Early events in tissues during infection with pathogenic (SIVmac239) and nonpathogenic (SIVmac1A11) molecular clones of simian immunodeficiency virus

HOME

HELP

FEEDBACK

SUBSCRIPTIONS

Early events in tissues during infection with pathogenic (SIVmac239) and nonpathogenic (SIVmac1A11) molecular clones of simian immunodeficiency virus

AA Lackner, P Vogel, RA Ramos, JD Kluge and M Marthas
New England Regional Primate Research Center, Harvard Medical School, Southborough, MA 01772.

The extent of virus replication, tissue distribution, localization of virus within tissues, and the presence of pathological lesions was examined early after experimental infection of rhesus monkeys with simian immunodeficiency virus (SIV). Three strains of SIV were used: molecularly cloned pathogenic SIVmac239; molecularly cloned nonpathogenic SIVmac1A11; and uncloned pathogenic SIVmac. The major targets of infection in all animals at 2 weeks postinoculation were the thymus and spleen. The distribution of virus within lymphoid organs varied with the viral inoculum: nonpathogenic SIVmac1A11 was present primarily within lymphoid follicles and in the thymic cortex; SIVmac239 was present primarily within periarteriolar lymphoid sheaths in the spleen, the paracortex of lymph nodes, and the medulla of the thymus; uncloned SIVmac was present in all these areas but tended to parallel the distribution of SIVmac239. Animals inoculated with nonpathogenic SIVmac1A11 had fewer SIV-positive cells by in situ hybridization and after 13 weeks postinoculation, virus was undetectable in any tissue from these animals. No significant pathological abnormalities were recognized in animals inoculated with this nonpathogenic virus. In contrast, nearly half of the animals inoculated with either SIVmac or SIVmac239 developed significant pathological lesions, including opportunistic infections by 13 weeks postinoculation, highlighting the virulence of these viruses. Our results indicate marked differences in tissue distribution between pathogenic and nonpathogenic molecular clones of SIV during the acute phase of infection. The most striking differences were the absence of SIVmac1A11 from the central nervous system and thymic medulla. The prominent early involvement of the thymus suggests that infection of this organ is a key event in the induction of immune suppression by SIV.

This article has been cited by other articles:

M. Mohan, P. P. Aye, J. T. Borda, X. Alvarez, and A. A. Lackner
CCAAT/Enhancer Binding Protein {beta} Is a Major Mediator of Inflammation and Viral Replication in the Gastrointestinal Tract of Simian Immunodeficiency Virus-Infected Rhesus Macaques
Am. J. Pathol., July 1, 2008; 173(1): 106 - 118.
[Abstract] [Full Text] [PDF]

J. T. Borda, X. Alvarez, M. Mohan, A. Hasegawa, A. Bernardino, S. Jean, P. Aye, and A. A. Lackner
CD163, a Marker of Perivascular Macrophages, Is Up-Regulated by Microglia in Simian Immunodeficiency Virus Encephalitis after Haptoglobin-Hemoglobin Complex Stimulation and Is Suggestive of Breakdown of the Blood-Brain Barrier
Am. J. Pathol., March 1, 2008; 172(3): 725 - 737.
[Abstract] [Full Text] [PDF]

M. Mohan, P. P. Aye, J. T. Borda, X. Alvarez, and A. A. Lackner
Gastrointestinal Disease in Simian Immunodeficiency Virus-Infected Rhesus Macaques Is Characterized by Proinflammatory Dysregulation of the Interleukin-6-Janus Kinase/Signal Transducer and Activator of Transcription3 Pathway
Am. J. Pathol., December 1, 2007; 171(6): 1952 - 1965.
[Abstract] [Full Text] [PDF]

J. T. Borda, X. Alvarez, I. Kondova, P. Aye, M. A. Simon, R. C. Desrosiers, and A. A. Lackner
Cell Tropism of Simian Immunodeficiency Virus in Culture Is Not Predictive of in Vivo Tropism or Pathogenesis
Am. J. Pathol., December 1, 2004; 165(6): 2111 - 2122.
[Abstract] [Full Text] [PDF]

R. S. Veazey and A. A. Lackner
Getting to the Guts of HIV Pathogenesis
J. Exp. Med., September 20, 2004; 200(6): 697 - 700.
[Abstract] [Full Text] [PDF]

