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HIV-1 Clade B and C Isolates Exhibit Differential Replication: Relevance to Macrophage-Mediated Neurotoxicity

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Abstract

HIV-associated neurocognitive disorders (HAND) continue to be a consequence of HIV-1 infection among clade B-infected individuals. In contrast, the incidence of severe neurological impairment is lower among clade C-infected patients in regions of Sub-Saharan Africa and India. Biological aspects such as replication, cytopathicity, inflammatory response, and neurotoxicity unique to each clade influence neuropathogenicity and ultimately affect the clinical outcome of the disease. We hypothesize that productive infection by clade C isolates leads to macrophage-mediated neurotoxicity, although to a lesser extent than clade B isolates. Using a panel of primary isolates of clades B and C we demonstrated that clade B has higher replication efficiency in monocyte-derived macrophages (MDM) through reverse transcriptase activity assay and HIV-1 p24 antigen ELISA. To test the neurotoxicity of clades B and C, we used an in vitro neurotoxicity model. Conditioned medium from clade B-infected MDM was neurotoxic to rat and human neuron cultures. In contrast, clade C isolates mediated neurotoxicity when a higher initial viral titer was used for MDM infection. Furthermore, neurotoxicity mediated by isolates of both clades correlated with virus replication in MDM. Together, these results suggest that in comparison to clade B, primary isolates of clade C have slower replication kinetics in primary MDM, leading to lower levels of macrophage-mediated neurotoxicity. Elucidating the differences in replication and macrophage-mediated neurotoxicity between isolates of HIV-1 clades B and C will provide important insights needed to clarify the disparity seen in HAND incidence.

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References

  • Abebe A, Demissie D, Goudsmit J, Brouwer M, Kuiken CL, Pollakis G, Schuitemaker H, Fontanet AL, Rinke de Wit TF (1999) HIV-1 subtype C syncytium- and non-syncytium-inducing phenotypes and coreceptor usage among Ethiopian patients with AIDS. AIDS 13:1305–1311

    Article  PubMed  CAS  Google Scholar 

  • Abraha A, Nankya IL, Gibson R, Demers K, Tebit DM, Johnston E, Katzenstein D, Siddiqui A, Herrera C, Fischetti L et al (2009) CCR5- and CXCR4-tropic subtype C human immunodeficiency virus type 1 isolates have a lower level of pathogenic fitness than other dominant group M subtypes: implications for the epidemic. J Virol 83:5592–5605

    Article  PubMed  CAS  Google Scholar 

  • Ayehunie S, Sonnerborg A, Yemane-Berhan T, Zewdie DW, Britton S, Strannegard O (1993) Raised levels of tumour necrosis factor-alpha and neopterin, but not interferon-alpha, in serum of HIV-1-infected patients from Ethiopia. Clin Exp Immunol 91:37–42

    Article  PubMed  CAS  Google Scholar 

  • Ball SC, Abraha A, Collins KR, Marozsan AJ, Baird H, Quinones-Mateu ME, Penn-Nicholson A, Murray M, Richard N, Lobritz M et al (2003) Comparing the ex vivo fitness of CCR5-tropic human immunodeficiency virus type 1 isolates of subtypes B and C. J Virol 77:1021–1038

    Article  PubMed  CAS  Google Scholar 

  • Boisse L, Gill MJ, Power C (2008) HIV infection of the central nervous system: clinical features and neuropathogenesis. Neurol Clin 26:799–819 x

    Article  PubMed  Google Scholar 

  • Burkala EJ, He J, West JT, Wood C, Petito CK (2005) Compartmentalization of HIV-1 in the central nervous system: role of the choroid plexus. AIDS 19:675–684

    Article  PubMed  CAS  Google Scholar 

  • Campbell GR, Watkins JD, Singh KK, Loret EP, Spector SA (2007) Human immunodeficiency virus type 1 subtype C Tat fails to induce intracellular calcium flux and induces reduced tumor necrosis factor production from monocytes. J Virol 81:5919–5928

    Article  PubMed  CAS  Google Scholar 

  • Centlivre M, Sommer P, Michel M, Ho Tsong Fang R, Gofflo S, Valladeau J, Schmitt N, Wain-Hobson S, Sala M (2006) The HIV-1 clade C promoter is particularly well adapted to replication in the gut in primary infection. AIDS 20:657–666

