Background An unexpectedly high seroprevalence and pathogenic potential of human parvovirus B19 (B19V) have been observed in certain malaria-endemic countries in parallel with local use of chloroquine (CQ) as first-line treatment for malaria. The aims of this study were to assess the effect of CQ and other common antimalarial drugs on B19V infection in vitro and the possible epidemiological consequences for children from Papua New Guinea (PNG). Methodology/Principal Findings Viral RNA, DNA and proteins were analyzed in different cell types following infection with B19V in the presence of a range of antimalarial drugs. Relationships between B19V infection status, prior 4-aminoquinoline use and anemia were assessed in 200 PNG children <10 years of age participating in a case-control study of severe infections. In CQ-treated cells, the synthesis of viral RNA, DNA and proteins was significantly higher and occurred earlier than in control cells. CQ facilitates B19V infection by minimizing intracellular degradation of incoming particles. Only amodiaquine amongst other antimalarial drugs had a similar effect. B19V IgM seropositivity was more frequent in 111 children with severe anemia (hemoglobin <50 g/L) than in 89 healthy controls (15.3% vs 3.4%; P = 0.008). In children who were either B19V IgM or PCR positive, 4-aminoquinoline use was associated with a significantly lower admission hemoglobin concentration. Conclusions/Significance Our data strongly suggest that 4-aminoquinoline drugs and their metabolites exacerbate B19V-associated anemia by promoting B19V replication. Consideration should be given for choosing a non-4-aminoquinoline drug to partner artemisinin compounds in combination antimalarial therapy.
References
[1]
Cossart YE, Field AM, Cant B, Widdow D (1975) Parvovirus-like particles in human sera. Lancet 7898: 72–73. doi: 10.1016/S0140-6736(75)91074-0
[2]
Broliden K, Tolfvenstam T, Norbeck O (2006) Clinical aspects of parvovirus B19 infection. J Intern Med 260: 285–304. doi: 10.1111/j.1365-2796.2006.01697.x
[3]
Pasvol G (2006) Parvovirus infection, malaria, and anemia in the tropics - a new hidden enemy? J Infect Dis 194: 141–42. doi: 10.1086/505086
[4]
Wildig J, Michon P, Siba P, Mellombo M, Ura A, et al. (2006) Parvovirus B19 infection contributes to severe anemia in young children in Papua New Guinea. J Infect Dis 194: 146–53. doi: 10.1086/505082
[5]
Jones PH, Pickett LC, Anderson MJ, Pasvol G (1990) Human parvovirus infection in children and severe anemia seen in an area endemic for malaria. J Trop Med Hyg 93: 67–70.
[6]
Yeats J, Daley H, Hardie D (1999) Parvovirus B19 infection does not contribute significantly to severe anemia in children with malaria in Malawi. Eur J Haematol 63: 276–77. doi: 10.1111/j.1600-0609.1999.tb01892.x
[7]
Newton CR, Warn PA, Winstanley PA, Peshu N, Pasvol G, et al. (1997) Severe anemia in children living in a malaria endemic area of Kenya. Trop Med Int Health 2: 165–78. doi: 10.1046/j.1365-3156.1997.d01-238.x
[8]
Tolfvenstam T, Enbom M, Ghebrekidan H, Rudén U, Linde A, et al. (2000) Seroprevalence of viral childhood infections in Eritrea. J Clin Virol 16: 49–54. doi: 10.1016/S1386-6532(99)00070-0
[9]
Savarino A, Boelaert JR, Cassone A, Majori G, Cauda R (2003) Effects of chloroquine on viral infections: an old drug against today's diseases? Lancet Infect Dis 3: 722–27. doi: 10.1016/S1473-3099(03)00806-5
[10]
Rolain JM, Colson P, Raoult D (2007) Recycling of chloroquine and its hydroxyl analogue to face bacterial, fungal and viral infections in the 21st century. Int J Antimicrob Agents 30: 297–308. doi: 10.1016/j.ijantimicag.2007.05.015
[11]
Maheshwari RK, Srikantan V, Bhartiya D (1991) Chloroquine enhances replication of Semliki Forest virus and encephalomyocarditis virus in mice. J Virol 65: 992–95.
