Bioinformatic analysis of neurotropic HIV envelope sequences identifies polymorphisms in the gp120 bridging sheet that increase macrophage-tropism through enhanced interactions with CCR5
Abstract Macrophages express low levels of the CD4 receptor compared to T-cells. Macrophage-tropic HIV strains replicating in brain of untreated patients with HIV-associated dementia (HAD) express Envs that are adapted to overcome this restriction through mechanisms that are poorly understood. Here,...
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| Veröffentlicht in: | Virology (New York, N.Y.) N.Y.), 2015-07, Vol.481, p.210-222 |
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| creator | Mefford, Megan E Kunstman, Kevin Wolinsky, Steven M Gabuzda, Dana |
| description | Abstract Macrophages express low levels of the CD4 receptor compared to T-cells. Macrophage-tropic HIV strains replicating in brain of untreated patients with HIV-associated dementia (HAD) express Envs that are adapted to overcome this restriction through mechanisms that are poorly understood. Here, bioinformatic analysis of env sequence datasets together with functional studies identified polymorphisms in the β3 strand of the HIV gp120 bridging sheet that increase M-tropism. D197, which results in loss of an N-glycan located near the HIV Env trimer apex, was detected in brain in some HAD patients, while position 200 was estimated to be under positive selection. D197 and T/V200 increased fusion and infection of cells expressing low CD4 by enhancing gp120 binding to CCR5. These results identify polymorphisms in the HIV gp120 bridging sheet that overcome the restriction to macrophage infection imposed by low CD4 through enhanced gp120–CCR5 interactions, thereby promoting infection of brain and other macrophage-rich tissues. |
| doi_str_mv | 10.1016/j.virol.2015.01.032 |
| format | Article |
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Macrophage-tropic HIV strains replicating in brain of untreated patients with HIV-associated dementia (HAD) express Envs that are adapted to overcome this restriction through mechanisms that are poorly understood. Here, bioinformatic analysis of env sequence datasets together with functional studies identified polymorphisms in the β3 strand of the HIV gp120 bridging sheet that increase M-tropism. D197, which results in loss of an N-glycan located near the HIV Env trimer apex, was detected in brain in some HAD patients, while position 200 was estimated to be under positive selection. D197 and T/V200 increased fusion and infection of cells expressing low CD4 by enhancing gp120 binding to CCR5. These results identify polymorphisms in the HIV gp120 bridging sheet that overcome the restriction to macrophage infection imposed by low CD4 through enhanced gp120–CCR5 interactions, thereby promoting infection of brain and other macrophage-rich tissues.</description><identifier>ISSN: 0042-6822</identifier><identifier>EISSN: 1096-0341</identifier><identifier>DOI: 10.1016/j.virol.2015.01.032</identifier><identifier>PMID: 25797607</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>60 APPLIED LIFE SCIENCES ; AIDS VIRUS ; Amino Acid Sequence ; AMINO ACIDS ; ANIMAL TISSUES ; BRAIN ; Brain - metabolism ; Brain - virology ; BRIDGES ; Bridging sheet ; CCR5 ; CD4 ; COMPARATIVE EVALUATIONS ; Computational Biology ; DATASETS ; Envelope ; HIV ; HIV Envelope Protein gp120 - chemistry ; HIV Envelope Protein gp120 - genetics ; HIV Envelope Protein gp120 - metabolism ; HIV Infections - genetics ; HIV Infections - metabolism ; HIV Infections - virology ; HIV-1 - chemistry ; HIV-1 - genetics ; HIV-1 - physiology ; Humans ; Infectious Disease ; INTERACTIONS ; Macrophage ; MACROPHAGES ; Macrophages - metabolism ; Macrophages - virology ; Molecular Sequence Data ; NERVOUS SYSTEM DISEASES ; PATIENTS ; Polymorphism, Single Nucleotide ; Protein Binding ; Protein Structure, Secondary ; RECEPTORS ; Receptors, CCR5 - genetics ; Receptors, CCR5 - metabolism ; Sequence Alignment ; STRAINS ; Tropism ; V1/V2 stem ; Viral Tropism</subject><ispartof>Virology (New York, N.Y.), 2015-07, Vol.481, p.210-222</ispartof><rights>Elsevier Inc.