Pediatric HIV-1 Acquisition and Lifelong Consequences of Infant Infection

Author(s): Cody S. Nelson, Genevieve G.A. Fouda, Sallie R. Permar*.

Journal Name: Current Immunology Reviews

Volume 15 , Issue 1 , 2019

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Increased availability of antiretroviral therapy to pregnant and breastfeeding women in resource-limited areas has proven remarkably successful at reducing HIV vertical transmission rates over the past several decades. Yet, still, more than 170,000 children are infected annually due to failures in therapy implementation, monitoring, and adherence. Mother-to-child transmission (MTCT) of HIV-1 can occur at one of several distinct stages of infant development – intrauterine, intrapartum, and postpartum. The heterogeneity of the maternal-fetal interface at each of these modes of transmission poses a challenge for the implementation of immune interventions to prevent all modes of HIV MTCT. However, using mother-infant human cohorts and nonhuman primate models of infant simian immunodeficiency virus (SIV) acquisition, investigators have made an important observation about the biology of pediatric HIV infection and have identified unique protective immune factors for each mode of transmission. Knowledge of immune factors protective against HIV MTCT will be critical to the development of targeted immune therapies to prevent infant HIV acquisition and to bring an end to the pediatric AIDS epidemic.

Keywords: Antiretroviral therapy, HIV, Mother-to-child transmission, pathogens, in utero, pregnancy.

Global H. IV/AIDS response: Epidemic update and health sector progress towards universal access.Progress Report 2014. Geneva, Switzerland: World Health Organization 2015.
Shapiro RL, Hughes MD, Ogwu A, et al. Antiretroviral regimens in pregnancy and breast-feeding in Botswana. N Engl J Med 2010; 362(24): 2282-94.
Watts DH, Williams PL, Kacanek D, et al. Combination antiretroviral use and preterm birth. J Infect Dis 2013; 207(4): 612-21.
Bae WH, Wester C, Smeaton LM, et al. Hematologic and hepatic toxicities associated with antenatal and postnatal exposure to maternal highly active antiretroviral therapy among infants. AIDS 2008; 22(13): 1633-40.
Lambert JS, Watts DH, Mofenson L, et al. Risk factors for preterm birth, low birth weight, and intrauterine growth retardation in infants born to HIV-infected pregnant women receiving zidovudine. Pediatric AIDS Clinical Trials Group 185 Team. AIDS 2000; 14(10): 1389-99.
Sagar M. Origin of the transmitted virus in HIV infection: infected cells versus cell-free virus. J Infect Dis 2014; 210(Suppl. 3): S667-73.
Dabis F, Msellati P, Newell ML, et al. Methodology of intervention trials to reduce mother to child transmission of HIV with special reference to developing countries 1995.
Munoz FMEJ. A step ahead. Infant protection through maternal immunzation. Pediatr Clin North Am 2000; 47: 449-63.
Gardner MB. SIV infected rhesus macaques: an AIDS model for immunoprevention and immunotherapy. Adv Exp Med Biol 1989; 251: 279-93.
Sui Y, Gordon S, Franchini G, Berzofsky JA. 2013.
Wood LF, Chahroudi A, Chen HL, Jaspan HB, Sodora DL. The oral mucosa immune environment and oral transmission of HIV/SIV. Immunol Rev 2013; 254(1): 34-53.
Schmitz JE, Korioth-Schmitz B. Immunopathogenesis of simian immunodeficiency virus infection in nonhuman primates. Curr Opin HIV AIDS 2013; 8(4): 273-9.
Van Rompay KK, McChesney MB, Aguirre NL, et al. Two low doses of tenofovir protect newborn macaques against oral simian immunodeficiency virus infection. J Infect Dis 2001; 184(4): 429-38.
Maidji E, McDonagh S, Genbacev O, Tabata T, Pereira L. Maternal antibodies enhance or prevent cytomegalovirus infection in the placenta by neonatal Fc receptor-mediated transcytosis. Am J Pathol 2006; 168(4): 1210-26.
Lee TH, Chafets DM, Biggar RJ, McCune JM, Busch MP. The role of transplacental microtransfusions of maternal lymphocytes in in utero HIV transmission. J Acquir Immune Defic Syndr 2010; 55(2): 143-7.