Sadoff L (1973) Antimalarial drugs and Burkitt's lymphoma. Lancet 7840: 1262–63. doi: 10.1016/S0140-6736(73)91000-3
[14]
Wong S, Brown KE (2006) Development of an improved method of detection of infectious parvovirus B19. J Clin Virol 35: 407–13. doi: 10.1016/j.jcv.2005.12.008
[15]
Bonvicini F, Filippone C, Manaresi E, Zerbini M, Musiani M, et al. (2008) HepG2 hepatocellular carcinoma cells are a non-permissive system for B19 virus infection. J Gen Virol 89: 3034–38. doi: 10.1099/vir.0.2008/004341-0
[16]
Pillet S, Fichelson S, Morinet F (2008) Human B19 Erythrovirus In Vitro Replication: What's New?. J Virol 82: 8951–53. doi: 10.1128/JVI.00929-08
[17]
B？nsch C, Kempf C, Ros C (2008) Interaction of Parvovirus B19 with Human Erythrocytes Alters Virus Structure and Cell Membrane Integrity. J Virol 82: 11784–91. doi: 10.1128/JVI.01399-08
[18]
Karunajeewa HA, Ilett KF, Mueller I, Siba P, Law I, et al. (2008) Pharmacokinetics and efficacy of piperaquine and chloroquine in Melanesian children with uncomplicated malaria. Antimicrob Agents Chemother 52: 237–43. doi: 10.1128/AAC.00555-07
[19]
Laurent F, Saivin S, Chretien P, Magnaval JF, Peyron F, et al. (1993) Pharmacokinetic and pharmacodynamic study of amodiaquine and its two metabolites after a single oral dose in human volunteers. Arzneimittelforschung 43: 612–16.
[20]
Maitland K, Marsh K (2004) Pathophysiology of severe malaria in children. Acta Tropica 90: 131–40. doi: 10.1016/j.actatropica.2003.11.010
[21]
Vihinen-Ranta M, Kalela A, M？kinen P, Kakkola L, Marjom？ki V, et al. (1998) Intracellular Route of Canine Parvovirus Entry. J Virol 72: 802–06.
[22]
Mani B, Baltzer C, Valle N, Almendral JM, Kempf C, et al. (2006) Low pH-dependent endosomal processing of the incoming parvovirus minute virus of mice virion leads to externalization of the VP1 N-terminal sequence (N-VP1), N-VP2 cleavage, and uncoating of the full-length genome. J Virol 80: 1015–24. doi: 10.1128/JVI.80.2.1015-1024.2006
[23]
Cotmore SF, Tattersall P (2007) Parvoviral host range and cell entry mechanisms. Adv Virus Res 70: 183–232. doi: 10.1016/S0065-3527(07)70005-2
[24]
Mani B, Gerber M, Lieby P, Boschetti N, Kempf C, et al. (2007) Molecular mechanism underlying B19 virus inactivation and comparison to other parvoviruses. Transfusion 47: 1765–74. doi: 10.1111/j.1537-2995.2007.01393.x
[25]
Suikkanen S, Aaltonen T, Nevalainen M, V？lilehto O, Lindholm L, et al. (2003) Exploitation of microtubule cytoskeleton and dynein during parvoviral traffic toward the nucleus. J Virol 77: 10270–79. doi: 10.1128/JVI.77.19.10270-10279.2003
[26]
McChesney EW, Banks WF, Fabian RJ (1967) Tissue distribution of chloroquine, hydroxychloroquine, and desethylchloroquine in the rat. Toxicology And Applied Pharmacology 10: 501–13. doi: 10.1016/0041-008X(67)90089-0
[27]
Grundmann M, Mikulikova I, Vrublovsky P (1971) Tissue distribution of subcutaneously administered chloroquine in the rat. Arzneim Forsch 21: 573–74.
[28]
Edwards G, Looareesuwan S, Davies AJ, Wattanagoon Y, Phillips RE, et al. (1988) Pharmacokinetics of chloroquine in Thais: plasma and red-cell concentrations following an intravenous infusion to healthy subjects and patients with Plasmodium vivax malaria. Br J Clin Pharmacol 25: 477–85. doi: 10.1111/j.1365-2125.1988.tb03332.x
[29]
World Health Organization (2006) Guidelines for the treatment of malaria. Geneva: World Health Organization; (WHO/HTM/MAL/2006.1108).
