R5 clade C SHIV strains with tier 1 or 2 neutralization sensitivity: tools to dissect env evolution and to develop AIDS vaccines in primate models
HIV-1 clade C (HIV-C) predominates worldwide, and anti-HIV-C vaccines are urgently needed. Neutralizing antibody (nAb) responses are considered important but have proved difficult to elicit. Although some current immunogens elicit antibodies that neutralize highly neutralization-sensitive (tier 1) H...
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| Veröffentlicht in: | PloS one 2010-07, Vol.5 (7), p.e11689 |
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| creator | Siddappa, Nagadenahalli B Watkins, Jennifer D Wassermann, Klemens J Song, Ruijiang Wang, Wendy Kramer, Victor G Lakhashe, Samir Santosuosso, Michael Poznansky, Mark C Novembre, Francis J Villinger, François Else, James G Montefiori, David C Rasmussen, Robert A Ruprecht, Ruth M |
| description | HIV-1 clade C (HIV-C) predominates worldwide, and anti-HIV-C vaccines are urgently needed. Neutralizing antibody (nAb) responses are considered important but have proved difficult to elicit. Although some current immunogens elicit antibodies that neutralize highly neutralization-sensitive (tier 1) HIV strains, most circulating HIVs exhibiting a less sensitive (tier 2) phenotype are not neutralized. Thus, both tier 1 and 2 viruses are needed for vaccine discovery in nonhuman primate models.
We constructed a tier 1 simian-human immunodeficiency virus, SHIV-1157ipEL, by inserting an "early," recently transmitted HIV-C env into the SHIV-1157ipd3N4 backbone [1] encoding a "late" form of the same env, which had evolved in a SHIV-infected rhesus monkey (RM) with AIDS. SHIV-1157ipEL was rapidly passaged to yield SHIV-1157ipEL-p, which remained exclusively R5-tropic and had a tier 1 phenotype, in contrast to "late" SHIV-1157ipd3N4 (tier 2). After 5 weekly low-dose intrarectal exposures, SHIV-1157ipEL-p systemically infected 16 out of 17 RM with high peak viral RNA loads and depleted gut CD4+ T cells. SHIV-1157ipEL-p and SHIV-1157ipd3N4 env genes diverge mostly in V1/V2. Molecular modeling revealed a possible mechanism for the increased neutralization resistance of SHIV-1157ipd3N4 Env: V2 loops hindering access to the CD4 binding site, shown experimentally with nAb b12. Similar mutations have been linked to decreased neutralization sensitivity in HIV-C strains isolated from humans over time, indicating parallel HIV-C Env evolution in humans and RM.
SHIV-1157ipEL-p, the first tier 1 R5 clade C SHIV, and SHIV-1157ipd3N4, its tier 2 counterpart, represent biologically relevant tools for anti-HIV-C vaccine development in primates. |
| doi_str_mv | 10.1371/journal.pone.0011689 |
| format | Article |
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We constructed a tier 1 simian-human immunodeficiency virus, SHIV-1157ipEL, by inserting an "early," recently transmitted HIV-C env into the SHIV-1157ipd3N4 backbone [1] encoding a "late" form of the same env, which had evolved in a SHIV-infected rhesus monkey (RM) with AIDS. SHIV-1157ipEL was rapidly passaged to yield SHIV-1157ipEL-p, which remained exclusively R5-tropic and had a tier 1 phenotype, in contrast to "late" SHIV-1157ipd3N4 (tier 2). After 5 weekly low-dose intrarectal exposures, SHIV-1157ipEL-p systemically infected 16 out of 17 RM with high peak viral RNA loads and depleted gut CD4+ T cells. SHIV-1157ipEL-p and SHIV-1157ipd3N4 env genes diverge mostly in V1/V2. Molecular modeling revealed a possible mechanism for the increased neutralization resistance of SHIV-1157ipd3N4 Env: V2 loops hindering access to the CD4 binding site, shown experimentally with nAb b12. Similar mutations have been linked to decreased neutralization sensitivity in HIV-C strains isolated from humans over time, indicating parallel HIV-C Env evolution in humans and RM.
