Decreased pre-existing Ad5 capsid and Ad35 neutralizing antibodies increase HIV-1 infection risk in the Step trial independent of vaccination
The Step trial raised the possibility that uncircumcised men with pre-existing Ad5 neutralizing antibodies carried an increased risk of HIV infection after vaccination. Thus, understanding Ad seropositivity in humans is important to the development of an AIDS vaccine. Here, we analyze the impact of...
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| Veröffentlicht in: | PloS one 2012-04, Vol.7 (4), p.e33969-e33969 |
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| creator | Cheng, Cheng Wang, Lingshu Wang, LingShu Gall, Jason G D Nason, Martha Schwartz, Richard M McElrath, M Juliana DeRosa, Steven C Hural, John Corey, Lawrence Buchbinder, Susan P Nabel, Gary J |
| description | The Step trial raised the possibility that uncircumcised men with pre-existing Ad5 neutralizing antibodies carried an increased risk of HIV infection after vaccination. Thus, understanding Ad seropositivity in humans is important to the development of an AIDS vaccine. Here, we analyze the impact of different Ad5-specific neutralizing antibodies on immune function and clinical outcome.
Ad seropositivity in the Step trial volunteers was analyzed using chimeric rAd5/35 vectors to characterize their specificity for Ad5 fiber and non-fiber external (capsid) proteins. Immune responses and HIV seropositivity were correlated with the specificity of Ad5-neutralizing antibodies. Neutralizing antibodies induced by the vaccine in Ad5 seronegative subjects were directed preferentially to Ad5 capsid proteins, although some fiber-neutralizing antibodies could be detected. Pre-vaccination Ad5 serostatus did not affect the capsid-directed response after three vaccinations. In contrast, anti-fiber antibody titers were significantly higher in volunteers who were Ad5 seropositive prior to vaccination. Those Ad5 seropositive subjects who generated anti-capsid responses showed a marked reduction in vaccine-induced CD8 responses. Unexpectedly, anti-vector immunity differed qualitatively in Ad5 seropositive participants who became HIV-1 infected compared to uninfected case controls; Ad5 seropositive participants who later acquired HIV had lower neutralizing antibodies to capsid. Moreover, Ad35 seropositivity was decreased in HIV-infected subjects compared with uninfected case controls, while seroprevalence for other serotypes including Ad14, Ad28 and Ad41 was similar in both groups.
Together, these findings suggest that the case subjects were less immunologically responsive prior to infection. Subjects infected during the Step trial had qualitative differences in immunity that increased their risk of HIV-1 infection independent of vaccination. |
| doi_str_mv | 10.1371/journal.pone.0033969 |
| format | Article |
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Ad seropositivity in the Step trial volunteers was analyzed using chimeric rAd5/35 vectors to characterize their specificity for Ad5 fiber and non-fiber external (capsid) proteins. Immune responses and HIV seropositivity were correlated with the specificity of Ad5-neutralizing antibodies. Neutralizing antibodies induced by the vaccine in Ad5 seronegative subjects were directed preferentially to Ad5 capsid proteins, although some fiber-neutralizing antibodies could be detected. Pre-vaccination Ad5 serostatus did not affect the capsid-directed response after three vaccinations. In contrast, anti-fiber antibody titers were significantly higher in volunteers who were Ad5 seropositive prior to vaccination. Those Ad5 seropositive subjects who generated anti-capsid responses showed a marked reduction in vaccine-induced CD8 responses. Unexpectedly, anti-vector immunity differed qualitatively in Ad5 seropositive participants who became HIV-1 infected compared to uninfected case controls; Ad5 seropositive participants who later acquired HIV had lower neutralizing antibodies to capsid. Moreover, Ad35 seropositivity was decreased in HIV-infected subjects compared with uninfected case controls, while seroprevalence for other serotypes including Ad14, Ad28 and Ad41 was similar in both groups.