Jourdain G, Mary JY, Coeur SL, et al. Risk factors for in utero or intrapartum mother-to-child transmission of human immunodeficiency virus type 1 in Thailand. J Infect Dis 2007; 196(11): 1629-36.
Fawzi W, Msamanga G, Renjifo B, et al. Predictors of intrauterine and intrapartum transmission of HIV-1 among Tanzanian women. AIDS 2001; 15(9): 1157-65.
Kumar SB, Rice CE, Milner DA Jr, et al. Elevated cytokine and chemokine levels in the placenta are associated with in-utero HIV-1 mother-to-child transmission. AIDS 2012; 26(6): 685-94.
St Louis ME, Kamenga M, Brown C, et al. Risk for perinatal HIV-1 transmission according to maternal immunologic, virologic, and placental factors. JAMA 1993; 269(22): 2853-9.
Rossi P, Moschese V, Broliden PA, et al. Presence of maternal antibodies to human immunodeficiency virus 1 envelope glycoprotein gp120 epitopes correlates with the uninfected status of children born to seropositive mothers. Proc Natl Acad Sci USA 1989; 86(20): 8055-8.
Pancino G, Leste-Lasserre T, Burgard M, et al. Apparent enhancement of perinatal transmission of human immunodeficiency virus type 1 by high maternal anti-gp160 antibody titer. J Infect Dis 1998; 177(6): 1737-41.
Markham RB, Coberly J, Ruff AJ, et al. Maternal IgG1 and IgA antibody to V3 loop consensus sequence and maternal-infant HIV-1 transmission. Lancet 1994; 343(8894): 390-1.
Rich KC, Fowler MG, Mofenson LM, et al. Maternal and infant factors predicting disease progression in human immunodeficiency virus type 1-infected infants. Women and Infants Transmission Study Group. Pediatrics 2000; 105(1): e8.
Permar SR, Fong Y, Vandergrift N, et al. Maternal HIV-1 envelope-specific antibody responses and reduced risk of perinatal transmission. J Clin Invest 2015; 125(7): 2702-6.
Scarlatti G, Albert J, Rossi P, et al. Mother-to-child transmission of human immunodeficiency virus type 1: Correlation with neutralizing antibodies against primary isolates. J Infect Dis 1993; 168(1): 207-10.
Dickover R, Garratty E, Yusim K, et al. Role of maternal autologous neutralizing antibody in selective perinatal transmission of human immunodeficiency virus type 1 escape variants. J Virol 2006; 80(13): 6525-33.
Wu X, Parast AB, Richardson BA, et al. Neutralization escape variants of human immunodeficiency virus type 1 are transmitted from mother to infant. J Virol 2006; 80(2): 835-44.
Chaillon A, Wack T, Braibant M, et al. The breadth and titer of maternal HIV-1-specific heterologous neutralizing antibodies are not associated with a lower rate of mother-to-child transmission of HIV-1. J Virol 2012; 86(19): 10540-6.
Lynch JB, Nduati R, Blish CA, et al. The breadth and potency of passively acquired human immunodeficiency virus type 1-specific neutralizing antibodies do not correlate with the risk of infant infection. J Virol 2011; 85(11): 5252-61.
Omenda MM, Milligan C, Odem-Davis K, et al. Evidence for efficient vertical transfer of maternal HIV-1 envelope-specific neutralizing antibodies but no association of such antibodies with reduced infant infection. J Acquir Immune Defic Syndr 2013; 64(2): 163-6.
Zack JA, Arrigo SJ, Weitsman SR, et al. HIV-1 entry into quiescent primary lymphocytes: Molecular analysis reveals a labile, latent viral structure. Cell 1990; 61(2): 213-22.
Reinhardt PP, Reinhardt B, Lathey JL, Spector SA. Human cord blood mononuclear cells are preferentially infected by non-syncytium-inducing, macrophage-tropic human immunodeficiency virus type 1 isolates. J Clin Microbiol 1995; 33(2): 292-7.
Sundaravaradan V, Saxena SK, Ramakrishnan R, et al. Differential HIV-1 replication in neonatal and adult blood mononuclear cells is influenced at the level of HIV-1 gene expression. Proc Natl Acad Sci USA 2006; 103(31): 11701-6.
Mold JE, Michaelsson J, Burt TD, et al. Maternal alloantigens promote the development of tolerogenic fetal regulatory T cells in utero. Science 2008; 322(5907): 1562-5.