SHIV-1157ipEL-p, the first tier 1 R5 clade C SHIV, and SHIV-1157ipd3N4, its tier 2 counterpart, represent biologically relevant tools for anti-HIV-C vaccine development in primates.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0011689</identifier><identifier>PMID: 20657739</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Acquired immune deficiency syndrome ; AIDS ; AIDS vaccines ; AIDS Vaccines - genetics ; AIDS Vaccines - immunology ; Animal behavior ; Animals ; Antibodies ; Antibodies, Neutralizing - immunology ; Binding sites ; CD4 antigen ; Disease Models, Animal ; Evolution ; Evolution, Molecular ; Genes, env - genetics ; HIV ; HIV-1 - genetics ; HIV-1 - immunology ; HIV-1 - pathogenicity ; Human immunodeficiency virus ; Human immunodeficiency virus 1 ; Infectious Diseases ; Infectious Diseases/HIV Infection and AIDS ; Lymphocytes ; Lymphocytes T ; Macaca mulatta ; Molecular modelling ; Molecular Sequence Data ; Monkeys & apes ; Mutagenesis, Site-Directed ; Mutation ; Neutralization ; Polymerase Chain Reaction ; Primates ; Ribonucleic acid ; RNA ; Sensitivity ; Simian/human immunodeficiency virus ; Strains (organisms) ; T cells ; Vaccine development ; Vaccines ; Virology ; Virology/Animal Models of Infection ; Virology/Immunodeficiency Viruses ; Virology/Vaccines ; Viruses</subject><ispartof>PloS one, 2010-07, Vol.5 (7), p.e11689</ispartof><rights>COPYRIGHT 2010 Public Library of Science</rights><rights>2010 Siddappa et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>Siddappa et al. 2010</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c723t-96cb3859e2635e8c4e267c0ca3dda7b5fbba34d1c599123441f80383e023b2bb3</citedby><cites>FETCH-LOGICAL-c723t-96cb3859e2635e8c4e267c0ca3dda7b5fbba34d1c599123441f80383e023b2bb3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2908149/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2908149/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79343,79344</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20657739$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Siddappa, Nagadenahalli B</creatorcontrib><creatorcontrib>Watkins, Jennifer D</creatorcontrib><creatorcontrib>Wassermann, Klemens J</creatorcontrib><creatorcontrib>Song, Ruijiang</creatorcontrib><creatorcontrib>Wang, Wendy</creatorcontrib><creatorcontrib>Kramer, Victor G</creatorcontrib><creatorcontrib>Lakhashe, Samir</creatorcontrib><creatorcontrib>Santosuosso, Michael</creatorcontrib><creatorcontrib>Poznansky, Mark C</creatorcontrib><creatorcontrib>Novembre, Francis J</creatorcontrib><creatorcontrib>Villinger, François</creatorcontrib><creatorcontrib>Else, James G</creatorcontrib><creatorcontrib>Montefiori, David C</creatorcontrib><creatorcontrib>Rasmussen, Robert A</creatorcontrib><creatorcontrib>Ruprecht, Ruth M</creatorcontrib><title>R5 clade C SHIV strains with tier 1 or 2 neutralization sensitivity: tools to dissect env evolution and to develop AIDS vaccines in primate models</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>HIV-1 clade C (HIV-C) predominates worldwide, and anti-HIV-C vaccines are urgently needed. Neutralizing antibody (nAb) responses are considered important but have proved difficult to elicit. Although some current immunogens elicit antibodies that neutralize highly neutralization-sensitive (tier 1) HIV strains, most circulating HIVs exhibiting a less sensitive (tier 2) phenotype are not neutralized. Thus, both tier 1 and 2 viruses are needed for vaccine discovery in nonhuman primate models.
We constructed a tier 1 simian-human immunodeficiency virus, SHIV-1157ipEL, by inserting an "early," recently transmitted HIV-C env into the SHIV-1157ipd3N4 backbone [1] encoding a "late" form of the same env, which had evolved in a SHIV-infected rhesus monkey (RM) with AIDS. SHIV-1157ipEL was rapidly passaged to yield SHIV-1157ipEL-p, which remained exclusively R5-tropic and had a tier 1 phenotype, in contrast to "late" SHIV-1157ipd3N4 (tier 2). After 5 weekly low-dose intrarectal exposures, SHIV-1157ipEL-p systemically infected 16 out of 17 RM with high peak viral RNA loads and depleted gut CD4+ T cells. SHIV-1157ipEL-p and SHIV-1157ipd3N4 env genes diverge mostly in V1/V2. Molecular modeling revealed a possible mechanism for the increased neutralization resistance of SHIV-1157ipd3N4 Env: V2 loops hindering access to the CD4 binding site, shown experimentally with nAb b12. Similar mutations have been linked to decreased neutralization sensitivity in HIV-C strains isolated from humans over time, indicating parallel HIV-C Env evolution in humans and RM.
