Abstract
Reduced pericytes’ coverage of endothelium in the brain is one of the structural changes leading to breach of the blood-brain barrier during HIV infection. We previously showed in central memory T (TCM) cells that HIV latency increases cellular susceptibility to DNA damage. In this study, we investigated susceptibility of primary brain pericytes infected with HIV-1 to DNA damage in response to glutamate and TNF-α, both known to induce neuronal death during chronic inflammatory conditions. To infect pericytes, we used a single-cycle HIV-1 pseudotyped with VSV-G envelope glycoprotein and maintained the cultures until latency was established. Our data indicate that pericytes silence HIV-1 expression at similar rate compared to primary TCM cells. TNF-α and IL-1β caused partial reactivation of the virus suggesting that progression of disease and neuroinflammation might facilitate virus reactivation from latency. Significant increases in the level of γH2AX, which reflect DNA damage, were observed in infected cultures exposed to TNF-α and glutamate at day 2 post-infection. Glutamate, an excitatory neurologic stimuli, also caused increases in the γH2AX level in latently infected pericytes, whereas PARP and DNA-PK inhibitors caused reductions in cell population suggesting that HIV-1 latency affects repairs of single- and double-strand DNA breaks. For comparison, we also analyzed latently infected astrocytes and determined that DNA damage response in astrocytes is less affected by HIV-1. In conclusion, our results indicate that productive infection and HIV-1 latency in pericytes interfere with DNA damage response, rendering them vulnerable to the agents that are characteristic of chronic neuroinflammatory disease conditions.
Similar content being viewed by others
References
Aguilera KY, Brekken RA (2014) Recruitment and retention: factors that affect pericyte migration. Cell Mol Life Sci 71:299–309. https://doi.org/10.1007/s00018-013-1432-z
Ame JC, Spenlehauer C, de Murcia G (2004) The PARP superfamily. Bioessays 26:882–893. https://doi.org/10.1002/bies.20085
Armulik A, Genove G, Mae M, Nisancioglu MH, Wallgard E, Niaudet C, He L, Norlin J, Lindblom P, Strittmatter K, Johansson BR, Betsholtz C (2010) Pericytes regulate the blood-brain barrier. Nature 468:557–561. https://doi.org/10.1038/nature09522
Badley AD, Pilon AA, Landay A, Lynch DH (2000) Mechanisms of HIV-associated lymphocyte apoptosis. Blood 96:2951–2964
Bakkenist CJ, Kastan MB (2003) DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature 421:499–506. https://doi.org/10.1038/nature01368
Beck C, Robert I, Reina-San-Martin B, Schreiber V, Dantzer F (2014) Poly(ADP-ribose) polymerases in double-strand break repair: focus on PARP1, PARP2 and PARP3. Exp Cell Res 329:18–25. https://doi.org/10.1016/j.yexcr.2014.07.003
Bell RD, Winkler EA, Sagare AP, Singh I, LaRue B, Deane R, Zlokovic BV (2010) Pericytes control key neurovascular functions and neuronal phenotype in the adult brain and during brain aging. Neuron 68:409–427. https://doi.org/10.1016/j.neuron.2010.09.043
Belzile JP, Abrahamyan LG, Gerard FC, Rougeau N, Cohen EA (2010) Formation of mobile chromatin-associated nuclear foci containing HIV-1 Vpr and VPRBP is critical for the induction of G2 cell cycle arrest. PLoS Pathog 6:e1001080. https://doi.org/10.1371/journal.ppat.1001080
Bosque A, Planelles V (2009) Induction of HIV-1 latency and reactivation in primary memory CD4+ T cells. Blood 113:58–65. https://doi.org/10.1182/blood-2008-07-168393