Flanagan KL, Halliday A, Burl S, et al. The effect of placental malaria infection on cord blood and maternal immunoregulatory responses at birth. Eur J Immunol 2010; 40(4): 1062-72.
Aguilar-Jimenez W, Zapata W, Rugeles MT. Differential expression of human beta defensins in placenta and detection of allelic variants in the DEFB1 gene from HIV-1 positive mothers. Biomedica 2011; 31(1): 44-54.
Johnson EL, Chakraborty R. Placental Hofbauer cells limit HIV-1 replication and potentially offset Mother to Child Transmission (MTCT) by induction of immunoregulatory cytokines. Retrovirology 2012; 9: 101.
Marlin R, Nugeyre MT, Duriez M, et al. Decidual soluble factors participate in the control of HIV-1 infection at the maternofetal interface. Retrovirology 2011; 8: 58.
Mandelbrot L, Burgard M, Teglas JP, et al. Frequent detection of HIV-1 in the gastric aspirates of neonates born to HIV-infected mothers. AIDS 1999; 13(15): 2143-9.
Elective caesarean-section versus vaginal delivery in prevention of vertical HIV-1 transmission: A randomised clinical trial. Lancet 1999; 353(9158): 1035-9.
Tobin NH, Aldrovandi GM. Immunology of pediatric HIV infection. Immunol Rev 2013; 254(1): 143-69.
Bryson YJ, Luzuriaga K, Sullivan JL, Wara DW. Proposed definitions for in utero versus intrapartum transmission of HIV-1. N Engl J Med 1992; 327(17): 1246-7.
Lallemant M, Jourdain G, Le Coeur S, et al. Single-dose perinatal nevirapine plus standard zidovudine to prevent mother-to-child transmission of HIV-1 in Thailand. N Engl J Med 2004; 351(3): 217-28.
Russell ES, Kwiek JJ, Keys J, et al. The genetic bottleneck in vertical transmission of subtype C HIV-1 is not driven by selection of especially neutralization-resistant virus from the maternal viral population. J Virol 2011; 85(16): 8253-62.
Barouch DH, Whitney JB, Moldt B, et al. Therapeutic efficacy of potent neutralizing HIV-1-specific monoclonal antibodies in SHIV-infected rhesus monkeys. Nature 2013; 503(7475): 224-8.
Shingai M, Nishimura Y, Klein F, et al. Antibody-mediated immunotherapy of macaques chronically infected with SHIV suppresses viraemia. Nature 2013; 503(7475): 277-80.
Ng CT, Jaworski JP, Jayaraman P, et al. Passive neutralizing antibody controls SHIV viremia and enhances B cell responses in infant macaques. Nat Med 2010; 16(10): 1117-9.
Baba TW, Liska V, Hofmann-Lehmann R, et al. Human neutralizing monoclonal antibodies of the IgG1 subtype protect against mucosal simian-human immunodeficiency virus infection. Nat Med 2000; 6(2): 200-6.
Hessell AJ, Jaworski JP, Epson E, et al. Early short-term treatment with neutralizing human monoclonal antibodies halts SHIV infection in infant macaques. Nat Med 2016; 22(4): 362-8.
Van de Perre P, Simonon A, Msellati P, et al. Postnatal transmission of human immunodeficiency virus type 1 from mother to infant. A prospective cohort study in Kigali, Rwanda. N Engl J Med 1991; 325(9): 593-8.
Neveu D, Viljoen J, Bland RM, et al. Cumulative exposure to cell-free HIV in breast milk, rather than feeding pattern per se, identifies postnatally infected infants. Clin Infect Dis 2011; 52(6): 819-25.
Semba RD, Neville MC. Breast-feeding, mastitis, and HIV transmission: Nutritional implications. Nutr Rev 1999; 57(5 Pt 1): 146-53.
Breastfeeding and the use of human milk. American Academy of Pediatrics. Work Group on Breastfeeding. Pediatrics 1997; 100(6): 1035-9.
Coutsoudis A, Pillay K, Spooner E, Kuhn L, Coovadia HM. Influence of infant-feeding patterns on early mother-to-child transmission of HIV-1 in Durban, South Africa: a prospective cohort study. South African Vitamin A Study Group. Lancet 1999; 354(9177): 471-6.