Together, these findings suggest that the case subjects were less immunologically responsive prior to infection. Subjects infected during the Step trial had qualitative differences in immunity that increased their risk of HIV-1 infection independent of vaccination.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0033969</identifier><identifier>PMID: 22496775</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Acquired immune deficiency syndrome ; Adenoviridae - genetics ; Adenoviridae - immunology ; Adenoviridae Infections - complications ; Adenoviridae Infections - immunology ; AIDS ; AIDS vaccines ; AIDS Vaccines - immunology ; Antibodies ; Antibodies, Neutralizing - blood ; Antibodies, Viral - immunology ; Antigens ; Biological activity ; Biology ; Cancer ; Capsid protein ; Capsid Proteins - genetics ; Capsid Proteins - immunology ; Capsids ; Case-Control Studies ; CD8 antigen ; Clinical trials ; Dietary fiber ; Enzyme-Linked Immunosorbent Assay ; Fibers ; Gene expression ; Gene therapy ; Genetic Vectors - genetics ; Genetic Vectors - immunology ; Health aspects ; Health risks ; HIV ; HIV infections ; HIV Infections - etiology ; HIV Seropositivity - immunology ; HIV-1 - genetics ; HIV-1 - immunology ; Human immunodeficiency virus ; Human immunodeficiency virus 1 ; Humans ; Immune response ; Immunity ; Immunity, Cellular - immunology ; Immunoglobulins ; Impact analysis ; Infection ; Infections ; Infectious diseases ; Male ; Medical research ; Medicine ; Neutralizing ; Proteins ; Risk ; Risk Factors ; Seroepidemiologic Studies ; Serotypes ; T-Lymphocytes - immunology ; Tumors ; Vaccination ; Vaccines ; Vectors (Biology) ; Viral proteins</subject><ispartof>PloS one, 2012-04, Vol.7 (4), p.e33969-e33969</ispartof><rights>COPYRIGHT 2012 Public Library of Science</rights><rights>2012. This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. 2012</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c791t-177f0df38aa259eb5873e269588b4ad8666a0cf74aba53b3a40fff1b1fb295f23</citedby><cites>FETCH-LOGICAL-c791t-177f0df38aa259eb5873e269588b4ad8666a0cf74aba53b3a40fff1b1fb295f23</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/PMC3319553/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3319553/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,315,728,781,785,865,886,2103,2929,23868,27926,27927,53793,53795</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22496775$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Kremer, Eric J.</contributor><creatorcontrib>Cheng, Cheng</creatorcontrib><creatorcontrib>Wang, Lingshu</creatorcontrib><creatorcontrib>Wang, LingShu</creatorcontrib><creatorcontrib>Gall, Jason G D</creatorcontrib><creatorcontrib>Nason, Martha</creatorcontrib><creatorcontrib>Schwartz, Richard M</creatorcontrib><creatorcontrib>McElrath, M Juliana</creatorcontrib><creatorcontrib>DeRosa, Steven C</creatorcontrib><creatorcontrib>Hural, John</creatorcontrib><creatorcontrib>Corey, Lawrence</creatorcontrib><creatorcontrib>Buchbinder, Susan P</creatorcontrib><creatorcontrib>Nabel, Gary J</creatorcontrib><title>Decreased pre-existing Ad5 capsid and Ad35 neutralizing antibodies increase HIV-1 infection risk in the Step trial independent of vaccination</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>The Step trial raised the possibility that uncircumcised men with pre-existing Ad5 neutralizing antibodies carried an increased risk of HIV infection after vaccination. Thus, understanding Ad seropositivity in humans is important to the development of an AIDS vaccine. Here, we analyze the impact of different Ad5-specific neutralizing antibodies on immune function and clinical outcome.