Brabers NA, Nottet HS (2006) Role of the pro-inflammatory cytokines TNF-alpha and IL-1beta in HIV-associated dementia. Eur J Clin Investig 36:447–458. https://doi.org/10.1111/j.1365-2362.2006.01657.x
Brahmachari S, Fung YK, Pahan K (2006) Induction of glial fibrillary acidic protein expression in astrocytes by nitric oxide. J Neurosci 26:4930–4939. https://doi.org/10.1523/JNEUROSCI.5480-05.2006
Cho HJ, Kuo AM, Bertrand L, Toborek M (2017) HIV alters gap junction-mediated intercellular communication in human brain pericytes. Front Mol Neurosci 10:410. https://doi.org/10.3389/fnmol.2017.00410
Chun TW, Engel D, Mizell SB, Ehler LA, Fauci AS (1998) Induction of HIV-1 replication in latently infected CD4+ T cells using a combination of cytokines. J Exp Med 188:83–91
Churchill MJ, Gorry PR, Cowley D, Lal L, Sonza S, Purcell DF, 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. https://doi.org/10.1080/13550280600748946
Cummins NW, Badley AD (2010) Mechanisms of HIV-associated lymphocyte apoptosis: 2010. Cell Death Dis 1:e99. https://doi.org/10.1038/cddis.2010.77
Davis AJ, Chen BP, Chen DJ (2014) DNA-PK: a dynamic enzyme in a versatile DSB repair pathway. DNA Repair (Amst) 17:21–29. https://doi.org/10.1016/j.dnarep.2014.02.020
de Silva S, Planelles V, Wu L (2012) Differential effects of Vpr on single-cycle and spreading HIV-1 infections in CD4+ T-cells and dendritic cells. PLoS One 7:e35385. https://doi.org/10.1371/journal.pone.0035385
Devadas K, Hardegen NJ, Wahl LM, Hewlett IK, Clouse KA, Yamada KM, Dhawan S (2004) Mechanisms for macrophage-mediated HIV-1 induction. J Immunol 173:6735–6744
Dykes C, Wu H, Sims M, Holden-Wiltse J, Demeter LM (2010) Human immunodeficiency virus type 1 protease inhibitor drug-resistant mutants give discordant results when compared in single-cycle and multiple-cycle fitness assays. J Clin Microbiol 48:4035–4043. https://doi.org/10.1128/JCM.00605-10
Eugenin EA, Clements JE, Zink MC, Berman JW (2011) Human immunodeficiency virus infection of human astrocytes disrupts blood-brain barrier integrity by a gap junction-dependent mechanism. J Neurosci 31:9456–9465. https://doi.org/10.1523/JNEUROSCI.1460-11.2011
Ferland-McCollough D, Slater S, Richard J, Reni C, Mangialardi G (2017) Pericytes, an overlooked player in vascular pathobiology. Pharmacol Ther 171:30–42. https://doi.org/10.1016/j.pharmthera.2016.11.008
Fernandez-Klett F, Potas JR, Hilpert D, Blazej K, Radke J, Huck J, Engel O, Stenzel W, Genove G, Priller J (2013) Early loss of pericytes and perivascular stromal cell-induced scar formation after stroke. J Cereb Blood Flow Metab 33:428–439. https://doi.org/10.1038/jcbfm.2012.187
Ferrarese C, Aliprandi A, Tremolizzo L, Stanzani L, De Micheli A, Dolara A, Frattola L (2001) Increased glutamate in CSF and plasma of patients with HIV dementia. Neurology 57:671–675
Ferrell D, Giunta B (2014) The impact of HIV-1 on neurogenesis: implications for HAND. Cell Mol Life Sci 71:4387–4392. https://doi.org/10.1007/s00018-014-1702-4
Gilley D, Tanaka H, Hande MP, Kurimasa A, Li GC, Oshimura M, Chen DJ (2001) DNA-PKcs is critical for telomere capping. Proc Natl Acad Sci U S A 98:15084–15088. https://doi.org/10.1073/pnas.261574698
Granowitz EV, Saget BM, Wang MZ, Dinarello CA, Skolnik PR (1995) Interleukin 1 induces HIV-1 expression in chronically infected U1 cells: blockade by interleukin 1 receptor antagonist and tumor necrosis factor binding protein type 1. Mol Med 1:667–677