Lewis P, Nduati R, Kreiss JK, et al. Cell-free human immunodeficiency virus type 1 in breast milk. J Infect Dis 1998; 177(1): 34-9.
Sabbaj S, Ibegbu CC, Kourtis AP. Cellular immunity in breast milk: Implications for postnatal transmission of HIV-1 to the infant. Adv Exp Med Biol 2012; 743: 161-9.
Farquhar C, VanCott TC, Mbori-Ngacha DA, et al. Salivary secretory leukocyte protease inhibitor is associated with reduced transmission of human immunodeficiency virus type 1 through breast milk. J Infect Dis 2002; 186(8): 1173-6.
Shugars DC. Endogenous mucosal antiviral factors of the oral cavity. J Infect Dis 1999; 179(Suppl. 3): S431-5.
Madsen J, Mollenhauer J, Holmskov U. Review: Gp-340/DMBT1 in mucosal innate immunity. Innate Immun 2010; 16(3): 160-7.
Fouda GG, Jaeger FH, Amos JD, et al. Tenascin-C is an innate broad-spectrum, HIV-1-neutralizing protein in breast milk. Proc Natl Acad Sci USA 2013; 110(45): 18220-5.
Mthembu Y, Lotz Z, Tyler M, et al. Purified human breast milk MUC1 and MUC4 inhibit human immunodeficiency virus. Neonatology 2014; 105(3): 211-7.
Fouda GG, Yates NL, Pollara J, et al. HIV-specific functional antibody responses in breast milk mirror those in plasma and are primarily mediated by IgG antibodies. J Virol 2011; 85(18): 9555-67.
Permar SR, Wilks AB, Ehlinger EP, et al. Limited contribution of mucosal IgA to Simian Immunodeficiency Virus (SIV)-specific neutralizing antibody response and virus envelope evolution in breast milk of SIV-infected, lactating rhesus monkeys. J Virol 2010; 84(16): 8209-18.
Sacha CR, Vandergrift N, Jeffries TL Jr, et al. Restricted isotype, distinct variable gene usage, and high rate of gp120 specificity of HIV-1 envelope-specific B cells in colostrum compared with those in blood of HIV-1-infected, lactating African women. Mucosal Immunol 2015; 8(2): 316-26.
Tuaillon E, Valea D, Becquart P, et al. Human milk-derived B cells: A highly activated switched memory cell population primed to secrete antibodies. J Immunol 2009; 182(11): 7155-62.
Rainwater SM, Wu X, Nduati R, et al. Cloning and characterization of functional subtype A HIV-1 envelope variants transmitted through breastfeeding. Curr HIV Res 2007; 5(2): 189-97.
Milligan C, Omenda MM, Chohan V, et al. Maternal neutralization-resistant virus variants do not predict infant HIV infection risk. MBio 2016; 7(1): e02221-15.
Mabuka J, Nduati R, Odem-Davis K, Peterson D, Overbaugh J. HIV-specific antibodies capable of ADCC are common in breastmilk and are associated with reduced risk of transmission in women with high viral loads. PLoS Pathog 2012; 8(6): e1002739.
Pollara J, McGuire E, Fouda GG, et al. Association of HIV-1 envelope-specific breast milk IgA responses with reduced risk of postnatal mother-to-child transmission of HIV-1. J Virol 2015; 89(19): 9952-61.
Bomsel M, Tudor D, Drillet AS, et al. Immunization with HIV-1 gp41 subunit virosomes induces mucosal antibodies protecting nonhuman primates against vaginal SHIV challenges. Immunity 2011; 34(2): 269-80.
Watkins JD, Sholukh AM, Mukhtar MM, et al. Anti-HIV IgA isotypes: differential virion capture and inhibition of transcytosis are linked to prevention of mucosal R5 SHIV transmission. AIDS 2013; 27(9): F13-20.
Sholukh AM, Watkins JD, Vyas HK, et al. Defense-in-depth by mucosally administered anti-HIV dimeric IgA2 and systemic IgG1 mAbs: complete protection of rhesus monkeys from mucosal SHIV challenge. Vaccine 2015; 33(17): 2086-95.
Gaillard P, Fowler MG, Dabis F, et al. Use of antiretroviral drugs to prevent HIV-1 transmission through breast-feeding: From animal studies to randomized clinical trials. J Acquir Immune Defic Syndr 2004; 35(2): 178-87.