    Article  PubMed  CAS  Google Scholar 

  • Clifford DB, Mitike MT, Mekonnen Y, Zhang J, Zenebe G, Melaku Z, Zewde A, Gessesse N, Wolday D, Messele T et al (2007) Neurological evaluation of untreated human immunodeficiency virus infected adults in Ethiopia. J Neurovirol 13:67–72

    Article  PubMed  Google Scholar 

  • Cui M, Huang Y, Zhao Y, Zheng J (2008) Transcription factor FOXO3a mediates apoptosis in HIV-1-infected macrophages. J Immunol 180:898–906

    PubMed  CAS  Google Scholar 

  • Derdeyn CA, Decker JM, Sfakianos JN, Wu X, O’Brien WA, Ratner L, Kappes JC, Shaw GM, Hunter E (2000) Sensitivity of human immunodeficiency virus type 1 to the fusion inhibitor T-20 is modulated by coreceptor specificity defined by the V3 loop of gp120. J Virol 74:8358–8367

    Article  PubMed  CAS  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 USA 103:15160–15165

    Article  PubMed  CAS  Google Scholar 

  • Gendelman HE, Orenstein JM, Martin MA, Ferrua C, Mitra R, Phipps T, Wahl LA, Lane HC, Fauci AS, Burke DS (1988) Efficient isolation and propagation of human immunodeficiency virus on recombinant colony-stimulating factor 1-treated monocytes. J Exp Med 167:1428–1441

    Article  PubMed  CAS  Google Scholar 

  • Gupta JD, Satishchandra P, Gopukumar K, Wilkie F, Waldrop-Valverde D, Ellis R, Ownby R, Subbakrishna DK, Desai A, Kamat A et al (2007) Neuropsychological deficits in human immunodeficiency virus type 1 clade C-seropositive adults from South India. J Neurovirol 13:195–202

    Article  PubMed  Google Scholar 

  • Huang Y, Erdmann N, Peng H, Herek S, Davis JS, Luo X, Ikezu T, Zheng J (2006) TRAIL-mediated apoptosis in HIV-1-infected macrophages is dependent on the inhibition of Akt-1 phosphorylation. J Immunol 177:2304–2313

    PubMed  CAS  Google Scholar 

  • Jiang Z, Piggee C, Heyes MP, Murphy C, Quearry B, Bauer M, Zheng J, Gendelman HE, Markey SP (2001) Glutamate is a mediator of neurotoxicity in secretions of activated HIV-1-infected macrophages. J Neuroimmunol 117:97–107

    Article  PubMed  CAS  Google Scholar 

  • Kamat A, Ravi V, Desai A, Satishchandra P, Satish KS, Kumar M (2009) Estimation of virological and immunological parameters in subjects from South India infected with human immunodeficiency virus type 1 clade C and correlation of findings with occurrence of neurological disease. J Neurovirol 15:25–35

    Article  PubMed  CAS  Google Scholar 

  • Kaul M, Zheng J, Okamoto S, Gendelman HE, Lipton SA (2005) HIV-1 infection and AIDS: consequences for the central nervous system. Cell Death Differ 12(Suppl 1):878–892

    Article  PubMed  CAS  Google Scholar 

  • Koenig S, Gendelman HE, Orenstein JM, Canto MCD, Pezeshkpour GH, Yungbluth M, Janotta F, Aksamit A, Martin MA, Fauci AS (1986) Detection of AIDS virus in macrophages in brain tissue from AIDS patients with encephalopathy. Science 233:1089–1093

    Article  PubMed  CAS  Google Scholar 

  • Kolson DL, Gonzalez-Scarano F (2000) HIV and HIV dementia. J Clin Invest 106:11–13

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Lawson VA, Oelrichs R, Guillon C, Imrie AA, Cooper DA, Deacon NJ, McPhee DA (2002) Adaptive changes after human immunodeficiency virus type 1 transmission. AIDS Res Hum Retroviruses 18:545–556

    Article  PubMed  CAS  Google Scholar 

  • Li W, Huang Y, Reid R, Steiner J, Malpica-Llanos T, Darden TA, Shankar SK, Mahadevan A, Satishchandra P, Nath A (2008) NMDA receptor activation by HIV-Tat protein is clade dependent. J Neurosci 28:12190–12198