Ad seropositivity in the Step trial volunteers was analyzed using chimeric rAd5/35 vectors to characterize their specificity for Ad5 fiber and non-fiber external (capsid) proteins. Immune responses and HIV seropositivity were correlated with the specificity of Ad5-neutralizing antibodies. Neutralizing antibodies induced by the vaccine in Ad5 seronegative subjects were directed preferentially to Ad5 capsid proteins, although some fiber-neutralizing antibodies could be detected. Pre-vaccination Ad5 serostatus did not affect the capsid-directed response after three vaccinations. In contrast, anti-fiber antibody titers were significantly higher in volunteers who were Ad5 seropositive prior to vaccination. Those Ad5 seropositive subjects who generated anti-capsid responses showed a marked reduction in vaccine-induced CD8 responses. Unexpectedly, anti-vector immunity differed qualitatively in Ad5 seropositive participants who became HIV-1 infected compared to uninfected case controls; Ad5 seropositive participants who later acquired HIV had lower neutralizing antibodies to capsid. Moreover, Ad35 seropositivity was decreased in HIV-infected subjects compared with uninfected case controls, while seroprevalence for other serotypes including Ad14, Ad28 and Ad41 was similar in both groups.
Together, these findings suggest that the case subjects were less immunologically responsive prior to infection. Subjects infected during the Step trial had qualitative differences in immunity that increased their risk of HIV-1 infection independent of vaccination.</description><subject>Acquired immune deficiency syndrome</subject><subject>Adenoviridae - genetics</subject><subject>Adenoviridae - immunology</subject><subject>Adenoviridae Infections - complications</subject><subject>Adenoviridae Infections - immunology</subject><subject>AIDS</subject><subject>AIDS vaccines</subject><subject>AIDS Vaccines - immunology</subject><subject>Antibodies</subject><subject>Antibodies, Neutralizing - blood</subject><subject>Antibodies, Viral - immunology</subject><subject>Antigens</subject><subject>Biological activity</subject><subject>Biology</subject><subject>Cancer</subject><subject>Capsid protein</subject><subject>Capsid Proteins - genetics</subject><subject>Capsid Proteins - immunology</subject><subject>Capsids</subject><subject>Case-Control Studies</subject><subject>CD8 antigen</subject><subject>Clinical trials</subject><subject>Dietary fiber</subject><subject>Enzyme-Linked Immunosorbent Assay</subject><subject>Fibers</subject><subject>Gene expression</subject><subject>Gene therapy</subject><subject>Genetic Vectors - genetics</subject><subject>Genetic Vectors - immunology</subject><subject>Health aspects</subject><subject>Health risks</subject><subject>HIV</subject><subject>HIV infections</subject><subject>HIV Infections - etiology</subject><subject>HIV Seropositivity - immunology</subject><subject>HIV-1 - genetics</subject><subject>HIV-1 - immunology</subject><subject>Human immunodeficiency virus</subject><subject>Human immunodeficiency virus 1</subject><subject>Humans</subject><subject>Immune response</subject><subject>Immunity</subject><subject>Immunity, Cellular - immunology</subject><subject>Immunoglobulins</subject><subject>Impact analysis</subject><subject>Infection</subject><subject>Infections</subject><subject>Infectious diseases</subject><subject>Male</subject><subject>Medical research</subject><subject>Medicine</subject><subject>Neutralizing</subject><subject>Proteins</subject><subject>Risk</subject><subject>Risk Factors</subject><subject>Seroepidemiologic Studies</subject><subject>Serotypes</subject><subject>T-Lymphocytes - immunology</subject><subject>Tumors</subject><subject>Vaccination</subject><subject>Vaccines</subject><subject>Vectors (Biology)</subject><subject>Viral