected MΦs/microglia from apoptosis is likely important to viral persistence. Macrophage colony-stimulating factor (M-CSF) is an important factor in MΦ survival and has been implicated in HIV neuropathogenesis through its ability to enhance the susceptibility of MΦs to infection and promote virus production. While M-CSF has been detected in cerebrospinal fluid of HIV-infected patients, the cellular source of M-CSF in the CNS is unknown. Here, we demonstrate, for the first time, that MΦs comprising perivascular cuffs and nodular lesions in SIV encephalitis (SIVE) brain are the principle source of M-CSF. These cells also serve as the primary reservoir of productive SIV infection in the brain. We further demonstrate that M-CSF and IL-34, which signal through the same receptor, cFMS, enhance HIV-1 production by microglia in vitro. This is attenuated by the addition of a receptor tyrosine kinase inhibitor with high specificity for cFMS, GW2580. Together, these data suggest that cFMS signaling may be an attractive target for eliminating long-lived MΦ reservoirs of HIV in the brain and other tissues.

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References

  • Allen JB, Wong HL, Guyre PM, Simon GL, Wahl SM (1991) Association of circulating receptor Fc gamma RIII-positive monocytes in AIDS patients with elevated levels of transforming growth factor-beta. J Clin Invest 87:1773–1779

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Al-Shatti T, Barr AE, Safadi FF, Amin M, Barbe MF (2005) Increase in inflammatory cytokines in median nerves in a rat model of repetitive motion injury. J Neuroimmunol 167:13–22

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Barve RA, Zack MD, Weiss D, Song RH, Beidler D, Head RD (2013) Transcriptional profiling and pathway analysis of CSF-1 and IL-34 effects on human monocyte differentiation. Cytokine 63:10–17

    Article  CAS  PubMed  Google Scholar 

  • Bergamini A, Perno CF, Dini L, Capozzi M, Pesce CD, Ventura L, Cappannoli L, Falasca L, Milanese G, Calio R et al (1994) Macrophage colony-stimulating factor enhances the susceptibility of macrophages to infection by human immunodeficiency virus and reduces the activity of compounds that inhibit virus binding. Blood 84:3405–3412

    CAS  PubMed  Google Scholar 

  • Chihara T, Suzu S, Hassan R, Chutiwitoonchai N, Hiyoshi M, Motoyoshi K, Kimura F, Okada S (2010) IL-34 and M-CSF share the receptor Fms but are not identical in biological activity and signal activation. Cell Death Differ 17:1917–1927

    Article  CAS  PubMed  Google Scholar 

  • Conway JG, McDonald B, Parham J, Keith B, Rusnak DW, Shaw E, Jansen M, Lin P, Payne A, Crosby RM, Johnson JH, Frick L, Lin MH, Depee S, Tadepalli S, Votta B, James I, Fuller K, Chambers TJ, Kull FC, Chamberlain SD, Hutchins JT (2005) Inhibition of colony-stimulating-factor-1 signaling in vivo with the orally bioavailable cFMS kinase inhibitor GW2580. Proc Natl Acad Sci U S A 102:16078–16083

    Article  PubMed Central  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

    Article  CAS  PubMed  Google Scholar 

  • Fischer-Smith T, Croul S, Adeniyi A, Rybicka K, Morgello S, Khalili K, Rappaport J (2004) Macrophage/microglial accumulation and proliferating cell nuclear antigen expression in the central nervous system in human immunodeficiency virus encephalopathy. Am J Pathol 164:2089–2099

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Fischer-Smith T, Bell C, Croul S, Lewis M, Rappaport J (2008a) Monocyte/macrophage trafficking in acquired immunodeficiency syndrome encephalitis: lessons from human and nonhuman primate studies. J Neurovirol 14:318–326

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Fischer-Smith T, Tedaldi EM, Rappaport J (2008b) CD163/CD16 coexpression by circulating monocytes/macrophages in HIV: potential biomarkers for HIV infection and AIDS progression. AIDS Res Hum Retrovir 24:417–421

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Foucher ED, Blanchard S, Preisser L, Garo E, Ifrah N, Guardiola P, Delneste Y, Jeannin P (2013) IL-34 induces the differentiation of human monocytes into immunosuppressive macrophages. antagonistic effects of GM-CSF and IFNgamma. PLoS ONE 8:e56045

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Frei K, Nohava K, Malipiero UV, Schwerdel C, Fontana A (1992) Production of macrophage colony-stimulating factor by astrocytes and brain macrophages. J Neuroimmunol 40:189–195

    Article  CAS  PubMed  Google Scholar 

  • Gallo P, Pagni S, Giometto B, Piccinno MG, Bozza F, Argentiero V, Tavolato B (1990) Macrophage-colony stimulating factor (M-CSF) in the cerebrospinal fluid. J Neuroimmunol 29:105–112

    Article  CAS  PubMed  Google Scholar 

  • Gallo P, Laverda AM, De Rossi A, Pagni S, Del Mistro A, Cogo P, Piccinno MG, Plebani A, Tavolato B, Chieco-Bianchi L (1991) Immunological markers in the cerebrospinal fluid of HIV-1-infected children. Acta Paediatr Scand 80:659–666

    Article  CAS  PubMed  Google Scholar 

  • Gruber MF, Weih KA, Boone EJ, Smith PD, Clouse KA (1995) Endogenous macrophage CSF production is associated with viral replication in HIV-1-infected human monocyte-derived macrophages. J Immunol 154:5528–5535

    CAS  PubMed  Google Scholar 

  • Hirsch V, Adger-Johnson D, Campbell B, Goldstein S, Brown C, Elkins WR, Montefiori DC (1997) A molecularly cloned, pathogenic, neutralization-resistant simian immunodeficiency virus, SIVsmE543-3. J Virol 71:1608–1620