</rights><rights>2015 Elsevier Inc.</rights><rights>Copyright © 2015 Elsevier Inc. All rights reserved.</rights><rights>2015 Published by Elsevier Inc. 2015</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c542t-2c1a63de1176782e584e9fbda8dcc4b3db459705559e4b3595aad3ef260faa473</citedby><cites>FETCH-LOGICAL-c542t-2c1a63de1176782e584e9fbda8dcc4b3db459705559e4b3595aad3ef260faa473</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0042682215000550$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>230,314,776,780,881,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25797607$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://www.osti.gov/biblio/22470176$$D View this record in Osti.gov$$Hfree_for_read</backlink></links><search><creatorcontrib>Mefford, Megan E</creatorcontrib><creatorcontrib>Kunstman, Kevin</creatorcontrib><creatorcontrib>Wolinsky, Steven M</creatorcontrib><creatorcontrib>Gabuzda, Dana</creatorcontrib><title>Bioinformatic analysis of neurotropic HIV envelope sequences identifies polymorphisms in the gp120 bridging sheet that increase macrophage-tropism through enhanced interactions with CCR5</title><title>Virology (New York, N.Y.)</title><addtitle>Virology</addtitle><description>Abstract Macrophages express low levels of the CD4 receptor compared to T-cells. Macrophage-tropic HIV strains replicating in brain of untreated patients with HIV-associated dementia (HAD) express Envs that are adapted to overcome this restriction through mechanisms that are poorly understood. Here, bioinformatic analysis of env sequence datasets together with functional studies identified polymorphisms in the β3 strand of the HIV gp120 bridging sheet that increase M-tropism. D197, which results in loss of an N-glycan located near the HIV Env trimer apex, was detected in brain in some HAD patients, while position 200 was estimated to be under positive selection. D197 and T/V200 increased fusion and infection of cells expressing low CD4 by enhancing gp120 binding to CCR5. These results identify polymorphisms in the HIV gp120 bridging sheet that overcome the restriction to macrophage infection imposed by low CD4 through enhanced gp120–CCR5 interactions, thereby promoting infection of brain and other macrophage-rich tissues.</description><subject>60 APPLIED LIFE SCIENCES</subject><subject>AIDS VIRUS</subject><subject>Amino Acid Sequence</subject><subject>AMINO ACIDS</subject><subject>ANIMAL TISSUES</subject><subject>BRAIN</subject><subject>Brain - metabolism</subject><subject>Brain - virology</subject><subject>BRIDGES</subject><subject>Bridging sheet</subject><subject>CCR5</subject><subject>CD4</subject><subject>COMPARATIVE EVALUATIONS</subject><subject>Computational Biology</subject><subject>DATASETS</subject><subject>Envelope</subject><subject>HIV</subject><subject>HIV Envelope Protein gp120 - chemistry</subject><subject>HIV Envelope Protein gp120 - genetics</subject><subject>HIV Envelope Protein gp120 - metabolism</subject><subject>HIV Infections - genetics</subject><subject>HIV Infections - metabolism</subject><subject>HIV Infections - virology</subject><subject>HIV-1 - chemistry</subject><subject>HIV-1 - genetics</subject><subject>HIV-1 - physiology</subject><subject>Humans</subject><subject>Infectious Disease</subject><subject>INTERACTIONS</subject><subject>Macrophage</subject><subject>MACROPHAGES</subject><subject>Macrophages - metabolism</subject><subject>Macrophages - virology</subject><subject>Molecular Sequence Data</subject><subject>NERVOUS SYSTEM DISEASES</subject><subject>PATIENTS</subject><subject>Polymorphism, Single Nucleotide</subject><subject>Protein Binding</subject><subject>Protein Structure, Secondary</subject><subject>RECEPTORS</subject><subject>Receptors, CCR5 - genetics</subject><subject>Receptors, CCR5 - metabolism</subject><subject>Sequence Alignment</subject><subject>STRAINS</subject><subject>Tropism</subject><subject>V1/V2 stem</subject><subject>Viral Tropism</subject><issn>0042-6822</issn><issn>1096-0341</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkk2P0zAQhiMEYsvCL0BClrhwabGdOB8HVoIK2JVWQuLrarnOpJmS2MF2i_rX-HVMtssKuHBynHln3pnxk2VPBV8JLsqXu9UBgx9Wkgu14mLFc3kvWwjelEueF-J-tuC8kMuylvIsexTjjtO9qvjD7EyqqqlKXi2yn2_Qo-t8GE1Cy4wzwzFiZL5jDvbBp-An-n959ZWBO8DgJ2ARvu_BWYgMW3AJO6TPyQ_H0YepxzhSwLHUA9tOQnK2Cdhu0W1Z7AESBUwigQ1gIrDRWLLozRaWN15xJEHw-21Phr0hm5bECYKxCb2L7Aemnq3XH9Xj7EFnhghPbs_z7Mu7t5_Xl8vrD--v1q-vl1YVMi2lFabMWxCiKqtagqoLaLpNa-rW2mKTt5tCNRVXSjVAV9UoY9ocOlnyzpiiys-zi1Pdab8ZobU0cjCDngKOJhy1N6j_jjjs9dYfdFHkVZ3PBZ6fCviYUEeLCWxvvXNgk5ayqDi1RqoXtzbB035j0iNGC8NgHPh91KKsRSPKsmhImp-ktLoYA3R3zQiuZzb0Tt-woWc2NBea2KCsZ3_OcZfzGwYSvDoJgLZ5QAhzr_NDtxjmVluP_zG4-CffDujQmuEbHCHu_D4QXjSJjlJz_WnGc6ZTKCJTKZ7_AnP35sw</recordid><startdate>20150701</startdate><enddate>20150701</enddate><creator>Mefford, Megan E</creator><creator>Kunstman, Kevin</creator><creator>Wolinsky, Steven M</creator><creator>Gabuzda, Dana</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>7X8</scope><scope>OTOTI</scope><scope>5PM</scope></search><sort><creationdate>20150701</creationdate><title>Bioinformatic analysis of neurotropic HIV envelope sequences identifies polymorphisms in the gp120 bridging sheet that increase macrophage-tropism through enhanced interactions with CCR5</title><author>Mefford, Megan E ; Kunstman, Kevin ; Wolinsky, Steven M ; Gabuzda, Dana</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c542t-2c1a63de1176782e584e9fbda8dcc4b3db459705559e4b3595aad3ef260faa473</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>60 APPLIED LIFE SCIENCES</topic><topic>AIDS VIRUS</topic><topic>Amino Acid Sequence</topic><topic>AMINO ACIDS</topic><topic>ANIMAL TISSUES</topic><topic>BRAIN</topic><topic>Brain - metabolism</topic><topic>Brain - virology</topic><topic>BRIDGES</topic><topic>Bridging sheet</topic><topic>CCR5</topic><topic>CD4</topic><topic>COMPARATIVE EVALUATIONS</topic><topic>Computational Biology</topic><topic>DATASETS</topic><topic>Envelope</topic><topic>HIV</topic><topic>HIV Envelope Protein gp120 - chemistry</topic><topic>HIV Envelope Protein gp120 - genetics</topic><topic>HIV Envelope Protein gp120 - metabolism</topic><topic>HIV Infections - genetics</topic><topic>HIV Infections - metabolism</topic><topic>HIV Infections - virology</topic><topic>HIV-1 - chemistry</topic><topic>HIV-1 - genetics</topic><topic>HIV-1 - physiology</topic><topic>Humans</topic><topic>Infectious Disease</topic><topic>INTERACTIONS</topic><topic>Macrophage</topic><topic>MACROPHAGES</topic><topic>Macrophages - metabolism</topic><topic>Macrophages - virology</topic><topic>Molecular Sequence Data</topic><topic>NERVOUS SYSTEM DISEASES</topic><topic>PATIENTS</topic><topic>Polymorphism, Single Nucleotide</topic><topic>Protein