Journal of NeuroVirology

, Volume 15, Issue 2, pp 139–152 | Cite as

Dual lentivirus infection potentiates neuroinflammation and neurodegeneration: viral copassage enhances neurovirulence

  • Amir Afkhami-Goli
  • Shu-Hong Liu
  • Yu Zhu
  • Joseph M. Antony
  • Hosseinali Arab
  • Christopher Power


Infection by multiple lentiviral strains is recognized as a major driving force in the human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) epidemic, but the neuropathogenic consequences of multivirus infections remain uncertain. Herein, we investigated the neurovirulence and underlying mechanisms of dual lentivirus infections with distinct viral strains. Experimental feline immunodeficiency virus (FIV) infections were performed using cultured cells and an in vivo model of AIDS neuropathogenesis. Dual infections were comprised of two FIV strains (FIV-Ch and FIV-PPR) as copassaged or superinfected viruses, with subsequent outcome analyses of host immune responses, viral load, neuropathological features, and neurobehavioral performance. Dual infections of feline macrophages resulted in greater IL-1β (interleukin-1b), TNF-α (tumor necrosis factor α), and IDO (indoleamine 2,3-dioxygenase) expression and associated neurotoxic properties. FIV coinfection and sequential superinfection in vivo also induced greater IL-1β, TNF-α, and IDO expression in the basal ganglia (BG) and cortex (CTX), compared to the monovirus- and mock-infected groups, although viral loads were similar in single virus and dual virusinfected animals. Immunoblot analyses disclosed lower synaptophysin immunoreactivity in the CTX resulting from FIV super- and coinfections. Cholinergic and GABAergic neuronal injury was evident in the CTX of animals with dual FIV infections. With increased glial activation and neuronal loss in dual FIV infected brains, immunohistochemical analysis also revealed elevated detection of cleaved caspase-3 in dysmorphic neurons, which was associated with worsened neurobehavioral abnormalities among animals infected with the copassaged viruses. Dual lentivirus infections caused an escalation in neuroinflammation and ensuing neurodegeneration, underscoring the contribution of infection by multiple viruses to neuropathogenesis.