Guo Z, Kozlov S, Lavin MF, Person MD, Paull TT (2010) ATM activation by oxidative stress. Science 330:517–521. https://doi.org/10.1126/science.1192912
Hall CN, Reynell C, Gesslein B, Hamilton NB, Mishra A, Sutherland BA, O'Farrell FM, Buchan AM, Lauritzen M, Attwell D (2014) Capillary pericytes regulate cerebral blood flow in health and disease. Nature 508:55–60. https://doi.org/10.1038/nature13165
Haughey NJ, Nath A, Mattson MP, Slevin JT, Geiger JD (2001) HIV-1 tat through phosphorylation of NMDA receptors potentiates glutamate excitotoxicity. J Neurochem 78:457–467
Herbein G, Van Lint C, Lovett JL, Verdin E (1998) Distinct mechanisms trigger apoptosis in human immunodeficiency virus type 1-infected and in uninfected bystander T lymphocytes. J Virol 72:660–670
Holguin A, O'Connor KA, Biedenkapp J, Campisi J, Wieseler-Frank J, Milligan ED, Hansen MK, Spataro L, Maksimova E, Bravmann C, Martin D, Fleshner M, Maier SF, Watkins LR (2004) HIV-1 gp120 stimulates proinflammatory cytokine-mediated pain facilitation via activation of nitric oxide synthase-I (nNOS). Pain 110:517–530. https://doi.org/10.1016/j.pain.2004.02.018
Jansson D, Rustenhoven J, Feng S, Hurley D, Oldfield RL, Bergin PS, Mee EW, Faull RL, Dragunow M (2014) A role for human brain pericytes in neuroinflammation. J Neuroinflammation 11:104. https://doi.org/10.1186/1742-2094-11-104
Kamouchi M, Kitazono T, Ago T, Wakisaka M, Kuroda J, Nakamura K, Hagiwara N, Ooboshi H, Ibayashi S, Iida M (2007) Hydrogen peroxide-induced Ca2+ responses in CNS pericytes. Neurosci Lett 416:12–16. https://doi.org/10.1016/j.neulet.2007.01.039
Khoronenkova SV, Dianov GL (2015) ATM prevents DSB formation by coordinating SSB repair and cell cycle progression. Proc Natl Acad Sci U S A 112:3997–4002. https://doi.org/10.1073/pnas.1416031112
Kritis AA, Stamoula EG, Paniskaki KA, Vavilis TD (2015) Researching glutamate—induced cytotoxicity in different cell lines: a comparative/collective analysis/study. Front Cell Neurosci 9:91. https://doi.org/10.3389/fncel.2015.00091
Lau A, Tymianski M (2010) Glutamate receptors, neurotoxicity and neurodegeneration. Pflugers Arch 460:525–542. https://doi.org/10.1007/s00424-010-0809-1
Liszewski MK, Yu JJ, O'Doherty U (2009) Detecting HIV-1 integration by repetitive-sampling Alu-gag PCR. Methods 47:254–260. https://doi.org/10.1016/j.ymeth.2009.01.002
Liu S, Wang X, Li Y, Xu L, Yu X, Ge L, Li J, Zhu Y, He S (2014) Necroptosis mediates TNF-induced toxicity of hippocampal neurons. Biomed Res Int 2014:290182–290111. https://doi.org/10.1155/2014/290182
Luo X, He JJ (2015) Cell-cell contact viral transfer contributes to HIV infection and persistence in astrocytes. J NeuroVirol 21:66–80. https://doi.org/10.1007/s13365-014-0304-0
Martins LJ, Bonczkowski P, Spivak AM, De Spiegelaere W, Novis CL, DePaula-Silva AB, Malatinkova E, Typsteen W, Bosque A, Vanderkerckhove L, Planelles V (2016) Modeling HIV-1 latency in primary T cells using a replication-competent virus. AIDS Res Hum Retrovir 32:187–193. https://doi.org/10.1089/aid.2015.0106
Melendez RI, Roman C, Capo-Velez CM, Lasalde-Dominicci JA (2016) Decreased glial and synaptic glutamate uptake in the striatum of HIV-1 gp120 transgenic mice. J NeuroVirol 22:358–365. https://doi.org/10.1007/s13365-015-0403-6