    Article  PubMed  CAS  Google Scholar 

  • Mahadevan A, Shankar SK, Satishchandra P, Ranga U, Chickabasaviah YT, Santosh V, Vasanthapuram R, Pardo CA, Nath A, Zink MC (2007) Characterization of human immunodeficiency virus (HIV)-infected cells in infiltrates associated with CNS opportunistic infections in patients with HIV clade C infection. J Neuropathol Exp Neurol 66:799–808

    Article  PubMed  Google Scholar 

  • Marozsan AJ, Fraundorf E, Abraha A, Baird H, Moore D, Troyer R, Nankja I, Arts EJ (2004) Relationships between infectious titer, capsid protein levels, and reverse transcriptase activities of diverse human immunodeficiency virus type 1 isolates. J Virol 78:11130–11141

    Article  PubMed  CAS  Google Scholar 

  • Michler K, Connell BJ, Venter WD, Stevens WS, Capovilla A, Papathanasopoulos MA (2008) Genotypic characterization and comparison of full-length envelope glycoproteins from South African HIV type 1 subtype C primary isolates that utilize CCR5 and/or CXCR4. AIDS Res Hum Retroviruses 24:743–751

    Article  PubMed  CAS  Google Scholar 

  • Mishra M, Vetrivel S, Siddappa NB, Ranga U, Seth P (2008) Clade-specific differences in neurotoxicity of human immunodeficiency virus-1 B and C Tat of human neurons: significance of dicysteine C30C31 motif. Ann Neurol 63:366–376

    Article  PubMed  CAS  Google Scholar 

  • Navia BA, Cho ES, Petito CK, Price RW (1986) The AIDS dementia complex: II. Neuropathology. Ann Neurol 19:525–535

    Article  PubMed  CAS  Google Scholar 

  • Platt EJ, Wehrly K, Kuhmann SE, Chesebro B, Kabat D (1998) Effects of CCR5 and CD4 cell surface concentrations on infections by macrophagetropic isolates of human immunodeficiency virus type 1. J Virol 72:2855–2864

    PubMed  CAS  Google Scholar 

  • Pollakis G, Abebe A, Kliphuis A, Chalaby MI, Bakker M, Mengistu Y, Brouwer M, Goudsmit J, Schuitemaker H, Paxton WA (2004) Phenotypic and genotypic comparisons of CCR5- and CXCR4-tropic human immunodeficiency virus type 1 biological clones isolated from subtype C-infected individuals. J Virol 78:2841–2852

    Article  PubMed  CAS  Google Scholar 

  • Power C, McArthur JC, Nath A, Wehrly K, Mayne M, Nishio J, Langelier T, Johnson RT, Chesebro B (1998) Neuronal death induced by brain-derived human immunodeficiency virus type 1 envelope genes differs between demented and nondemented AIDS patients. J Virol 72:9045–9053

    PubMed  CAS  Google Scholar 

  • Rao VR, Sas AR, Eugenin EA, Siddappa NB, Bimonte-Nelson H, Berman JW, Ranga U, Tyor WR, Prasad VR (2008) HIV-1 clade-specific differences in the induction of neuropathogenesis. J Neurosci 28:10010–10016

    Article  PubMed  CAS  Google Scholar 

  • Riedel D, Ghate M, Nene M, Paranjape R, Mehendale S, Bollinger R, Sacktor N, McArthur J, Nath A (2006) Screening for human immunodeficiency virus (HIV) dementia in an HIV clade C-infected population in India. J Neurovirol 12:34–38

    Article  PubMed  CAS  Google Scholar 

  • Simon V, Padte N, Murray D, Vanderhoeven J, Wrin T, Parkin N, Di Mascio M, Markowitz M (2003) Infectivity and replication capacity of drug-resistant human immunodeficiency virus type 1 variants isolated during primary infection. J Virol 77:7736–7745

    Article  PubMed  CAS  Google Scholar 

  • Thompson DA, Cormier EG, Dragic T (2002) CCR5 and CXCR4 usage by non-clade B human immunodeficiency virus type 1 primary isolates. J Virol 76:3059–3064

