A Simian Human Immunodeficiency Virus with a Nonfunctional Vpu (ΔvpuSHIVKU-1bMC33) Isolated from a Macaque with NeuroAIDS Has Selected for Mutations in Env and Nef That Contributed to Its Pathogenic Phenotype
Previous studies have shown that passage of nonpathogenic SHIV-4 through a series of macaques results in the selection of variants of the virus that are capable of causing rapid subtotal loss of CD4+ T cells and AIDS within 6–8 months following inoculation into pig-tailed macaques. Using a pathogeni...
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Veröffentlicht in: | Virology (New York, N.Y.) N.Y.), 2001-03, Vol.282 (1), p.123-140 |
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creator | Singh, Dinesh K. McCormick, Coleen Pacyniak, Erik Lawrence, Kathi Dalton, Steven B. Pinson, Dave M. Sun, Francis Berman, Nancy E.J. Calvert, Meredith Gunderson, Robert S. Wong, Scott W. Stephens, Edward B. |
description | Previous studies have shown that passage of nonpathogenic SHIV-4 through a series of macaques results in the selection of variants of the virus that are capable of causing rapid subtotal loss of CD4+ T cells and AIDS within 6–8 months following inoculation into pig-tailed macaques. Using a pathogenic variant of SHIV-4 known as SHIVKU-1bMC33, we reported that a mutant of this virus with the majority of the vpu deleted was still capable of causing profound CD4+ T cell loss and neuroAIDS in pig-tailed macaques (McCormick-Davis et al., 2000, Virology 272, 112–116). In this study, we have analyzed the tissue-specific changes in the env and nef in one macaque that developed neuroAIDS (macaque 50 O) and in three macaques that developed only a moderate or no significant loss of CD4+ T cells and no neurological disease (macaques 50 Y, 20220, 20228) following inoculation with ΔvpuSHIVKU-1bMC33. Sequence analysis of the gp120 region of env isolated from lymphoid tissues (lymph node and spleen) of macaques 50 Y, 20220, and 20228 revealed no consensus amino acid substitutions. In contrast, analysis of the gp120 sequences isolated from lymphoid and CNS tissues (parietal cortex, basal ganglia, and pons) of macaque 50 O revealed numerous amino acid substitutions. The significance of the amino acid substitutions in gp120 was supported by neutralization assays which showed that the virus isolated from the lymph node of macaque 50 O was neutralization resistant compared to the parental SHIVKU-1bMC33. Analysis of changes in the nef gene from macaque 50 O revealed in-frame deletions in Nef that ranged from 4 to 13 amino acids in length, whereas the nef genes isolated from the other three macaques revealed no deletions or consensus amino acid substitutions. Inoculation of the virus isolated from the lymph node of the macaque which developed neuroAIDS, SHIV50OLNV, into four pig-tailed macaques resulted in a severe loss of the circulating CD4+ T cells within 2 weeks postinoculation, which was maintained for up to 20 weeks postinoculation, confirming that this virus had indeed become more pathogenic in pig-tailed macaques. Taken together, these observations suggest that ΔvpuSHIVKU-1bMC33 has a low pathogenic phenotype in macaques but that individual pig-tailed macaques can select for additional mutations within the Env and Nef which can compensate for the lack of an intact Vpu and ultimately increase its pathogenicity. |
doi_str_mv | 10.1006/viro.2000.0821 |
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Using a pathogenic variant of SHIV-4 known as SHIVKU-1bMC33, we reported that a mutant of this virus with the majority of the vpu deleted was still capable of causing profound CD4+ T cell loss and neuroAIDS in pig-tailed macaques (McCormick-Davis et al., 2000, Virology 272, 112–116). In this study, we have analyzed the tissue-specific changes in the env and nef in one macaque that developed neuroAIDS (macaque 50 O) and in three macaques that developed only a moderate or no significant loss of CD4+ T cells and no neurological disease (macaques 50 Y, 20220, 20228) following inoculation with ΔvpuSHIVKU-1bMC33. Sequence analysis of the gp120 region of env isolated from lymphoid tissues (lymph node and spleen) of macaques 50 Y, 20220, and 