proteins</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNqNk9tu1DAQhiMEoqXwBggiISG42MWO7Ti-QarKoStVqkSht9bEh12XbJzaTlV4B94Zh91WXdSLKlKSmXzzZw6eoniJ0RwTjj9c-DH00M0H35s5QoSIWjwq9rEg1ayuEHl8532veBbjBUKMNHX9tNirKipqztl-8eeTUcFANLocgpmZaxeT65floWalgiE6XUKvs0lY2ZsxBejc7wmAPrnWa2di6fqNRHm8OJ_hbFqjkvN9GVz8mc0yrUx5lsxQpuCgyx5tBpNvfSq9La9AKdfDFPG8eGKhi-bF9nlQ_Pjy-fvR8ezk9Ovi6PBkprjAaYY5t0hb0gBUTJiWNZyYqhasaVoKOtdYA1KWU2iBkZYARdZa3GLbVoLZihwUrze6Q-ej3HYySkwoEpRVlGRisSG0hws5BLeG8Et6cPKfw4elhJCc6oxslUWMa6h4SykTXGhStdogpBqlKais9XH7t7FdG61y3bmNO6K7X3q3kkt_JQnBgrEpmXdbgeAvRxOTXLuoTNdBb_yY80aYizqzD0ERoqjGnGX0zX_o_Y3YUkvItebZ-pyimkTlIeUcU9FUTabm91D50mbtVD6h1mX_TsD7nYDMJHOdljDGKBdn3x7Onp7vsm_vsCsDXVpF343T6Yq7IN2AKvgYg7G388BITgt20w05LZjcLlgOe3V3lrdBNxtF_gJBJiFL</recordid><startdate>20120404</startdate><enddate>20120404</enddate><creator>Cheng, Cheng</creator><creator>Wang, Lingshu</creator><creator>Wang, LingShu</creator><creator>Gall, Jason G D</creator><creator>Nason, Martha</creator><creator>Schwartz, Richard M</creator><creator>McElrath, M Juliana</creator><creator>DeRosa, Steven C</creator><creator>Hural, John</creator><creator>Corey, Lawrence</creator><creator>Buchbinder, Susan P</creator><creator>Nabel, Gary J</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><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>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20120404</creationdate><title>Decreased pre-existing Ad5 capsid and Ad35 neutralizing antibodies increase HIV-1 infection risk in the Step trial independent of vaccination</title><author>Cheng, Cheng ; Wang, Lingshu ; Wang, LingShu ; Gall, Jason G D ; Nason, Martha ; Schwartz, Richard M ; McElrath, M Juliana ; DeRosa, Steven C ; Hural, John ; Corey, Lawrence ; Buchbinder, Susan P ; Nabel, Gary J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c791t-177f0df38aa259eb5873e269588b4ad8666a0cf74aba53b3a40fff1b1fb295f23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Acquired immune deficiency syndrome</topic><topic>Adenoviridae - genetics</topic><topic>Adenoviridae - immunology</topic><topic>Adenoviridae Infections - complications</topic><topic>Adenoviridae Infections - immunology</topic><topic>AIDS</topic><topic>AIDS vaccines</topic><topic>AIDS Vaccines - immunology</topic><topic>Antibodies</topic><topic>Antibodies, Neutralizing - blood</topic><topic>Antibodies, Viral - immunology</topic><topic>Antigens</topic><topic>Biological activity</topic><topic>Biology</topic><topic>Cancer</topic><topic>Capsid protein</topic><topic>Capsid Proteins - genetics</topic><topic>Capsid Proteins - immunology</topic><topic>Capsids</topic><topic>Case-Control Studies</topic><topic>CD8 antigen</topic><topic>Clinical trials</topic><topic>Dietary fiber</topic><topic>Enzyme-Linked Immunosorbent Assay</topic><topic>Fibers</topic><topic>Gene expression</topic><topic>Gene therapy</topic><topic>Genetic Vectors - genetics</topic><topic>Genetic Vectors - immunology</topic><topic>Health aspects</topic><topic>Health risks</topic><topic>HIV</topic><topic>HIV infections</topic><topic>HIV Infections - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Cheng, Cheng</au><au>Wang, Lingshu</au><au>Wang, LingShu</au><au>Gall, Jason G D</au><au>Nason, Martha</au><au>Schwartz, Richard M</au><au>McElrath, M Juliana</au><au>DeRosa, Steven C</au><au>Hural, John</au><au>Corey, Lawrence</au><au>Buchbinder, Susan P</au><au>Nabel, Gary J</au><au>Kremer, Eric J.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Decreased pre-existing Ad5 capsid and Ad35 neutralizing antibodies increase HIV-1 infection risk in the Step trial independent of vaccination</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2012-04-04</date><risdate>2012</risdate><volume>7</volume><issue>4</issue><spage>e33969</spage><epage>e33969</epage><pages>e33969-e33969</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>The Step trial raised the possibility that uncircumcised men with pre-existing Ad5 neutralizing antibodies carried an increased risk of HIV infection after vaccination. Thus, understanding Ad seropositivity in humans is important to the development of an AIDS vaccine. Here, we analyze the impact of different Ad5-specific neutralizing antibodies on immune function and clinical outcome.