S. P. O'Neil, C. Suwyn, D. C. Anderson, G. Niedziela, J. Bradley, F. J. Novembre, J. G. Herndon, and H. M. McClure
Correlation of Acute Humoral Response with Brain Virus Burden and Survival Time in Pig-Tailed Macaques Infected with the Neurovirulent Simian Immunodeficiency Virus SIVsmmFGb
Am. J. Pathol., April 1, 2004; 164(4): 1157 - 1172.
[Abstract] [Full Text] [PDF]

M. Magierowska, F. Bernardin, S. Garg, S. Staprans, M. D. Miller, K. K. A. Van Rompay, and E. L. Delwart
Highly Uneven Distribution of Tenofovir-Selected Simian Immunodeficiency Virus in Different Anatomical Sites of Rhesus Macaques
J. Virol., March 1, 2004; 78(5): 2434 - 2444.
[Abstract] [Full Text] [PDF]

R. A. Reyes, D. R. Canfield, U. Esser, L. A. Adamson, C. R. Brown, C. Cheng-Mayer, M. B. Gardner, J. M. Harouse, and P. A. Luciw
Induction of Simian AIDS in Infant Rhesus Macaques Infected with CCR5- or CXCR4-Utilizing Simian-Human Immunodeficiency Viruses Is Associated with Distinct Lesions of the Thymus
J. Virol., February 15, 2004; 78(4): 2121 - 2130.
[Abstract] [Full Text] [PDF]

M. Moniuszko, C. Brown, R. Pal, E. Tryniszewska, W.-P. Tsai, V. M. Hirsch, and G. Franchini
High Frequency of Virus-Specific CD8+ T Cells in the Central Nervous System of Macaques Chronically Infected with Simian Immunodeficiency Virus SIVmac251
J. Virol., November 15, 2003; 77(22): 12346 - 12351.
[Abstract] [Full Text] [PDF]

T. Morin, F. Guiguen, B. A. Bouzar, S. Villet, T. Greenland, D. Grezel, F. Gounel, K. Gallay, C. Garnier, J. Durand, et al.
Clearance of a Productive Lentivirus Infection in Calves Experimentally Inoculated with Caprine Arthritis-Encephalitis Virus
J. Virol., June 1, 2003; 77(11): 6430 - 6437.
[Abstract] [Full Text] [PDF]

N. Schmitt, L. Chene, D. Boutolleau, M.-T. Nugeyre, E. Guillemard, P. Versmisse, C. Jacquemot, F. Barre-Sinoussi, and N. Israel
Positive Regulation of CXCR4 Expression and Signaling by Interleukin-7 in CD4+ Mature Thymocytes Correlates with Their Capacity To Favor Human Immunodeficiency X4 Virus Replication
J. Virol., May 15, 2003; 77(10): 5784 - 5793.
[Abstract] [Full Text] [PDF]

A. Shen, M. C. Zink, J. L. Mankowski, K. Chadwick, J. B. Margolick, L. M. Carruth, M. Li, J. E. Clements, and R. F. Siliciano
Resting CD4+ T Lymphocytes but Not Thymocytes Provide a Latent Viral Reservoir in a Simian Immunodeficiency Virus-Macaca nemestrina Model of Human Immunodeficiency Virus Type 1-Infected Patients on Highly Active Antiretroviral Therapy
J. Virol., April 15, 2003; 77(8): 4938 - 4949.
[Abstract] [Full Text] [PDF]

C. Sugimoto, K. Tadakuma, I. Otani, T. Moritoyo, H. Akari, F. Ono, Y. Yoshikawa, T. Sata, S. Izumo, and K. Mori
nef Gene Is Required for Robust Productive Infection by Simian Immunodeficiency Virus of T-Cell-Rich Paracortex in Lymph Nodes
J. Virol., April 1, 2003; 77(7): 4169 - 4180.
[Abstract] [Full Text] [PDF]

C. L. Fuller, Y. K. Choi, B. A. Fallert, S. Capuano III, P. Rajakumar, M. Murphey-Corb, and T. A. Reinhart
Restricted SIV Replication in Rhesus Macaque Lung Tissues During the Acute Phase of Infection
Am. J. Pathol., September 1, 2002; 161(3): 969 - 978.
[Abstract] [Full Text] [PDF]