FIV nervous system dual infection neuroinflammation neuron glia apoptosis 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Altfeld M, Allen TM, Yu, XG, Johnston, MN, Agrawal, D, Korber, BT, Montefiori, DC, O’Connor, DH, Davis, BT, Lee, PK, Maier, EL, Harlow, J, Goulder, PJ, Brander, C, Rosenberg ES, Walker BD (2002). HIV-1 superinfection despite broad CD8+ T-cell responses containing replication of the primary virus. Nature, 420: 434–439.CrossRefPubMedGoogle Scholar
  2. Andersson, S., Norrgren, H., Dias, F, Biberfeld, G, Albert, J., 1999. Molecular characterization of human immunodeficiency virus (HIV)-1 and -2 in individuals from guinea-bissau with single or dual infections: predominance of a distinct HIV-1 subtype A/G recombinant in West Africa. Virology. 262: 312–320.CrossRefPubMedGoogle Scholar
  3. Becker-Pergola, G, Mellquist, JL, Guay, L, Mmiro, F, Ndugwa, C, Kataaha, P, Jackson, JB, Eshleman, SH, 2000. Identification of diverse HIV type 1 subtypes and dual HIV type 1 infection in pregnant Ugandan women. AIDS Res Hum Retroviruses. 16: 1099–1104.CrossRefPubMedGoogle Scholar
  4. Bendinelli, M, Pistello, M, Lombardi, S, Poli, A, Garzelli, C, Matteucci, D, Ceccherini-Nelli, L, Malvaldi, G, Tozzini, F, 1995. Feline immunodeficiency virus: an interesting model for AIDS studies and an important cat pathogen. Clin Microbiol Rev. 8: 87–112.PubMedGoogle Scholar
  5. Blackard, JT, Cohen, DE, Mayer, KH, 2002. Human immunodeficiency virus superinfection and recombination: current state of knowledge and potential clinical consequences. Clin Infect Dis. 34: 1108–1114.CrossRefPubMedGoogle Scholar
  6. Brumme, ZL, Harrigan, PR, 2006. The impact of human genetic variation on HIV disease in the era of HAART. AIDS Rev. 8: 78–87.PubMedGoogle Scholar
  7. Fang, G, Weiser, B, Kuiken, C, Philpott, SM, Rowland-Jones, S, Plummer, F, Kimani, J, Shi, B, Kaul, R, Bwayo, J, Anzala, O and Burger, H, 2004. Recombination following superinfection by HIV-1. AIDS. 18: 153–159.CrossRefPubMedGoogle Scholar
  8. Georges-Courbot, MC, Lu, CY, Makuwa, M, Telfer, P, Onanga, R, Dubreuil, G, Chen, Z, Smith, SM, Georges, A, Gao, F, Hahn, BH, Marx, PA, 1998. Natural infection of a household pet red-capped mangabey (Cercocebus torquatus torquatus) with a new simian immunodeficiency virus. J Virol. 72: 600–608.PubMedGoogle Scholar
  9. Hu, DJ, Subbarao, S, Vanichseni, S, Mock, PA, Ramos, A, Nguyen, L, Chaowanachan, T, Griensven, F, Choopanya, K, Mastro, TD, Tappero, JW, 2005. Frequency of HIV-1 dual subtype infections, including intersubtype superinfections, among injection drug users in Bangkok, Thailand. AIDS. 19: 303–308.PubMedGoogle Scholar
  10. Iversen, AK, Learn, GH, Fugger, L, Gerstoft, J, Mullins, JI, Skinhoj, P, 1999. Presence of multiple HIV subtypes and a high frequency of subtype chimeric viruses in heterosexually infected women. J Acquir Immune Defic Syndr. 22: 325–332.PubMedGoogle Scholar
  11. Jin, MJ, Hui, H, Robertson, DL, Muller, MC, Barre-Sinoussi, F, Hirsch, VM, Allan, JS, Shaw, GM, Sharp, PM, Hahn, BH, 1994. Mosaic genome structure of simian immunodeficiency virus from west African green monkeys. EMBO J. 13: 2935–2947.PubMedGoogle Scholar
  12. Johnston, JB, Jiang, Y, van Marle, G, Mayne, MB, Ni, W, Holden, J, McArthur, JC, Power, C, 2000. Lentivirus infection in the brain induces matrix metalloproteinase expression: role of envelope diversity. J Virol. 74: 7211–7220.CrossRefPubMedGoogle Scholar
  13. Johnston, JB, Silva, C, Hiebert, T, Buist, R, Dawood, MR, Peeling, J, Power, C, 2002a. Neurovirulence depends on virus input titer in brain in feline immunodeficiency virus infection: evidence for activation of innate immunity and neuronal injury. J NeuroVirol. 8: 420–431.CrossRefPubMedGoogle Scholar