SHIV-1157ipEL-p, the first tier 1 R5 clade C SHIV, and SHIV-1157ipd3N4, its tier 2 counterpart, represent biologically relevant tools for anti-HIV-C vaccine development in primates.</description><subject>Acquired immune deficiency syndrome</subject><subject>AIDS</subject><subject>AIDS vaccines</subject><subject>AIDS Vaccines - genetics</subject><subject>AIDS Vaccines - immunology</subject><subject>Animal behavior</subject><subject>Animals</subject><subject>Antibodies</subject><subject>Antibodies, Neutralizing - immunology</subject><subject>Binding sites</subject><subject>CD4 antigen</subject><subject>Disease Models, Animal</subject><subject>Evolution</subject><subject>Evolution, Molecular</subject><subject>Genes, env - genetics</subject><subject>HIV</subject><subject>HIV-1 - genetics</subject><subject>HIV-1 - immunology</subject><subject>HIV-1 - pathogenicity</subject><subject>Human immunodeficiency virus</subject><subject>Human immunodeficiency virus 1</subject><subject>Infectious Diseases</subject><subject>Infectious Diseases/HIV Infection and AIDS</subject><subject>Lymphocytes</subject><subject>Lymphocytes T</subject><subject>Macaca mulatta</subject><subject>Molecular modelling</subject><subject>Molecular Sequence Data</subject><subject>Monkeys & apes</subject><subject>Mutagenesis, Site-Directed</subject><subject>Mutation</subject><subject>Neutralization</subject><subject>Polymerase Chain Reaction</subject><subject>Primates</subject><subject>Ribonucleic acid</subject><subject>RNA</subject><subject>Sensitivity</subject><subject>Simian/human immunodeficiency virus</subject><subject>Strains (organisms)</subject><subject>T cells</subject><subject>Vaccine development</subject><subject>Vaccines</subject><subject>Virology</subject><subject>Virology/Animal Models of Infection</subject><subject>Virology/Immunodeficiency 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Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Siddappa, Nagadenahalli B</au><au>Watkins, Jennifer D</au><au>Wassermann, Klemens J</au><au>Song, Ruijiang</au><au>Wang, Wendy</au><au>Kramer, Victor G</au><au>Lakhashe, Samir</au><au>Santosuosso, Michael</au><au>Poznansky, Mark C</au><au>Novembre, Francis J</au><au>Villinger, François</au><au>Else, James G</au><au>Montefiori, David C</au><au>Rasmussen, Robert A</au><au>Ruprecht, Ruth M</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>R5 clade C SHIV strains with tier 1 or 2 neutralization sensitivity: tools to dissect env evolution and to develop AIDS vaccines in primate models</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2010-07-21</date><risdate>2010</risdate><volume>5</volume><issue>7</issue><spage>e11689</spage><pages>e11689-</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>HIV-1 clade C (HIV-C) predominates worldwide, and anti-HIV-C vaccines are urgently needed. Neutralizing antibody (nAb) responses are considered important but have proved difficult to elicit. Although some current immunogens elicit antibodies that neutralize highly neutralization-sensitive (tier 1) HIV strains, most circulating HIVs exhibiting a less sensitive (tier 2) phenotype are not neutralized. Thus, both tier 1 and 2 viruses are needed for vaccine discovery in nonhuman primate models.
We constructed a tier 1 simian-human immunodeficiency virus, SHIV-1157ipEL, by inserting an "early," recently transmitted HIV-C env into the SHIV-1157ipd3N4 backbone [1] encoding a "late" form of the same env, which had evolved in a SHIV-infected rhesus monkey (RM) with AIDS. SHIV-1157ipEL was rapidly passaged to yield SHIV-1157ipEL-p, which remained exclusively R5-tropic and had a tier 1 phenotype, in contrast to "late" SHIV-1157ipd3N4 (tier 2). After 5 weekly low-dose intrarectal exposures, SHIV-1157ipEL-p systemically infected 16 out of 17 RM with high peak viral RNA loads and depleted gut CD4+ T cells. SHIV-1157ipEL-p and SHIV-1157ipd3N4 env genes diverge mostly in V1/V2. Molecular modeling revealed a possible mechanism for the increased neutralization resistance of SHIV-1157ipd3N4 Env: V2 loops hindering access to the CD4 binding site, shown experimentally with nAb b12. Similar mutations have been linked to decreased neutralization sensitivity in HIV-C strains isolated from humans over time, indicating parallel HIV-C Env evolution in humans and RM.
SHIV-1157ipEL-p, the first tier 1 R5 clade C SHIV, and SHIV-1157ipd3N4, its tier 2 counterpart, represent biologically relevant tools for anti-HIV-C vaccine development in primates.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>20657739</pmid><doi>10.1371/journal.pone.0011689</doi><tpages>e11689</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2010-07, Vol.5 (7), p.e11689 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1292468734 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Free Full-Text Journals in Chemistry; Public Library of Science (PLoS) |
| subjects | Acquired immune deficiency syndrome AIDS AIDS vaccines AIDS Vaccines - genetics AIDS Vaccines - immunology Animal behavior Animals Antibodies Antibodies, Neutralizing - immunology Binding sites CD4 antigen Disease Models, Animal Evolution Evolution, Molecular Genes, env - genetics HIV HIV-1 - genetics HIV-1 - immunology HIV-1 - pathogenicity Human immunodeficiency virus Human immunodeficiency virus 1 Infectious Diseases Infectious Diseases/HIV Infection and AIDS Lymphocytes Lymphocytes T Macaca mulatta Molecular modelling Molecular Sequence Data Monkeys & apes Mutagenesis, Site-Directed Mutation Neutralization Polymerase Chain Reaction Primates Ribonucleic acid RNA Sensitivity Simian/human immunodeficiency virus Strains (organisms) T cells Vaccine development Vaccines Virology Virology/Animal Models of Infection Virology/Immunodeficiency Viruses Virology/Vaccines Viruses |
| title | R5 clade C SHIV strains with tier 1 or 2 neutralization sensitivity: tools to dissect env evolution and to develop AIDS vaccines in primate models |
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