Haynes BF, Gilbert PB, McElrath MJ, et al. Immune-correlates analysis of an HIV-1 vaccine efficacy trial. N Engl J Med 2012; 366(14): 1275-86.
Tomaras GD, Ferrari G, Shen X, et al. Vaccine-induced plasma IgA specific for the C1 region of the HIV-1 envelope blocks binding and effector function of IgG. Proc Natl Acad Sci USA 2013; 110(22): 9019-24.
Mestecky J, Jackson S, Moldoveanu Z, et al. Paucity of antigen-specific IgA responses in sera and external secretions of HIV-type 1-infected individuals. AIDS Res Hum Retroviruses 2004; 20(9): 972-88.
Nelson CS, Pollara J, Kunz EL, et al. Combined HIV-1 envelope systemic and mucosal immunization of lactating rhesus monkeys induces a robust immunoglobulin a isotype B cell response in breast milk. J Virol 2016; 90(10): 4951-65.
Fouda GG, Eudailey J, Kunz EL, et al. Systemic administration of an HIV-1 broadly neutralizing dimeric IgA yields mucosal secretory IgA and virus neutralization. Mucosal Immunol 2017; 10(1): 228-37.
Kourtis AP, Butera S, Ibegbu C, Belec L, Duerr A. Breast milk and HIV-1: Vector of transmission or vehicle of protection? Lancet Infect Dis 2003; 3(12): 786-93.
Wirt DP, Adkins LT, Palkowetz KH, Schmalstieg FC, Goldman AS. Activated and memory T lymphocytes in human milk. Cytometry 1992; 13(3): 282-90.
Kourtis AP, Ibegbu CC, Theiler R, et al. Breast milk CD4+ T cells express high levels of C chemokine receptor 5 and CXC chemokine receptor 4 and are preserved in HIV-infected mothers receiving highly active antiretroviral therapy. J Infect Dis 2007; 195(7): 965-72.
Sabbaj S, Ghosh MK, Edwards BH, et al. Breast milk-derived antigen-specific CD8+ T cells: An extralymphoid effector memory cell population in humans. J Immunol 2005; 174(5): 2951-6.
Weiler IJ, Hickler W, Sprenger R. Demonstration that milk cells invade the suckling neonatal mouse. Am J Reprod Immunol 1983; 4(2): 95-8.
Head JR, Beer AE, Billingham RE. Significance of the cellular component of the maternal immunologic endowment in milk. Transplant Proc 1977; 9(2): 1465-71.
Lohman-Payne B, Slyker JA, Moore S, et al. Breast milk cellular HIV-specific interferon gamma responses are associated with protection from peripartum HIV transmission. AIDS 2012; 26(16): 2007-16.
Koulinska IN, Villamor E, Chaplin B, et al. Transmission of cell-free and cell-associated HIV-1 through breast-feeding. J Acquir Immune Defic Syndr 2006; 41(1): 93-9.
Rousseau CM, Nduati RW, Richardson BA, et al. Longitudinal analysis of human immunodeficiency virus type 1 RNA in breast milk and of its relationship to infant infection and maternal disease. J Infect Dis 2003; 187(5): 741-7.
Ndirangu J, Viljoen J, Bland RM, et al. Cell-free (RNA) and cell-associated (DNA) HIV-1 and postnatal transmission through breastfeeding. PLoS One 2012; 7(12): e51493.
Becquart P, Petitjean G, Tabaa YA, et al. Detection of a large T-cell reservoir able to replicate HIV-1 actively in breast milk. AIDS 2006; 20(10): 1453-5.
Mansour RG, Stamper L, Jaeger F, et al. The presence and anti-hiv-1 function of tenascin c in breast milk and genital fluids. PLoS One 2016; 11(5): e0155261.
Moriuchi M, Moriuchi H. A milk protein lactoferrin enhances human T cell leukemia virus type I and suppresses HIV-1 infection. J Immunol 2001; 166(6): 4231-6.
Bode L, Kuhn L, Kim HY, et al. Human milk oligosaccharide concentration and risk of postnatal transmission of HIV through breastfeeding. Am J Clin Nutr 2012; 96(4): 831-9.
Chahroudi A, Cartwright E, Lee ST, et al. Target cell availability, rather than breast milk factors, dictates mother-to-infant transmission of SIV in sooty mangabeys and rhesus macaques. PLoS Pathog 2014; 10(3): e1003958.