Musante V, Summa M, Neri E, Puliti A, Godowicz TT, Severi P, Battaglia G, Raiteri M, Pittaluga A (2010) The HIV-1 viral protein Tat increases glutamate and decreases GABA exocytosis from human and mouse neocortical nerve endings. Cereb Cortex 20:1974–1984. https://doi.org/10.1093/cercor/bhp274
Nakagawa S, Castro V, Toborek M (2012) Infection of human pericytes by HIV-1 disrupts the integrity of the blood-brain barrier. J Cell Mol Med 16:2950–2957. https://doi.org/10.1111/j.1582-4934.2012.01622.x
Nath A, Hartloper V, Furer M, Fowke KR (1995) Infection of human fetal astrocytes with HIV-1: viral tropism and the role of cell to cell contact in viral transmission. J Neuropathol Exp Neurol 54:320–330
Niu F, Yao H, Zhang W, Sutliff RL, Buch S (2014) Tat 101-mediated enhancement of brain pericyte migration involves platelet-derived growth factor subunit B homodimer: implications for human immunodeficiency virus-associated neurocognitive disorders. J Neurosci 34:11812–11825. https://doi.org/10.1523/JNEUROSCI.1139-14.2014
Oguariri RM, Brann TW, Imamichi T (2007) Hydroxyurea and interleukin-6 synergistically reactivate HIV-1 replication in a latently infected promonocytic cell line via SP1/SP3 transcription factors. J Biol Chem 282:3594–3604. https://doi.org/10.1074/jbc.M608150200
Olive PL (2009) Endogenous DNA breaks: gammaH2AX and the role of telomeres. Aging (Albany NY) 1:154–156. https://doi.org/10.18632/aging.100025
Persidsky Y, Hill J, Zhang M, Dykstra H, Winfield M, Reichenbach NL, Potula R, Mukherjee A, Ramirez SH, Rom S (2016) Dysfunction of brain pericytes in chronic neuroinflammation. J Cereb Blood Flow Metab 36:794–807. https://doi.org/10.1177/0271678X15606149
Piekna-Przybylska D, Maggirwar SB (2018) CD4+ memory T cells infected with latent HIV-1 are susceptible to drugs targeting telomeres. Cell Cycle 17:2187–2203. https://doi.org/10.1080/15384101.2018.1520568
Piekna-Przybylska D, Sharma G, Maggirwar SB, Bambara RA (2017) Deficiency in DNA damage response, a new characteristic of cells infected with latent HIV-1. Cell Cycle 16:968–978. https://doi.org/10.1080/15384101.2017.1312225
Planelles V, Bachelerie F, Jowett JB, Haislip A, Xie Y, Banooni P, Masuda T, Chen IS (1995) Fate of the human immunodeficiency virus type 1 provirus in infected cells: a role for vpr. J Virol 69:5883–5889
Poli G, Kinter AL, Fauci AS (1994) Interleukin 1 induces expression of the human immunodeficiency virus alone and in synergy with interleukin 6 in chronically infected U1 cells: inhibition of inductive effects by the interleukin 1 receptor antagonist. Proc Natl Acad Sci U S A 91:108–112
Potter MC, Figuera-Losada M, Rojas C, Slusher BS (2013) Targeting the glutamatergic system for the treatment of HIV-associated neurocognitive disorders. J NeuroImmune Pharmacol 8:594–607. https://doi.org/10.1007/s11481-013-9442-z
Roshal M, Kim B, Zhu Y, Nghiem P, Planelles V (2003) Activation of the ATR-mediated DNA damage response by the HIV-1 viral protein R. J Biol Chem 278:25879–25886. https://doi.org/10.1074/jbc.M303948200
Rustenhoven J, Jansson D, Smyth LC, Dragunow M (2017) Brain pericytes as mediators of neuroinflammation. Trends Pharmacol Sci 38:291–304. https://doi.org/10.1016/j.tips.2016.12.001
Saleh S, Wightman F, Ramanayake S, Alexander M, Kumar N, Khoury G, Pereira C, Purcell D, Cameron PU, Lewin SR (2011) Expression and reactivation of HIV in a chemokine induced model of HIV latency in primary resting CD4+ T cells. Retrovirology 8:80. https://doi.org/10.1186/1742-4690-8-80