D. L. Sodora, J. M. Milush, F. Ware, A. Wozniakowski, L. Montgomery, H. M. McClure, A. A. Lackner, M. Marthas, V. Hirsch, R. P. Johnson, et al.
Decreased Levels of Recent Thymic Emigrants in Peripheral Blood of Simian Immunodeficiency Virus-Infected Macaques Correlate with Alterations within the Thymus
J. Virol., August 28, 2002; 76(19): 9981 - 9990.
[Abstract] [Full Text] [PDF]

C. E. Nesbit and S. A. Schwartz
In Vitro and Animal Models of Human Immunodeficiency Virus Infection of the Central Nervous System
Clin. Vaccine Immunol., May 1, 2002; 9(3): 515 - 524.
[Full Text] [PDF]

T. G. D'Aversa, K. M. Weidenheim, and J. W. Berman
CD40-CD40L Interactions Induce Chemokine Expression by Human Microglia : Implications for Human Immunodeficiency Virus Encephalitis and Multiple Sclerosis
Am. J. Pathol., February 1, 2002; 160(2): 559 - 567.
[Abstract] [Full Text] [PDF]

T. Igarashi, C. R. Brown, R. A. Byrum, Y. Nishimura, Y. Endo, R. J. Plishka, C. Buckler, A. Buckler-White, G. Miller, V. M. Hirsch, et al.
Rapid and Irreversible CD4+ T-Cell Depletion Induced by the Highly Pathogenic Simian/Human Immunodeficiency Virus SHIVDH12R Is Systemic and Synchronous
J. Virol., January 1, 2002; 76(1): 379 - 391.
[Abstract] [Full Text] [PDF]

M. C. G. Marcondes, E. M. E. Burudi, S. Huitron-Resendiz, M. Sanchez-Alavez, D. Watry, M. Zandonatti, S. J. Henriksen, and H. S. Fox
Highly Activated CD8+ T Cells in the Brain Correlate with Early Central Nervous System Dysfunction in Simian Immunodeficiency Virus Infection
J. Immunol., November 1, 2001; 167(9): 5429 - 5438.
[Abstract] [Full Text] [PDF]

K. C. Williams, S. Corey, S. V. Westmoreland, D. Pauley, H. Knight, C. deBakker, X. Alvarez, and A. A. Lackner
Perivascular Macrophages Are the Primary Cell Type Productively Infected by Simian Immunodeficiency Virus in the Brains of Macaques: Implications for the Neuropathogenesis of AIDS
J. Exp. Med., April 9, 2001; 193(8): 905 - 916.
[Abstract] [Full Text] [PDF]

M. Rosenzweig, M. Connole, A. Forand-Barabasz, M.-P. Tremblay, R. P. Johnson, and A. A. Lackner
Mechanisms Associated with Thymocyte Apoptosis Induced by Simian Immunodeficiency Virus
J. Immunol., September 15, 2000; 165(6): 3461 - 3468.
[Abstract] [Full Text] [PDF]

L. A. Obert and E. A. Hoover
Relationship of Lymphoid Lesions to Disease Course in Mucosal Feline Immunodeficiency Virus Type C Infection
Vet. Pathol., September 1, 2000; 37(5): 386 - 401.
[Abstract] [Full Text] [PDF]

F. Eitner, Y. Cui, G. Grouard-Vogel, K. L. Hudkins, A. Schmidt, T. Birkebak, M. B. Agy, S.-L. Hu, W. R. Morton, D. M. Anderson, et al.
Rapid Shift from Virally Infected Cells to Germinal Center-Retained Virus after HIV-2 Infection of Macaques
Am. J. Pathol., April 1, 2000; 156(4): 1197 - 1207.
[Abstract] [Full Text] [PDF]

S. V. Westmoreland, K. C. Williams, M. A. Simon, M. E. Bahn, A. E. Rullkoetter, M. W. Elliott, C. D. deBakker, H. L. Knight, and A. A. Lackner
Neuropathogenesis of Simian Immunodeficiency Virus in Neonatal Rhesus Macaques
Am. J. Pathol., October 1, 1999; 155(4): 1217 - 1228.
[Abstract] [Full Text] [PDF]