20228 revealed no consensus amino acid substitutions. In contrast, analysis of the gp120 sequences isolated from lymphoid and CNS tissues (parietal cortex, basal ganglia, and pons) of macaque 50 O revealed numerous amino acid substitutions. The significance of the amino acid substitutions in gp120 was supported by neutralization assays which showed that the virus isolated from the lymph node of macaque 50 O was neutralization resistant compared to the parental SHIVKU-1bMC33. Analysis of changes in the nef gene from macaque 50 O revealed in-frame deletions in Nef that ranged from 4 to 13 amino acids in length, whereas the nef genes isolated from the other three macaques revealed no deletions or consensus amino acid substitutions. Inoculation of the virus isolated from the lymph node of the macaque which developed neuroAIDS, SHIV50OLNV, into four pig-tailed macaques resulted in a severe loss of the circulating CD4+ T cells within 2 weeks postinoculation, which was maintained for up to 20 weeks postinoculation, confirming that this virus had indeed become more pathogenic in pig-tailed macaques. Taken together, these observations suggest that ΔvpuSHIVKU-1bMC33 has a low pathogenic phenotype in macaques but that individual pig-tailed macaques can select for additional mutations within the Env and Nef which can compensate for the lack of an intact Vpu and ultimately increase its pathogenicity.</description><identifier>ISSN: 0042-6822</identifier><identifier>EISSN: 1096-0341</identifier><identifier>DOI: 10.1006/viro.2000.0821</identifier><identifier>PMID: 11259196</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Acquired Immunodeficiency Syndrome - immunology ; Acquired Immunodeficiency Syndrome - virology ; Amino Acid Sequence ; Animals ; Basal Ganglia - virology ; Brain - virology ; CD4 antigen ; CD4 Lymphocyte Count ; Central Nervous System Infections - virology ; Consensus Sequence ; Disease Models, Animal ; env gene ; Gene Products, env - genetics ; Gene Products, nef - genetics ; HIV Envelope Protein gp120 - genetics ; HIV-1 - pathogenicity ; Human Immunodeficiency Virus Proteins ; Leukocytes, Mononuclear - virology ; Lymph Nodes - virology ; Macaca nemestrina ; Molecular Sequence Data ; nef gene ; nef Gene Products, Human Immunodeficiency Virus ; Reassortant Viruses - pathogenicity ; Simian Immunodeficiency Virus - genetics ; Simian Immunodeficiency Virus - pathogenicity ; Simian/human immunodeficiency virus 4 ; Spleen - virology ; Viral Regulatory and Accessory Proteins - genetics ; Viral Regulatory and Accessory Proteins - isolation & purification ; vpu gene</subject><ispartof>Virology (New York, N.Y.), 2001-03, Vol.282 (1), p.123-140</ispartof><rights>2001 Academic Press</rights><rights>Copyright 2001 Academic Press.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c411t-134e5f21a6807602a94784f9bf90e0ce16aa677edcc57a99aa345a548bcba9a13</citedby><cites>FETCH-LOGICAL-c411t-134e5f21a6807602a94784f9bf90e0ce16aa677edcc57a99aa345a548bcba9a13</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1006/viro.2000.0821$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/11259196$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Singh, Dinesh K.</creatorcontrib><creatorcontrib>McCormick, Coleen</creatorcontrib><creatorcontrib>Pacyniak, Erik</creatorcontrib><creatorcontrib>Lawrence, Kathi</creatorcontrib><creatorcontrib>Dalton, Steven B.</creatorcontrib><creatorcontrib>Pinson, Dave M.</creatorcontrib><creatorcontrib>Sun, Francis</creatorcontrib><creatorcontrib>Berman, Nancy E.J.</creatorcontrib><creatorcontrib>Calvert, Meredith</creatorcontrib><creatorcontrib>Gunderson, Robert S.</creatorcontrib><creatorcontrib>Wong, Scott W.</creatorcontrib><creatorcontrib>Stephens, Edward B.</creatorcontrib><title>A Simian Human Immunodeficiency Virus with a Nonfunctional Vpu (ΔvpuSHIVKU-1bMC33) Isolated from a Macaque with NeuroAIDS Has Selected for Mutations in Env and Nef That Contributed to Its Pathogenic Phenotype</title><title>Virology (New York, N.Y.)