Saylor D, Dickens AM, Sacktor N, Haughey N, Slusher B, Pletnikov M, Mankowski JL, Brown A, Volsky DJ, McArthur JC (2016) HIV-associated neurocognitive disorder—pathogenesis and prospects for treatment. Nat Rev Neurol 12:234–248. https://doi.org/10.1038/nrneurol.2016.27
Schreiber V, Ame JC, Dolle P, Schultz I, Rinaldi B, Fraulob V, Menissier-de Murcia J, de Murcia G (2002) Poly(ADP-ribose) polymerase-2 (PARP-2) is required for efficient base excision DNA repair in association with PARP-1 and XRCC1. J Biol Chem 277:23028–23036. https://doi.org/10.1074/jbc.M202390200
Schweighardt B, Atwood WJ (2001) HIV type 1 infection of human astrocytes is restricted by inefficient viral entry. AIDS Res Hum Retrovir 17:1133–1142. https://doi.org/10.1089/088922201316912745
Scutari R, Alteri C, Perno CF, Svicher V, Aquaro S (2017) The role of HIV infection in neurologic injury. Brain Sci 7. doi: https://doi.org/10.3390/brainsci7040038
Sczepanski JT, Wong RS, McKnight JN, Bowman GD, Greenberg MM (2010) Rapid DNA-protein cross-linking and strand scission by an abasic site in a nucleosome core particle. Proc Natl Acad Sci U S A 107:22475–22480. https://doi.org/10.1073/pnas.1012860108
Sengillo JD, Winkler EA, Walker CT, Sullivan JS, Johnson M, Zlokovic BV (2013) Deficiency in mural vascular cells coincides with blood-brain barrier disruption in Alzheimer’s disease. Brain Pathol 23:303–310. https://doi.org/10.1111/bpa.12004
Soriano-Sarabia N, Bateson RE, Dahl NP, Crooks AM, Kuruc JD, Margolis DM, Archin NM (2014) Quantitation of replication-competent HIV-1 in populations of resting CD4+ T cells. J Virol 88:14070–14077. https://doi.org/10.1128/JVI.01900-14
Sun Y, Huang YC, Xu QZ, Wang HP, Bai B, Sui JL, Zhou PK (2006) HIV-1 Tat depresses DNA-PK(CS) expression and DNA repair, and sensitizes cells to ionizing radiation. Int J Radiat Oncol Biol Phys 65:842–850. https://doi.org/10.1016/j.ijrobp.2006.02.040
Tachiwana H, Shimura M, Nakai-Murakami C, Tokunaga K, Takizawa Y, Sata T, Kurumizaka H, Ishizaka Y (2006) HIV-1 Vpr induces DNA double-strand breaks. Cancer Res 66:627–631. https://doi.org/10.1158/0008-5472.CAN-05-3144
Tardieu M, Hery C, Peudenier S, Boespflug O, Montagnier L (1992) Human immunodeficiency virus type 1-infected monocytic cells can destroy human neural cells after cell-to-cell adhesion. Ann Neurol 32:11–17. https://doi.org/10.1002/ana.410320104
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 12:97–110
Thompson KA, McArthur JC, Wesselingh SL (2001) Correlation between neurological progression and astrocyte apoptosis in HIV-associated dementia. Ann Neurol 49:745–752
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. https://doi.org/10.1016/j.ajpath.2011.06.039
Tornatore C, Chandra R, Berger JR, Major EO (1994) HIV-1 infection of subcortical astrocytes in the pediatric central nervous system. Neurology 44:481–487
Tweedie D, Sambamurti K, Greig NH (2007) TNF-alpha inhibition as a treatment strategy for neurodegenerative disorders: new drug candidates and targets. Curr Alzheimer Res 4:378–385
Vazquez-Santiago FJ, Noel RJ Jr, Porter JT, Rivera-Amill V (2014) Glutamate metabolism and HIV-associated neurocognitive disorders. J NeuroVirol 20:315–331. https://doi.org/10.1007/s13365-014-0258-2
Vesce S, Bezzi P, Rossi D, Meldolesi J, Volterra A (1997) HIV-1 gp120 glycoprotein affects the astrocyte control of extracellular glutamate by both inhibiting the uptake and stimulating the release of the amino acid. FEBS Lett 411:107–109