Ad seropositivity in the Step trial volunteers was analyzed using chimeric rAd5/35 vectors to characterize their specificity for Ad5 fiber and non-fiber external (capsid) proteins. Immune responses and HIV seropositivity were correlated with the specificity of Ad5-neutralizing antibodies. Neutralizing antibodies induced by the vaccine in Ad5 seronegative subjects were directed preferentially to Ad5 capsid proteins, although some fiber-neutralizing antibodies could be detected. Pre-vaccination Ad5 serostatus did not affect the capsid-directed response after three vaccinations. In contrast, anti-fiber antibody titers were significantly higher in volunteers who were Ad5 seropositive prior to vaccination. Those Ad5 seropositive subjects who generated anti-capsid responses showed a marked reduction in vaccine-induced CD8 responses. Unexpectedly, anti-vector immunity differed qualitatively in Ad5 seropositive participants who became HIV-1 infected compared to uninfected case controls; Ad5 seropositive participants who later acquired HIV had lower neutralizing antibodies to capsid. Moreover, Ad35 seropositivity was decreased in HIV-infected subjects compared with uninfected case controls, while seroprevalence for other serotypes including Ad14, Ad28 and Ad41 was similar in both groups.
Together, these findings suggest that the case subjects were less immunologically responsive prior to infection. Subjects infected during the Step trial had qualitative differences in immunity that increased their risk of HIV-1 infection independent of vaccination.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>22496775</pmid><doi>10.1371/journal.pone.0033969</doi><tpages>e33969</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2012-04, Vol.7 (4), p.e33969-e33969 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1340945243 |
| source | MEDLINE; Directory of Open Access Journals; Public Library of Science; PubMed Central; Free Full-Text Journals in Chemistry; EZB Electronic Journals Library |
| subjects | Acquired immune deficiency syndrome Adenoviridae - genetics Adenoviridae - immunology Adenoviridae Infections - complications Adenoviridae Infections - immunology AIDS AIDS vaccines AIDS Vaccines - immunology Antibodies Antibodies, Neutralizing - blood Antibodies, Viral - immunology Antigens Biological activity Biology Cancer Capsid protein Capsid Proteins - genetics Capsid Proteins - immunology Capsids Case-Control Studies CD8 antigen Clinical trials Dietary fiber Enzyme-Linked Immunosorbent Assay Fibers Gene expression Gene therapy Genetic Vectors - genetics Genetic Vectors - immunology Health aspects Health risks HIV HIV infections HIV Infections - etiology HIV Seropositivity - immunology HIV-1 - genetics HIV-1 - immunology Human immunodeficiency virus Human immunodeficiency virus 1 Humans Immune response Immunity Immunity, Cellular - immunology Immunoglobulins Impact analysis Infection Infections Infectious diseases Male Medical research Medicine Neutralizing Proteins Risk Risk Factors Seroepidemiologic Studies Serotypes T-Lymphocytes - immunology Tumors Vaccination Vaccines Vectors (Biology) Viral proteins |
| title | Decreased pre-existing Ad5 capsid and Ad35 neutralizing antibodies increase HIV-1 infection risk in the Step trial independent of vaccination |
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