</title><addtitle>Virology</addtitle><description>Previous studies have shown that passage of nonpathogenic SHIV-4 through a series of macaques results in the selection of variants of the virus that are capable of causing rapid subtotal loss of CD4+ T cells and AIDS within 6–8 months following inoculation into pig-tailed macaques. Using a pathogenic variant of SHIV-4 known as SHIVKU-1bMC33, we reported that a mutant of this virus with the majority of the vpu deleted was still capable of causing profound CD4+ T cell loss and neuroAIDS in pig-tailed macaques (McCormick-Davis et al., 2000, Virology 272, 112–116). In this study, we have analyzed the tissue-specific changes in the env and nef in one macaque that developed neuroAIDS (macaque 50 O) and in three macaques that developed only a moderate or no significant loss of CD4+ T cells and no neurological disease (macaques 50 Y, 20220, 20228) following inoculation with ΔvpuSHIVKU-1bMC33. Sequence analysis of the gp120 region of env isolated from lymphoid tissues (lymph node and spleen) of macaques 50 Y, 20220, and 20228 revealed no consensus amino acid substitutions. In contrast, analysis of the gp120 sequences isolated from lymphoid and CNS tissues (parietal cortex, basal ganglia, and pons) of macaque 50 O revealed numerous amino acid substitutions. The significance of the amino acid substitutions in gp120 was supported by neutralization assays which showed that the virus isolated from the lymph node of macaque 50 O was neutralization resistant compared to the parental SHIVKU-1bMC33. Analysis of changes in the nef gene from macaque 50 O revealed in-frame deletions in Nef that ranged from 4 to 13 amino acids in length, whereas the nef genes isolated from the other three macaques revealed no deletions or consensus amino acid substitutions. Inoculation of the virus isolated from the lymph node of the macaque which developed neuroAIDS, SHIV50OLNV, into four pig-tailed macaques resulted in a severe loss of the circulating CD4+ T cells within 2 weeks postinoculation, which was maintained for up to 20 weeks postinoculation, confirming that this virus had indeed become more pathogenic in pig-tailed macaques. Taken together, these observations suggest that ΔvpuSHIVKU-1bMC33 has a low pathogenic phenotype in macaques but that individual pig-tailed macaques can select for additional mutations within the Env and Nef which can compensate for the lack of an intact Vpu and ultimately increase its pathogenicity.</description><subject>Acquired Immunodeficiency Syndrome - immunology</subject><subject>Acquired Immunodeficiency Syndrome - virology</subject><subject>Amino Acid Sequence</subject><subject>Animals</subject><subject>Basal Ganglia - virology</subject><subject>Brain - virology</subject><subject>CD4 antigen</subject><subject>CD4 Lymphocyte Count</subject><subject>Central Nervous System Infections - virology</subject><subject>Consensus Sequence</subject><subject>Disease Models, Animal</subject><subject>env gene</subject><subject>Gene Products, env - genetics</subject><subject>Gene Products, nef - genetics</subject><subject>HIV Envelope Protein gp120 - genetics</subject><subject>HIV-1 - pathogenicity</subject><subject>Human Immunodeficiency Virus Proteins</subject><subject>Leukocytes, Mononuclear - virology</subject><subject>Lymph Nodes - virology</subject><subject>Macaca nemestrina</subject><subject>Molecular Sequence Data</subject><subject>nef gene</subject><subject>nef Gene Products, Human Immunodeficiency Virus</subject><subject>Reassortant Viruses - pathogenicity</subject><subject>Simian Immunodeficiency Virus - genetics</subject><subject>Simian Immunodeficiency Virus - pathogenicity</subject><subject>Simian/human immunodeficiency virus 4</subject><subject>Spleen - virology</subject><subject>Viral Regulatory and Accessory Proteins - genetics</subject><subject>Viral Regulatory and Accessory Proteins - isolation & purification</subject><subject>vpu gene</subject><issn>0042-6822</issn><issn>1096-0341</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2001</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkcuO0zAUQCMEYsrAliXyCsEixc7by6oMNGI6jNSZbqMb54YaJXbHj6L-B9-FxB_hTCuxQmzszbnH8j1R9JrROaO0-HCQRs8TSumcVgl7Es0Y5UVM04w9jWaUZklcVElyEb2w9nugsrKkz6MLxpKcM17Mot8LspGjBEVWfgxnPY5e6Q57KSQqcSRbabwlP6TbESA3WvVeCSe1goFs9568-_XzsPebVb39ch-zdr1M0_ektnoAhx3pjR7D2BoEPHg8WW7QG72oP27ICizZ4IDiEdWGrL2DyW2JVORKHQioLvA9uduBI0utnJGtn2inSe0suQW3099QSUFud6i0O-7xZfSsh8Hiq_N9Gd1_urpbruLrr5_r5eI6FhljLmZphnmfMCgqWhY0AZ6VVdbztucUqUBWABRliZ0QeQmcA6RZDnlWtaIFDiy9jN6evHujw-esa0ZpBQ4DKNTeNmXBeZInyX9BFt7Ny6IM4PwECqOtNdg3eyNHMMeG0Waq3Uy1m6l2M9UOA2_OZt-O2P3Fz3kDUJ0ADIs4SDSNfcyKnTRh7U2n5b_cfwCyK7th</recordid><startdate>20010330</startdate><enddate>20010330</enddate><creator>Singh, Dinesh K.