C. D. Katsetos, J. E. Fincke, A. Legido, H. W. Lischner, J.-P. de Chadarevian, E. M. Kaye, C. D. Platsoucas, and E. L. Oleszak
Angiocentric CD3+ T-Cell Infiltrates in Human Immunodeficiency Virus Type 1-Associated Central Nervous System Disease in Children
Clin. Vaccine Immunol., January 1, 1999; 6(1): 105 - 114.
[Abstract] [Full Text] [PDF]

T. F.�W. Horn, S. Huitron-Resendiz, M. R. Weed, S. J. Henriksen, and H. S. Fox
Early physiological abnormalities after simian immunodeficiency virus infection
PNAS, December 8, 1998; 95(25): 15072 - 15077.
[Abstract] [Full Text] [PDF]

J. J. Wykrzykowska, M. Rosenzweig, R. S. Veazey, M. A. Simon, K. Halvorsen, R. C. Desrosiers, R. P. Johnson, and A. A. Lackner
Early Regeneration of Thymic Progenitors in Rhesus Macaques Infected with Simian Immunodeficiency Virus
J. Exp. Med., June 1, 1998; 187(11): 1767 - 1778.
[Abstract] [Full Text] [PDF]

C. J. Miller, M. Marthas, J. Greenier, D. Lu, P. J. Dailey, and Y. Lu
In Vivo Replication Capacity Rather Than In Vitro Macrophage Tropism Predicts Efficiency of Vaginal Transmission of Simian Immunodeficiency Virus or Simian/Human Immunodeficiency Virus in Rhesus Macaques
J. Virol., April 1, 1998; 72(4): 3248 - 3258.
[Abstract] [Full Text] [PDF]

				J. T. Borda, X. Alvarez, M. Mohan, A. Hasegawa, A. Bernardino, S. Jean, P. Aye, and A. A. Lackner CD163, a Marker of Perivascular Macrophages, Is Up-Regulated by Microglia in Simian Immunodeficiency Virus Encephalitis after Haptoglobin-Hemoglobin Complex Stimulation and Is Suggestive of Breakdown of the Blood-Brain Barrier Am. J. Pathol., March 1, 2008; 172(3): 725 - 737. [Abstract] [Full Text] [PDF]

				J. T. Borda, X. Alvarez, I. Kondova, P. Aye, M. A. Simon, R. C. Desrosiers, and A. A. Lackner Cell Tropism of Simian Immunodeficiency Virus in Culture Is Not Predictive of in Vivo Tropism or Pathogenesis Am. J. Pathol., December 1, 2004; 165(6): 2111 - 2122. [Abstract] [Full Text] [PDF]

				R. S. Veazey and A. A. Lackner Getting to the Guts of HIV Pathogenesis J. Exp. Med., September 20, 2004; 200(6): 697 - 700. [Abstract] [Full Text] [PDF]

				S. P. O'Neil, C. Suwyn, D. C. Anderson, G. Niedziela, J. Bradley, F. J. Novembre, J. G. Herndon, and H. M. McClure Correlation of Acute Humoral Response with Brain Virus Burden and Survival Time in Pig-Tailed Macaques Infected with the Neurovirulent Simian Immunodeficiency Virus SIVsmmFGb Am. J. Pathol., April 1, 2004; 164(4): 1157 - 1172. [Abstract] [Full Text] [PDF]

				M. Magierowska, F. Bernardin, S. Garg, S. Staprans, M. D. Miller, K. K. A. Van Rompay, and E. L. Delwart Highly Uneven Distribution of Tenofovir-Selected Simian Immunodeficiency Virus in Different Anatomical Sites of Rhesus Macaques J. Virol., March 1, 2004; 78(5): 2434 - 2444. [Abstract] [Full Text] [PDF]

				R. A. Reyes, D. R. Canfield, U. Esser, L. A. Adamson, C. R. Brown, C. Cheng-Mayer, M. B. Gardner, J. M. Harouse, and P. A. Luciw Induction of Simian AIDS in Infant Rhesus Macaques Infected with CCR5- or CXCR4-Utilizing Simian-Human Immunodeficiency Viruses Is Associated with Distinct Lesions of the Thymus J. Virol., February 15, 2004; 78(4): 2121 - 2130. [Abstract] [Full Text] [PDF]