    Article  PubMed  CAS  Google Scholar 

  • Wei X, Decker JM, Liu H, Zhang Z, Arani RB, Kilby JM, Saag MS, Wu X, Shaw GM, Kappes JC (2002) Emergence of resistant human immunodeficiency virus type 1 in patients receiving fusion inhibitor (T-20) monotherapy. Antimicrob Agents Chemother 46:1896–1905

    Article  PubMed  CAS  Google Scholar 

  • Yepthomi T, Paul R, Vallabhaneni S, Kumarasamy N, Tate DF, Solomon S, Flanigan T (2006) Neurocognitive consequences of HIV in southern India: a preliminary study of clade C virus. J Int Neuropsychol Soc 12:424–430

    Article  PubMed  Google Scholar 

  • Zhang H, Hoffmann F, He J, He X, Kankasa C, Ruprecht R, West JT, Orti G, Wood C (2005) Evolution of subtype C HIV-1 Env in a slowly progressing Zambian infant. Retrovirology 2:67

    Article  PubMed  Google Scholar 

  • Zhang H, Hoffmann F, He J, He X, Kankasa C, West JT, Mitchell CD, Ruprecht RM, Orti G, Wood C (2006) Characterization of HIV-1 subtype C envelope glycoproteins from perinatally infected children with different courses of disease. Retrovirology 3:73

    Article  PubMed  Google Scholar 

  • Zhang H, Tully DC, Hoffmann FG, He J, Kankasa C, Wood C (2010) Restricted genetic diversity of HIV-1 subtype C envelope glycoprotein from perinatally infected Zambian infants. PLoSONE 5(2):e9294

    Google Scholar 

  • Zhao J, Lopez AL, Erichsen D, Herek S, Cotter RL, Curthoys NP, Zheng J (2004) Mitochondrial glutaminase enhances extracellular glutamate production in HIV-1-infected macrophages: linkage to HIV-1 associated dementia. J Neurochem 88:169–180

    Article  PubMed  CAS  Google Scholar 

  • Zheng J, Gendelman HE (1997) The HIV-1 associated dementia complex: a metabolic encephalopathy fueled by viral replication in mononuclear phagocytes. Curr Opin Neurol 10:319–325

    Article  PubMed  CAS  Google Scholar 

  • Zheng J, Thylin M, Ghorpade A, Xiong H, Persidsky Y, Cotter R, Niemann D, Che M, Zeng Y, Gelbard H et al (1999) Intracellular CXCR4 signaling, neuronal apoptosis and neuropathogenic mechanisms of HIV-1-associated dementia. J Neuroimmunol 98:185–200

    Article  PubMed  CAS  Google Scholar 

  • Zheng J, Thylin MR, Cotter RL, Lopez AL, Ghorpade A, Persidsky Y, Xiong H, Leisman GB, Che MH, Gendelman HE (2001) HIV-1 infected and immune competent mononuclear phagocytes induce quantitative alterations in neuronal dendritic arbor: relevance for HIV-1-associated dementia. Neurotoxi Res 3:443–459

    Article  CAS  Google Scholar 

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Acknowledgments

We thank Dr. Nicholas P. Whitney for assistance with immunocytochemistry, microscopy, and revision of the manuscript; Dr. Hui Peng, Dr. Changhai Tian, and Dr. Min Cui for helpful discussions regarding experiments and the manuscript. Myhanh Che, Na Ly, and Emilie Scoggins provided exceptional administrative support. This work was supported in part by research grants by the National Institutes of Health, Grant numbers: R01NS41858, R01NS61642, R21MH83525, P20RR15635, and P01NS43985; National Natural Science Foundation of China, Grant number: 81028007 to Jialin C. Zheng; CA75903 and NCRR COBRE grant RR15635 to Charles Wood; and University of Nebraska Medical Center graduate student fellowship to Agnes A. Constantino.

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Correspondence to Jialin C. Zheng.

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Constantino, A.A., Huang, Y., Zhang, H. et al. HIV-1 Clade B and C Isolates Exhibit Differential Replication: Relevance to Macrophage-Mediated Neurotoxicity. Neurotox Res 20, 277–288 (2011). https://doi.org/10.1007/s12640-011-9241-3

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