  14. Johnston, JB, Silva, C, Power, C, 2002b. Envelope genemediated neurovirulence in feline immunodeficiency virus infection: induction of matrix metalloproteinases and neuronal injury. J Virol. 76: 2622–2633.CrossRefPubMedGoogle Scholar
  15. Jost, S, Bernard, MC, Kaiser, L, Yerly, S, Hirschel, B, Samri, A, Autran, B, Goh, LE, Perrin, L, 2002. A patient with HIV-1 superinfection. N Engl J Med. 347: 731–736.CrossRefPubMedGoogle Scholar
  16. Kantor, R, Katzenstein, D, 2004. Drug resistance in nonsubtype B HIV-1. J Clin Virol. 29: 152–159.CrossRefPubMedGoogle Scholar
  17. Kim, JH, McLinden, RJ, Mosca, JD, Burke, DS, Boswell, RN, Birx, DL, Redfield, RR, 1996. Transcriptional effects of superinfection in HIV chronically infected T cells: studies in dually infected clones. J Acquir Immune Defic Syndr Hum Retrovirol. 12: 329–342.PubMedGoogle Scholar
  18. Kim, JH, Mosca, JD, Vahey, MT, McLinden, RJ, Burke, DS, Redfield, RR, 1993. Consequences of human immunodeficiency virus type 1 superinfection of chronically infected cells. AIDS Res Hum Retroviruses. 9: 875–882.CrossRefPubMedGoogle Scholar
  19. Klausner, RD, Fauci, AS, Corey, L, Nabel, GJ, Gayle, H, Berkley, S, Haynes, BF, Baltimore, D, Collins, C, Douglas, RG, Esparza, J, Francis, DP, Ganguly, NK, Gerberding, JL, Johnston, MI, Kazatchkine, MD, McMichael, AJ, Makgoba, MW, Pantaleo, G, Piot, P, Shao, Y, Tramont, E, Varmus, H, Wasserheit, JN, 2003. Medicine. The need for a global HIV vaccine enterprise. Science. 300: 2036–2039.Google Scholar
  20. Koelsch, KK, Smith, DM, Little, SJ, Ignacio, CC, Macaranas, TR, Brown, AJ, Petropoulos, CJ, Richman, DD, Wong, JK, 2003. Clade B HIV-1 superinfection with wild-type virus after primary infection with drugresistant clade B virus. AIDS. 17: F11-F16.CrossRefPubMedGoogle Scholar
  21. Long, EM, Martin HL Jr, Kreiss, JK, Rainwater, SM, Lavreys, L, Jackson, DJ, Rakwar, J, Mandaliya, K, Overbaugh, J, 2000. Gender differences in HIV-1 diversity at time of infection. Nat Med. 6: 71–75.CrossRefPubMedGoogle Scholar
  22. McCutchan, FE, Hoelscher, M, Tovanabutra, S, Piyasirisilp, S, Sanders-Buell, E, Ramos, G, Jagodzinski, L, Polonis, V, Maboko, L, Mmbando, D, Hoffmann, O, Riedner, G, von Sonnenburg, F, Robb, M, Birx, DL, 2005. In-depth analysis of a heterosexually acquired human immunodeficiency virus type 1 superinfection: evolution, temporal fluctuation, and intercompartment dynamics from the seronegative window period through 30 months postinfection. J Virol. 79: 11693–11704.CrossRefPubMedGoogle Scholar
  23. Nath, A, Conant, K, Chen, P, Scott, C, Major, EO, 1999. Transient exposure to HIV-1 Tat protein results in cytokine production in macrophages and astrocytes. A hit and run phenomenon. J Biol Chem. 274: 17098–17102.CrossRefPubMedGoogle Scholar
  24. Nethe, M, Berkhout, B, van der Kuyl, AC, 2005. Retroviral superinfection resistance. Retrovirology. 2: 52.CrossRefPubMedGoogle Scholar
  25. Noorbakhsh, F, Tang, Q, Liu, S, Silva, C, van Marle, G, Power, C, 2006. Lentivirus envelope protein exerts differential neuropathogenic effects depending on the site of expression and target cell. Virology. 348: 260–276.CrossRefPubMedGoogle Scholar
  26. Otten, RA, Ellenberger, DL, Adams, DR, Fridlund, CA, Jackson, E, Pieniazek, D, Rayfield, MA, 1999. Identification of a window period for susceptibility to dual infection with two distinct human immunodeficiency virus type 2 isolates in a Macaca nemestrina (pig-tailed macaque) model. J Infect Dis. 180: 673–684.CrossRefPubMedGoogle Scholar
  27. Patrick, MK, Johnston, JB, Power, C, 2002. Lentiviral neuropathogenesis: comparative neuroinvasion, neurotropism, neurovirulence, and host neurosusceptibility. J Virol. 76: 7923–7931.CrossRefPubMedGoogle Scholar