				M. Moniuszko, C. Brown, R. Pal, E. Tryniszewska, W.-P. Tsai, V. M. Hirsch, and G. Franchini High Frequency of Virus-Specific CD8+ T Cells in the Central Nervous System of Macaques Chronically Infected with Simian Immunodeficiency Virus SIVmac251 J. Virol., November 15, 2003; 77(22): 12346 - 12351. [Abstract] [Full Text] [PDF]

				T. Morin, F. Guiguen, B. A. Bouzar, S. Villet, T. Greenland, D. Grezel, F. Gounel, K. Gallay, C. Garnier, J. Durand, et al. Clearance of a Productive Lentivirus Infection in Calves Experimentally Inoculated with Caprine Arthritis-Encephalitis Virus J. Virol., June 1, 2003; 77(11): 6430 - 6437. [Abstract] [Full Text] [PDF]

				N. Schmitt, L. Chene, D. Boutolleau, M.-T. Nugeyre, E. Guillemard, P. Versmisse, C. Jacquemot, F. Barre-Sinoussi, and N. Israel Positive Regulation of CXCR4 Expression and Signaling by Interleukin-7 in CD4+ Mature Thymocytes Correlates with Their Capacity To Favor Human Immunodeficiency X4 Virus Replication J. Virol., May 15, 2003; 77(10): 5784 - 5793. [Abstract] [Full Text] [PDF]

				A. Shen, M. C. Zink, J. L. Mankowski, K. Chadwick, J. B. Margolick, L. M. Carruth, M. Li, J. E. Clements, and R. F. Siliciano Resting CD4+ T Lymphocytes but Not Thymocytes Provide a Latent Viral Reservoir in a Simian Immunodeficiency Virus-Macaca nemestrina Model of Human Immunodeficiency Virus Type 1-Infected Patients on Highly Active Antiretroviral Therapy J. Virol., April 15, 2003; 77(8): 4938 - 4949. [Abstract] [Full Text] [PDF]

				C. Sugimoto, K. Tadakuma, I. Otani, T. Moritoyo, H. Akari, F. Ono, Y. Yoshikawa, T. Sata, S. Izumo, and K. Mori nef Gene Is Required for Robust Productive Infection by Simian Immunodeficiency Virus of T-Cell-Rich Paracortex in Lymph Nodes J. Virol., April 1, 2003; 77(7): 4169 - 4180. [Abstract] [Full Text] [PDF]

				C. L. Fuller, Y. K. Choi, B. A. Fallert, S. Capuano III, P. Rajakumar, M. Murphey-Corb, and T. A. Reinhart Restricted SIV Replication in Rhesus Macaque Lung Tissues During the Acute Phase of Infection Am. J. Pathol., September 1, 2002; 161(3): 969 - 978. [Abstract] [Full Text] [PDF]

				D. L. Sodora, J. M. Milush, F. Ware, A. Wozniakowski, L. Montgomery, H. M. McClure, A. A. Lackner, M. Marthas, V. Hirsch, R. P. Johnson, et al. Decreased Levels of Recent Thymic Emigrants in Peripheral Blood of Simian Immunodeficiency Virus-Infected Macaques Correlate with Alterations within the Thymus J. Virol., August 28, 2002; 76(19): 9981 - 9990. [Abstract] [Full Text] [PDF]

				C. E. Nesbit and S. A. Schwartz In Vitro and Animal Models of Human Immunodeficiency Virus Infection of the Central Nervous System Clin. Vaccine Immunol., May 1, 2002; 9(3): 515 - 524. [Full Text] [PDF]

				T. G. D'Aversa, K. M. Weidenheim, and J. W. Berman CD40-CD40L Interactions Induce Chemokine Expression by Human Microglia : Implications for Human Immunodeficiency Virus Encephalitis and Multiple Sclerosis Am. J. Pathol., February 1, 2002; 160(2): 559 - 567. [Abstract] [Full Text] [PDF]

				T. Igarashi, C. R. Brown, R. A. Byrum, Y. Nishimura, Y. Endo, R. J. Plishka, C. Buckler, A. Buckler-White, G. Miller, V. M. Hirsch, et al. Rapid and Irreversible CD4+ T-Cell Depletion Induced by the Highly Pathogenic Simian/Human Immunodeficiency Virus SHIVDH12R Is Systemic and Synchronous J. Virol., January 1, 2002; 76(1): 379 - 391. [Abstract] [Full Text] [PDF]