    PubMed Central  CAS  PubMed  Google Scholar 

  • Kalter DC, Nakamura M, Turpin JA, Baca LM, Hoover DL, Dieffenbach C, Ralph P, Gendelman HE, Meltzer MS (1991) Enhanced HIV replication in macrophage colony-stimulating factor-treated monocytes. J Immunol 146:298–306

    CAS  PubMed  Google Scholar 

  • Laske C, Stransky E, Hoffmann N, Maetzler W, Straten G, Eschweiler GW, Leyhe T (2010) Macrophage colony-stimulating factor (M-CSF) in plasma and CSF of patients with mild cognitive impairment and Alzheimer's disease. Curr Alzheimer Res 7:409–414

    Article  CAS  PubMed  Google Scholar 

  • Lentz MR, Degaonkar M, Mohamed MA, Kim H, Conant K, Halpern EF, Sacktor N, Barker PB, Pomper MG (2010) Exploring the relationship of macrophage colony-stimulating factor levels on neuroaxonal metabolism and cognition during chronic human immunodeficiency virus infection. J Neurovirol 16:368–376

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Lin H, Lee E, Hestir K, Leo C, Huang M, Bosch E, Halenbeck R, Wu G, Zhou A, Behrens D, Hollenbaugh D, Linnemann T, Qin M, Wong J, Chu K, Doberstein SK, Williams LT (2008) Discovery of a cytokine and its receptor by functional screening of the extracellular proteome. Science 320:807–811

    Article  CAS  PubMed  Google Scholar 

  • Locher C, Vanham G, Kestens L, Kruger M, Ceuppens JL, Vingerhoets J, Gigase P (1994) Expression patterns of Fc gamma receptors, HLA-DR and selected adhesion molecules on monocytes from normal and HIV-infected individuals. Clin Exp Immunol 98:115–122

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Munn DH, Cheung NK (1989) Antibody-dependent antitumor cytotoxicity by human monocytes cultured with recombinant macrophage colony-stimulating factor. Induction of efficient antibody-mediated antitumor cytotoxicity not detected by isotope release assays. J Exp Med 170:511–526

    Article  CAS  PubMed  Google Scholar 

  • Raivich G, Haas S, Werner A, Klein MA, Kloss C, Kreutzberg GW (1998) Regulation of MCSF receptors on microglia in the normal and injured mouse central nervous system: a quantitative immunofluorescence study using confocal laser microscopy. J Comp Neurol 395:342–358

    Article  CAS  PubMed  Google Scholar 

  • Ritter M, Buechler C, Langmann T, Orso E, Klucken J, Schmitz G (1999) The scavenger receptor CD163: regulation, promoter structure and genomic organization. Pathobiology 67:257–261

    Article  CAS  PubMed  Google Scholar 

  • 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 8:136–142

    Article  PubMed  Google Scholar 

  • Tavazzi E, Morrison D, Sullivan P, Morgello S, Fischer T (2014) Brain inflammation is a common feature of hiv-infected patients without hiv encephalitis or productive brain infection. Curr HIV Res

  • Thieblemont N, Weiss L, Sadeghi HM, Estcourt C, Haeffner-Cavaillon N (1995) CD14 low CD16 high: a cytokine-producing monocyte subset which expands during human immunodeficiency virus infection. Eur J Immunol 25:3418–3424

    Article  CAS  PubMed  Google Scholar 

  • Thompson KA, Cherry CL, Bell JE, McLean CA (2011) Brain cell reservoirs of latent virus in presymptomatic HIV-infected individuals. Am J Pathol 179:1623–1629

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Tyor WR, Glass JD, Griffin JW, Becker PS, McArthur JC, Bezman L, Griffin DE (1992) Cytokine expression in the brain during the acquired immunodeficiency syndrome. Ann Neurol 31:349–360

    Article  CAS  PubMed  Google Scholar 

  • Wang Y, Szretter KJ, Vermi W, Gilfillan S, Rossini C, Cella M, Barrow AD, Diamond MS, Colonna M (2012) IL-34 is a tissue-restricted ligand of CSF1R required for the development of Langerhans cells and microglia. Nat Immunol 13:753–760

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Wei S, Nandi S, Chitu V, Yeung YG, Yu W, Huang M, Williams LT, Lin H, Stanley ER (2010) Functional overlap but differential expression of CSF-1 and IL-34 in their CSF-1 receptor-mediated regulation of myeloid cells. J Leukoc Biol 88:495–505

    Article  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors would like to thank Dr. Mary Barbe and the Basic Science Core II of the Comprehensive NeuroAIDS Center (CNAC; P30 MH0921777) for assisting with the immunohistochemical quantification. CNAC Basic Science Core I provided the primary microglial cell cultures.

Conflict of interest

Dr. Tracy Fischer and Lindsey Gerngross have no ethical or financial conflicts of interest to declare.

Funding sources

RO1 NS063605; T32 MH079785; P30 MH09217

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  1. Department of Neuroscience, Center for Neurovirology, Temple University School of Medicine, Philadelphia, PA, USA

    Lindsey Gerngross & Tracy Fischer

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  1. Lindsey Gerngross
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  2. Tracy Fischer
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Correspondence to Tracy Fischer.

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Gerngross, L., Fischer, T. Evidence for cFMS signaling in HIV production by brain macrophages and microglia. J. Neurovirol. 21, 249–256 (2015). https://doi.org/10.1007/s13365-014-0270-6

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  • DOI: https://doi.org/10.1007/s13365-014-0270-6

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