  28. Persidsky, Y, Buttini, M, Limoges, J, Bock, P, Gendelman, HE, 1997. An analysis of HIV-1-associated inflammatory products in brain tissue of humans and SCID mice with HIV-1 encephalitis. J NeuroVirol. 3: 401–416.CrossRefPubMedGoogle Scholar
  29. Phillips, TR, Prospero-Garcia, O, Puaoi, DL, Lerner, DL, Fox, HS, Olmsted, RA, Bloom, FE, Henriksen, SJ, Elder, JH, 1994. Neurological abnormalities associated with feline immunodeficiency virus infection. J Gen Virol. 75(Pt 5): 979–987.CrossRefPubMedGoogle Scholar
  30. Power, C, 2001. Retroviral diseases of the nervous system: pathogenic host response or viral gene-mediated neurovirulence? Trends Neurosci. 24: 162–169.CrossRefPubMedGoogle Scholar
  31. Power, C, Buist, R, Johnston, JB, Del Bigio, MR, Ni, W, Dawood, MR, Peeling, J, 1998. Neurovirulence in feline immunodeficiency virus-infected neonatal cats is viral strain specific and dependent on systemic immune suppression. J Virol. 72: 9109–9115.PubMedGoogle Scholar
  32. Power, C, Henry, S, Del Bigio, MR, Larsen, PH, Corbett, D, Imai, Y, Yong, VW, Peeling, J, 2003. Intracerebral hemorrhage induces macrophage activation and matrix metalloproteinases. Ann Neurol. 53: 731–742.CrossRefPubMedGoogle Scholar
  33. Power, C, Moench, T, Peeling, J, Kong, PA, Langelier, T, 1997. Feline immunodeficiency virus causes increased glutamate levels and neuronal loss in brain. Neuroscience. 77: 1175–1185.CrossRefPubMedGoogle Scholar
  34. Prospero-Garcia, O, Huitron-Resendiz, S, Casalman, SC, Sanchez-Alavez, M, Diaz-Ruiz, O, Navarro, L, Lerner, DL, Phillips, TR, Elder, JH, Henriksen, SJ, 1999. Feline immunodeficiency virus envelope protein (FIVgp120) causes electrophysiological alterations in rats. Brain Res. 836: 203–209.CrossRefPubMedGoogle Scholar
  35. Ramos, A, Hu, DJ, Nguyen, L, Phan, KO, Vanichseni, S, Promadej, N, Choopanya, K, Callahan, M, Young, NL, McNicholl, J, Mastro, TD, Folks, TM, Subbarao, S, 2002. Intersubtype human immunodeficiency virus type 1 superinfection following seroconversion to primary infection in two injection drug users. J Virol. 76: 7444–7452.CrossRefPubMedGoogle Scholar
  36. Ramos, A, Tanuri, A, Schechter, M, Rayfield, MA, Hu, DJ, Cabral, MC, Bandea, CI, Baggs, J, Pieniazek, D, 1999. Dual and recombinant infections: an integral part of the HIV-1 epidemic in Brazil. Emerg Infect Dis. 5: 65–74.CrossRefPubMedGoogle Scholar
  37. Salemi, M, Lamers, SL, Yu, S, de Oliveira, T, Fitch, WM, McGrath, MS, 2005. Phylodynamic analysis of human immunodeficiency virus type 1 in distinct brain compartments provides a model for the neuropathogenesis of AIDS. J Virol. 79: 11343–11352.CrossRefPubMedGoogle Scholar
  38. Sardar, AM, Reynolds, GP, 1995. Frontal cortex indoleamine-2,3-dioxygenase activity is increased in HIV-1-associated dementia. Neurosci Lett. 187: 9–12.CrossRefPubMedGoogle Scholar
  39. Sarr, AD, Sankale, JL, Gueye-Ndiaye, A, Essex, M, Mboup, S, Kanki, PJ, 2000. Genetic analysis of HIV type 2 in monotypic and dual HIV infections. AIDS Res Hum Retroviruses. 16: 295–298.CrossRefPubMedGoogle Scholar
  40. Schwarcz, R, Pellicciari, R, 2002. Manipulation of brain kynurenines: glial targets, neuronal effects, and clinical opportunities. J Pharmacol Exp Ther. 303: 1–10.CrossRefPubMedGoogle Scholar
  41. Silva, C, Zhang, K, Tsutsui, S, Holden, JK, Gill, MJ, Power, C, 2003. Growth hormone prevents human immunodeficiency virus-induced neuronal p53 expression. Ann Neurol. 54: 605–614.CrossRefPubMedGoogle Scholar