				M. C. G. Marcondes, E. M. E. Burudi, S. Huitron-Resendiz, M. Sanchez-Alavez, D. Watry, M. Zandonatti, S. J. Henriksen, and H. S. Fox Highly Activated CD8+ T Cells in the Brain Correlate with Early Central Nervous System Dysfunction in Simian Immunodeficiency Virus Infection J. Immunol., November 1, 2001; 167(9): 5429 - 5438. [Abstract] [Full Text] [PDF]

				K. C. Williams, S. Corey, S. V. Westmoreland, D. Pauley, H. Knight, C. deBakker, X. Alvarez, and A. A. Lackner Perivascular Macrophages Are the Primary Cell Type Productively Infected by Simian Immunodeficiency Virus in the Brains of Macaques: Implications for the Neuropathogenesis of AIDS J. Exp. Med., April 9, 2001; 193(8): 905 - 916. [Abstract] [Full Text] [PDF]

				M. Rosenzweig, M. Connole, A. Forand-Barabasz, M.-P. Tremblay, R. P. Johnson, and A. A. Lackner Mechanisms Associated with Thymocyte Apoptosis Induced by Simian Immunodeficiency Virus J. Immunol., September 15, 2000; 165(6): 3461 - 3468. [Abstract] [Full Text] [PDF]

				L. A. Obert and E. A. Hoover Relationship of Lymphoid Lesions to Disease Course in Mucosal Feline Immunodeficiency Virus Type C Infection Vet. Pathol., September 1, 2000; 37(5): 386 - 401. [Abstract] [Full Text] [PDF]

REGULAR ARTICLES

Early events in tissues during infection with pathogenic (SIVmac239) and nonpathogenic (SIVmac1A11) molecular clones of simian immunodeficiency virus

				F. Eitner, Y. Cui, G. Grouard-Vogel, K. L. Hudkins, A. Schmidt, T. Birkebak, M. B. Agy, S.-L. Hu, W. R. Morton, D. M. Anderson, et al. Rapid Shift from Virally Infected Cells to Germinal Center-Retained Virus after HIV-2 Infection of Macaques Am. J. Pathol., April 1, 2000; 156(4): 1197 - 1207. [Abstract] [Full Text] [PDF]

				S. V. Westmoreland, K. C. Williams, M. A. Simon, M. E. Bahn, A. E. Rullkoetter, M. W. Elliott, C. D. deBakker, H. L. Knight, and A. A. Lackner Neuropathogenesis of Simian Immunodeficiency Virus in Neonatal Rhesus Macaques Am. J. Pathol., October 1, 1999; 155(4): 1217 - 1228. [Abstract] [Full Text] [PDF]

				C. D. Katsetos, J. E. Fincke, A. Legido, H. W. Lischner, J.-P. de Chadarevian, E. M. Kaye, C. D. Platsoucas, and E. L. Oleszak Angiocentric CD3+ T-Cell Infiltrates in Human Immunodeficiency Virus Type 1-Associated Central Nervous System Disease in Children Clin. Vaccine Immunol., January 1, 1999; 6(1): 105 - 114. [Abstract] [Full Text] [PDF]

				T. F.�W. Horn, S. Huitron-Resendiz, M. R. Weed, S. J. Henriksen, and H. S. Fox Early physiological abnormalities after simian immunodeficiency virus infection PNAS, December 8, 1998; 95(25): 15072 - 15077. [Abstract] [Full Text] [PDF]

				J. J. Wykrzykowska, M. Rosenzweig, R. S. Veazey, M. A. Simon, K. Halvorsen, R. C. Desrosiers, R. P. Johnson, and A. A. Lackner Early Regeneration of Thymic Progenitors in Rhesus Macaques Infected with Simian Immunodeficiency Virus J. Exp. Med., June 1, 1998; 187(11): 1767 - 1778. [Abstract] [Full Text] [PDF]

				C. J. Miller, M. Marthas, J. Greenier, D. Lu, P. J. Dailey, and Y. Lu In Vivo Replication Capacity Rather Than In Vitro Macrophage Tropism Predicts Efficiency of Vaginal Transmission of Simian Immunodeficiency Virus or Simian/Human Immunodeficiency Virus in Rhesus Macaques J. Virol., April 1, 1998; 72(4): 3248 - 3258. [Abstract] [Full Text] [PDF]