</creator><creator>McCormick, Coleen</creator><creator>Pacyniak, Erik</creator><creator>Lawrence, Kathi</creator><creator>Dalton, Steven B.</creator><creator>Pinson, Dave M.</creator><creator>Sun, Francis</creator><creator>Berman, Nancy E.J.</creator><creator>Calvert, Meredith</creator><creator>Gunderson, Robert S.</creator><creator>Wong, Scott W.</creator><creator>Stephens, Edward B.</creator><general>Elsevier Inc</general><scope>6I.</scope><scope>AAFTH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7U9</scope><scope>H94</scope><scope>7X8</scope></search><sort><creationdate>20010330</creationdate><title>A Simian Human Immunodeficiency Virus with a Nonfunctional Vpu (ΔvpuSHIVKU-1bMC33) Isolated from a Macaque with NeuroAIDS Has Selected for Mutations in Env and Nef That Contributed to Its Pathogenic Phenotype</title><author>Singh, Dinesh K. ; McCormick, Coleen ; Pacyniak, Erik ; Lawrence, Kathi ; Dalton, Steven B. ; Pinson, Dave M. ; Sun, Francis ; Berman, Nancy E.J. ; Calvert, Meredith ; Gunderson, Robert S. ; Wong, Scott W. ; Stephens, Edward B.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c411t-134e5f21a6807602a94784f9bf90e0ce16aa677edcc57a99aa345a548bcba9a13</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2001</creationdate><topic>Acquired Immunodeficiency Syndrome - immunology</topic><topic>Acquired Immunodeficiency Syndrome - virology</topic><topic>Amino Acid Sequence</topic><topic>Animals</topic><topic>Basal Ganglia - virology</topic><topic>Brain - virology</topic><topic>CD4 antigen</topic><topic>CD4 Lymphocyte Count</topic><topic>Central Nervous System Infections - virology</topic><topic>Consensus Sequence</topic><topic>Disease Models, Animal</topic><topic>env gene</topic><topic>Gene Products, env - genetics</topic><topic>Gene Products, nef - genetics</topic><topic>HIV Envelope Protein gp120 - genetics</topic><topic>HIV-1 - pathogenicity</topic><topic>Human Immunodeficiency Virus Proteins</topic><topic>Leukocytes, Mononuclear - virology</topic><topic>Lymph Nodes - virology</topic><topic>Macaca nemestrina</topic><topic>Molecular Sequence Data</topic><topic>nef gene</topic><topic>nef Gene Products, Human Immunodeficiency Virus</topic><topic>Reassortant Viruses - pathogenicity</topic><topic>Simian Immunodeficiency Virus - genetics</topic><topic>Simian Immunodeficiency Virus - pathogenicity</topic><topic>Simian/human immunodeficiency virus 4</topic><topic>Spleen - virology</topic><topic>Viral Regulatory and Accessory Proteins - genetics</topic><topic>Viral Regulatory and Accessory Proteins - isolation & purification</topic><topic>vpu gene</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Singh, Dinesh K.</creatorcontrib><creatorcontrib>McCormick, Coleen</creatorcontrib><creatorcontrib>Pacyniak, Erik</creatorcontrib><creatorcontrib>Lawrence, Kathi</creatorcontrib><creatorcontrib>Dalton, Steven B.</creatorcontrib><creatorcontrib>Pinson, Dave M.</creatorcontrib><creatorcontrib>Sun, Francis</creatorcontrib><creatorcontrib>Berman, Nancy E.J.</creatorcontrib><creatorcontrib>Calvert, Meredith</creatorcontrib><creatorcontrib>Gunderson, Robert S.</creatorcontrib><creatorcontrib>Wong, Scott W.</creatorcontrib><creatorcontrib>Stephens, Edward B.</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Virology and AIDS Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Virology (New York, N.Y.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Singh, Dinesh K.</au><au>McCormick, Coleen</au><au>Pacyniak, Erik</au><au>Lawrence, Kathi</au><au>Dalton, Steven B.</au><au>Pinson, Dave M.</au><au>Sun, Francis</au><au>Berman, Nancy E.J.</au><au>Calvert, Meredith</au><au>Gunderson, Robert S.</au><au>Wong, Scott W.</au><au>Stephens, Edward B.