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MiniCD4 protein resistance mutations affect binding to the HIV-1 gp120 CD4 binding site and decrease entry efficiency

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dc.contributor.author Grupping, K.
dc.contributor.author Selhorst, P.
dc.contributor.author Michiels, J.
dc.contributor.author Vereecken, K.
dc.contributor.author Heyndrickx, L.
dc.contributor.author Kessler, P.
dc.contributor.author Vanham, G.
dc.contributor.author Martin, L.
dc.contributor.author Ariën, K. K.
dc.date.accessioned 2012-05-08T14:19:39Z
dc.date.available 2012-05-08T14:19:39Z
dc.date.issued 2012
dc.identifier.issn 1742-4690
dc.identifier.doi http://dx.doi.org/10.1186/1742-4690-9-36
dc.identifier.other ITG-B1B
dc.identifier.other ITG-B2B
dc.identifier.other ITG-B3B
dc.identifier.other ITG-B4B
dc.identifier.other ITG-B5A
dc.identifier.other ITG-B7A
dc.identifier.other ITG-BLA
dc.identifier.other DBM
dc.identifier.other U-VIROL
dc.identifier.other JIF
dc.identifier.other DOI
dc.identifier.other CPDF
dc.identifier.other URL
dc.identifier.other Electronic
dc.identifier.other Abstract
dc.identifier.other UPD46
dc.identifier.uri http://hdl.handle.net/10390/6997
dc.description.abstract BACKGROUND: Binding of the viral envelope protein (Env), and particularly of its gp120 subunit, to the cellular CD4 receptor is the first essential step of the HIV-1 entry process. The CD4 binding site (CD4bs) of gp120, and especially a recessed cavity occupied by the CD4 Phe43 residue, are known to be highly conserved among the different circulating subtypes and therefore constitute particularly interesting targets for vaccine and drug design. The miniCD4 proteins are a promising class of CD4bs inhibitors. Studying virus evolution under pressure of CD4bs inhibitors could provide insight on the gp120-CD4 interaction and viral entry. RESULTS: The present study reports on the resistance induction of two subtype B HIV-1 against the most active miniCD4, M48U1, and its ancestor, M48, and how these mutated positions affect CD4bs recognition, entry efficiency, and sensitivity to other CD4bs inhibitors. Resistance against M48U1 was always associated with S375R/N substitution in both BaL and SF162; M48 resistance was associated with D474N substitution in SF162 and with H105Y substitution in BaL. In addition, some other mutations at position V255 and G471 were of importance for SF162 resistant viruses. Except for 474, all of these mutated positions are conserved, and introducing them into an SF162 Env expressing infectious molecular clone (pBRNL4.3 SF162) resulted in decreased entry efficiency. Furthermore, resistant mutants showed at least some cross-resistance towards other CD4bs inhibitors, the V3 monoclonal antibody 447-52D and some even against the monoclonal antibody 17b, of which the epitope overlaps the co-receptor binding site. CONCLUSIONS: The mutations H105Y, V255M, S375R/N, G471R/E, and D474N are found to be involved in resistance towards M48 and M48U1. All mutated positions are part of, or in close proximity to, the CD4bs; most are highly conserved, and all have an impact on the entry efficiency, suggesting their importance for optimal virus infectivity. en
dc.language English en
dc.subject Viral diseases en
dc.subject HIV-1 en
dc.subject AIDS en
dc.subject Infectivity en
dc.subject CD4 receptor en
dc.subject Envelope proteins en
dc.subject env en
dc.subject GP120 en
dc.subject MiniCD4 en
dc.subject Mutations en
dc.subject Inhibitory activity en
dc.subject Resistance en
dc.title MiniCD4 protein resistance mutations affect binding to the HIV-1 gp120 CD4 binding site and decrease entry efficiency en
dc.type Article-E en
dc.citation.issue 36 en
dc.citation.jtitle Retrovirology en
dc.citation.volume 9 en
dc.identifier.pmid http://www.ncbi.nlm.nih.gov/pubmed/22551420
dc.identifier.url http://www.retrovirology.com/content/9/1/36
dc.citation.jabbreviation Retrovirology en


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