  42. Smit, TK, Brew, BJ, Tourtellotte, W, Morgello, S, Gelman, BB, Saksena, NK, 2004. Independent evolution of human immunodeficiency virus (HIV) drug resistance mutations in diverse areas of the brain in HIV-infected patients, with and without dementia, on antiretroviral treatment. J Virol. 78: 10133–10148.CrossRefPubMedGoogle Scholar
  43. Smith, DM, Wong, JK, Hightower, GK, Ignacio, CC, Koelsch, KK, Petropoulos, CJ, Richman, DD, Little, SJ, 2005. HIV drug resistance acquired through superinfection. AIDS. 19: 1251–1256.CrossRefPubMedGoogle Scholar
  44. Takeb, EY, Kusagawa, S, Motomura, K, 2004. Molecular epidemiology of HIV: tracking AIDS pandemic. Pediatr Int. 46: 236–244.CrossRefGoogle Scholar
  45. Takehisa, J, Zekeng, L, Miura, T, Ido, E, Yamashita, M, Mboudjeka, I, Gurtler, LG, Hayami, M, Kaptue, L, 1997. Triple HIV-1 infection with group O and Group M of different clades in a single Cameroonian AIDS patient. J Acquir Immune Defic Syndr Hum Retrovirol. 14: 81–82.PubMedGoogle Scholar
  46. Taylor, BS, Sobieszczyk, ME, McCutchan, FE, Hammer, SM, 2008. The challenge of HIV-1 subtype diversity. N Engl J Med. 358: 1590–1602.CrossRefPubMedGoogle Scholar
  47. Thomson, MM, Delgado, E, Manjon, N, Ocampo, A, Villahermosa, ML, Marino, A, Herrero, I, Cuevas, MT, Vazquez-de Parga, E, Perez-Alvarez, L, Medrano, L, Taboada, JA, Najera, R, 2001. HIV-1 genetic diversity in Galicia Spain: BG intersubtype recombinant viruses circulating among injecting drug users. AIDS. 15: 509–516.CrossRefPubMedGoogle Scholar
  48. Tsutsui, S, Schnermann, J, Noorbakhsh, F, Henry, S, Yong, VW, Winston, BW, Warren, K, Power, C, 2004. A1 adenosine receptor upregulation and activation attenuates neuroinflammation and demyelination in a model of multiple sclerosis. J Neurosci. 24: 1521–1529.CrossRefPubMedGoogle Scholar
  49. van Marle, G, Antony, JM, Silva, C, Sullivan, A, Power, C, 2005. Aberrant cortical neurogenesis in a pediatric neuroAIDS model: neurotrophic effects of growth hormone. AIDS. 19: 1781–1791.CrossRefPubMedGoogle Scholar
  50. Weed, MR, Hienz, RD, Brady, JV, Adams, RJ, Mankowski, JL, Clements, JE, Zink, MC, 2003. Central nervous system correlates of behavioral deficits following simian immunodeficiency virus infection. J NeuroVirol. 9: 452–464.PubMedGoogle Scholar
  51. Yerly, S, Jost, S, Monnat, M, Telenti, A, Cavassini, M, Chave, JP, Kaiser, L, Burgisser, P, Perrin, L, 2004. HIV-1 co/super-infection in intravenous drug users. AIDS. 18: 1413–1421.CrossRefPubMedGoogle Scholar
  52. Zhang, K, Hawken, M, Rana, F, Welte, FJ, Gartner, S, Goldsmith, MA, Power, C, 2001. Human immunodeficiency virus type 1 clade A and D neurotropism: molecular evolution, recombination, and coreceptor use. Virology. 283: 19–30.CrossRefPubMedGoogle Scholar
  53. Zink, MC, Clements, JE, 2002. A novel simian immunodeficiency virus model that provides insight into mechanisms of human immunodeficiency virus central nervous system disease. J NeuroVirol. 8 (Suppl 2): 42–48.CrossRefPubMedGoogle Scholar
  54. Zink, MC, Laast, VA, Helke, KL, Brice, AK, Barber, SA, Clements, JE, Mankowski, JL, 2006. From mice to macaques—animal models of HIV nervous system disease. Curr HIV Res. 4: 293–305.CrossRefPubMedGoogle Scholar

Copyright information

© Journal of NeuroVirology, Inc. 2009

Authors and Affiliations

  • Amir Afkhami-Goli
    • 1
    • 2
  • Shu-Hong Liu
    • 3
  • Yu Zhu
    • 1
  • Joseph M. Antony
    • 1
  • Hosseinali Arab
    • 2
  • Christopher Power
    • 1
    • 3
  1. 1.Departments of Medicine and Medical Microbiology and ImmunologyUniversity of AlbertaEdmontonCanada
  2. 2.Department of Pharmacology, Faculty of Veterinary MedicineUniversity of TehranTehranIran
  3. 3.Department of Clinical NeurosciencesUniversity of CalgaryCalgaryCanada

Personalised recommendations