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A Simian Human Immunodeficiency Virus with a Nonfunctional Vpu (ΔvpuSHIVKU-1bMC33) Isolated from a Macaque with NeuroAIDS Has Selected for Mutations in Env and Nef That Contributed to Its Pathogenic Phenotype</atitle><jtitle>Virology (New York, N.Y.)</jtitle><addtitle>Virology</addtitle><date>2001-03-30</date><risdate>2001</risdate><volume>282</volume><issue>1</issue><spage>123</spage><epage>140</epage><pages>123-140</pages><issn>0042-6822</issn><eissn>1096-0341</eissn><abstract>Previous studies have shown that passage of nonpathogenic SHIV-4 through a series of macaques results in the selection of variants of the virus that are capable of causing rapid subtotal loss of CD4+ T cells and AIDS within 6–8 months following inoculation into pig-tailed macaques. Using a pathogenic variant of SHIV-4 known as SHIVKU-1bMC33, we reported that a mutant of this virus with the majority of the vpu deleted was still capable of causing profound CD4+ T cell loss and neuroAIDS in pig-tailed macaques (McCormick-Davis et al., 2000, Virology 272, 112–116). In this study, we have analyzed the tissue-specific changes in the env and nef in one macaque that developed neuroAIDS (macaque 50 O) and in three macaques that developed only a moderate or no significant loss of CD4+ T cells and no neurological disease (macaques 50 Y, 20220, 20228) following inoculation with ΔvpuSHIVKU-1bMC33. Sequence analysis of the gp120 region of env isolated from lymphoid tissues (lymph node and spleen) of macaques 50 Y, 20220, and 20228 revealed no consensus amino acid substitutions. In contrast, analysis of the gp120 sequences isolated from lymphoid and CNS tissues (parietal cortex, basal ganglia, and pons) of macaque 50 O revealed numerous amino acid substitutions. The significance of the amino acid substitutions in gp120 was supported by neutralization assays which showed that the virus isolated from the lymph node of macaque 50 O was neutralization resistant compared to the parental SHIVKU-1bMC33. Analysis of changes in the nef gene from macaque 50 O revealed in-frame deletions in Nef that ranged from 4 to 13 amino acids in length, whereas the nef genes isolated from the other three macaques revealed no deletions or consensus amino acid substitutions. Inoculation of the virus isolated from the lymph node of the macaque which developed neuroAIDS, SHIV50OLNV, into four pig-tailed macaques resulted in a severe loss of the circulating CD4+ T cells within 2 weeks postinoculation, which was maintained for up to 20 weeks postinoculation, confirming that this virus had indeed become more pathogenic in pig-tailed macaques. Taken together, these observations suggest that ΔvpuSHIVKU-1bMC33 has a low pathogenic phenotype in macaques but that individual pig-tailed macaques can select for additional mutations within the Env and Nef which can compensate for the lack of an intact Vpu and ultimately increase its pathogenicity.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>11259196</pmid><doi>10.1006/viro.2000.0821</doi><tpages>18</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Acquired Immunodeficiency Syndrome - immunology Acquired Immunodeficiency Syndrome - virology Amino Acid Sequence Animals Basal Ganglia - virology Brain - virology CD4 antigen CD4 Lymphocyte Count Central Nervous System Infections - virology Consensus Sequence Disease Models, Animal env gene Gene Products, env - genetics Gene Products, nef - genetics HIV Envelope Protein gp120 - genetics HIV-1 - pathogenicity Human Immunodeficiency Virus Proteins Leukocytes, Mononuclear - virology Lymph Nodes - virology Macaca nemestrina Molecular Sequence Data nef gene nef Gene Products, Human Immunodeficiency Virus Reassortant Viruses - pathogenicity Simian Immunodeficiency Virus - genetics Simian Immunodeficiency Virus - pathogenicity Simian/human immunodeficiency virus 4 Spleen - virology Viral Regulatory and Accessory Proteins - genetics Viral Regulatory and Accessory Proteins - isolation & purification vpu gene |
title | A Simian Human Immunodeficiency Virus with a Nonfunctional Vpu (ΔvpuSHIVKU-1bMC33) Isolated from a Macaque with NeuroAIDS Has Selected for Mutations in Env and Nef That Contributed to Its Pathogenic Phenotype |
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