Ward IM, Wu X, Chen J (2001) Threonine 68 of Chk2 is phosphorylated at sites of DNA strand breaks. J Biol Chem 276:47755–47758. https://doi.org/10.1074/jbc.C100587200
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 83:7089–7093
Williams ES, Klingler R, Ponnaiya B, Hardt T, Schrock E, Lees-Miller SP, Meek K, Ullrich RL, Bailey SM (2009) Telomere dysfunction and DNA-PKcs deficiency: characterization and consequence. Cancer Res 69:2100–2107. https://doi.org/10.1158/0008-5472.CAN-08-2854
Winkler EA, Sengillo JD, Sullivan JS, Henkel JS, Appel SH, Zlokovic BV (2013) Blood-spinal cord barrier breakdown and pericyte reductions in amyotrophic lateral sclerosis. Acta Neuropathol 125:111–120. https://doi.org/10.1007/s00401-012-1039-8
Yan C, Lu J, Zhang G, Gan T, Zeng Q, Shao Z, Duerksen-Hughes PJ, Yang J (2011) Benzo[a]pyrene induces complex H2AX phosphorylation patterns by multiple kinases including ATM, ATR, and DNA-PK. Toxicol in Vitro 25:91–99. https://doi.org/10.1016/j.tiv.2010.09.012
Yan S, Sorrell M, Berman Z (2014) Functional interplay between ATM/ATR-mediated DNA damage response and DNA repair pathways in oxidative stress. Cell Mol Life Sci 71:3951–3967. https://doi.org/10.1007/s00018-014-1666-4
Zhu Y, Gelbard HA, Roshal M, Pursell S, Jamieson BD, Planelles V (2001) Comparison of cell cycle arrest, transactivation, and apoptosis induced by the simian immunodeficiency virus SIVagm and human immunodeficiency virus type 1 vpr genes. J Virol 75:3791–3801. https://doi.org/10.1128/JVI.75.8.3791-3801.2001
Zimmerman ES, Chen J, Andersen JL, Ardon O, Dehart JL, Blackett J, Choudhary SK, Camerini D, Nghiem P, Planelles V (2004) Human immunodeficiency virus type 1 Vpr-mediated G2 arrest requires Rad17 and Hus1 and induces nuclear BRCA1 and gamma-H2AX focus formation. Mol Cell Biol 24:9286–9294. https://doi.org/10.1128/MCB.24.21.9286-9294.2004
Zou JY, Crews FT (2005) TNF alpha potentiates glutamate neurotoxicity by inhibiting glutamate uptake in organotypic brain slice cultures: neuroprotection by NF kappa B inhibition. Brain Res 1034:11–24. https://doi.org/10.1016/j.brainres.2004.11.014
Acknowledgements
We would like to thank Dr. Vicente Planelles for providing the DHIV construct. We would like to thank Dr. Meera Singh, Dr. Vir Singh, Dr. Sumanun Noina Suwunnakorn, Emily Weber, Sydney Simpson, and Jacob Botros-Greenlee for editing the manuscript and for their valuable comments.
Funding
This research was supported by the National Institutes of Health (NIH) grant R21 AI131961 to D.P.P. and also NIH grants R01 NS066801 and R01 NS054578 to S.B.M. The work was also supported by the University of Rochester Center for AIDS Research (NIH P30 AI078498). Funding for open access charge: National Institutes of Health.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
The Research Subjects Review Board at the University of Rochester Medical Center approved studies involving human samples. All the study participants were adults and blood samples were obtained after written informed consent, in accordance with the Declaration of Helsinki.
Conflict of interest
The authors declare that they have no conflict of interest.
Rights and permissions
About this article
Cite this article
Piekna-Przybylska, D., Nagumotu, K., Reid, D.M. et al. HIV-1 infection renders brain vascular pericytes susceptible to the extracellular glutamate. J. Neurovirol. 25, 114–126 (2019). https://doi.org/10.1007/s13365-018-0693-6
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s13365-018-0693-6