Binding</topic><topic>Protein Structure, Secondary</topic><topic>RECEPTORS</topic><topic>Receptors, CCR5 - genetics</topic><topic>Receptors, CCR5 - metabolism</topic><topic>Sequence Alignment</topic><topic>STRAINS</topic><topic>Tropism</topic><topic>V1/V2 stem</topic><topic>Viral Tropism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Mefford, Megan E</creatorcontrib><creatorcontrib>Kunstman, Kevin</creatorcontrib><creatorcontrib>Wolinsky, Steven M</creatorcontrib><creatorcontrib>Gabuzda, Dana</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>MEDLINE - Academic</collection><collection>OSTI.GOV</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Virology (New York, N.Y.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Mefford, Megan E</au><au>Kunstman, Kevin</au><au>Wolinsky, Steven M</au><au>Gabuzda, Dana</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Bioinformatic analysis of neurotropic HIV envelope sequences identifies polymorphisms in the gp120 bridging sheet that increase macrophage-tropism through enhanced interactions with CCR5</atitle><jtitle>Virology (New York, N.Y.)</jtitle><addtitle>Virology</addtitle><date>2015-07-01</date><risdate>2015</risdate><volume>481</volume><spage>210</spage><epage>222</epage><pages>210-222</pages><issn>0042-6822</issn><eissn>1096-0341</eissn><abstract>Abstract Macrophages express low levels of the CD4 receptor compared to T-cells. Macrophage-tropic HIV strains replicating in brain of untreated patients with HIV-associated dementia (HAD) express Envs that are adapted to overcome this restriction through mechanisms that are poorly understood. Here, bioinformatic analysis of env sequence datasets together with functional studies identified polymorphisms in the β3 strand of the HIV gp120 bridging sheet that increase M-tropism. D197, which results in loss of an N-glycan located near the HIV Env trimer apex, was detected in brain in some HAD patients, while position 200 was estimated to be under positive selection. D197 and T/V200 increased fusion and infection of cells expressing low CD4 by enhancing gp120 binding to CCR5. These results identify polymorphisms in the HIV gp120 bridging sheet that overcome the restriction to macrophage infection imposed by low CD4 through enhanced gp120–CCR5 interactions, thereby promoting infection of brain and other macrophage-rich tissues.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>25797607</pmid><doi>10.1016/j.virol.2015.01.032</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | 60 APPLIED LIFE SCIENCES AIDS VIRUS Amino Acid Sequence AMINO ACIDS ANIMAL TISSUES BRAIN Brain - metabolism Brain - virology BRIDGES Bridging sheet CCR5 CD4 COMPARATIVE EVALUATIONS Computational Biology DATASETS Envelope HIV HIV Envelope Protein gp120 - chemistry HIV Envelope Protein gp120 - genetics HIV Envelope Protein gp120 - metabolism HIV Infections - genetics HIV Infections - metabolism HIV Infections - virology HIV-1 - chemistry HIV-1 - genetics HIV-1 - physiology Humans Infectious Disease INTERACTIONS Macrophage MACROPHAGES Macrophages - metabolism Macrophages - virology Molecular Sequence Data NERVOUS SYSTEM DISEASES PATIENTS Polymorphism, Single Nucleotide Protein Binding Protein Structure, Secondary RECEPTORS Receptors, CCR5 - genetics Receptors, CCR5 - metabolism Sequence Alignment STRAINS Tropism V1/V2 stem Viral Tropism |
| title | Bioinformatic analysis of neurotropic HIV envelope sequences identifies polymorphisms in the gp120 bridging sheet that increase macrophage-tropism through enhanced interactions with CCR5 |
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