Lifson JD, Hwang KM, Nara PL, et al. Synthetic CD4 peptide derivatives that inhibit HIV infection and cytopathicity. Science 1988; 241(4866): 712-6.
Dunn D, Group HIVPPMCS. Short-term risk of disease progression in HIV-1-infected children receiving no antiretroviral therapy or zidovudine monotherapy: A meta-analysis. Lancet 2003; 362(9396): 1605-11.
McIntosh K, FitzGerald G, Pitt J, et al. A comparison of peripheral blood coculture versus 18- or 24-month serology in the diagnosis of human immunodeficiency virus infection in the offspring of infected mothers. Women and Infants Transmission Study. J Infect Dis 1998; 178(2): 560-3.
Hu Z, Luo Z, Wan Z, et al. HIV-associated memory B cell perturbations. Vaccine 2015; 33(22): 2524-9.
Obaro SK, Pugatch D, Luzuriaga K. Immunogenicity and efficacy of childhood vaccines in HIV-1-infected children. Lancet Infect Dis 2004; 4(8): 510-8.
Iwajomo OH, Finn A, Moons P, et al. Deteriorating pneumococcal-specific B-cell memory in minimally symptomatic African children with HIV infection. J Infect Dis 2011; 204(4): 534-43.
Bamford A, Hart M, Lyall H, et al. The influence of paediatric HIV infection on circulating B cell subsets and CXCR5(+) T helper cells. Clin Exp Immunol 2015; 181(1): 110-7.
Ghosh S, Feyen O, Jebran AF, et al. Memory B cell function in HIV-infected children-decreased memory B cells despite ART. Pediatr Res 2009; 66(2): 185-90.
Cubas RA, Mudd JC, Savoye AL, et al. Inadequate T follicular cell help impairs B cell immunity during HIV infection. Nat Med 2013; 19(4): 494-9.
Moir S, Ogwaro KM, Malaspina A, et al. Perturbations in B cell responsiveness to CD4+ T cell help in HIV-infected individuals. Proc Natl Acad Sci USA 2003; 100(10): 6057-62.
Titanji K, Chiodi F, Bellocco R, et al. Primary HIV-1 infection sets the stage for important B lymphocyte dysfunctions. AIDS 2005; 19(17): 1947-55.
Lane HC, Masur H, Edgar LC, et al. Abnormalities of B-cell activation and immunoregulation in patients with the acquired immunodeficiency syndrome. N Engl J Med 1983; 309(8): 453-8.
Jiang W, Lederman MM, Mohner RJ, et al. Impaired naive and memory B-cell responsiveness to TLR9 stimulation in human immunodeficiency virus infection. J Virol 2008; 82(16): 7837-45.
Rethi B, Sammicheli S, Amu S, et al. Concerted effect of lymphopenia, viraemia and T-cell activation on Fas expression of peripheral B cells in HIV-1-infected patients. AIDS 2013; 27(2): 155-62.
Moir S, Ho J, Malaspina A, et al. Evidence for HIV-associated B cell exhaustion in a dysfunctional memory B cell compartment in HIV-infected viremic individuals. J Exp Med 2008; 205(8): 1797-805.
Doi H, Tanoue S, Kaplan DE. Peripheral CD27-CD21- B-cells represent an exhausted lymphocyte population in hepatitis C cirrhosis. Clin Immunol 2014; 150(2): 184-91.
Illingworth J, Butler NS, Roetynck S, et al. Chronic exposure to Plasmodium falciparum is associated with phenotypic evidence of B and T cell exhaustion. J Immunol 2013; 190(3): 1038-47.
Jacobi AM, Reiter K, Mackay M, et al. Activated memory B cell subsets correlate with disease activity in systemic lupus erythematosus: Delineation by expression of CD27, IgD, and CD95. Arthritis Rheum 2008; 58(6): 1762-73.
Shaw GM. Novel SHIV Design to Recapitulate HIV-1 Transmission, Persistence and Pathogenesis as a Guide for Vaccine and Cure Research. Keystone HIV Vaccines Symposium. Olympic Valley, CA. 2016.

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Year: 2019
Page: [131 - 138]
Pages: 8
DOI: 10.2174/1573395514666180531074047
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