Alternative coreceptor requirements for efficient CCR5- and CXCR4-mediated HIV-1 entry into macrophages
Macrophage tropism of human immunodeficiency virus type 1 (HIV-1) is distinct from coreceptor specificity of the viral envelope glycoproteins (Env), but the virus-cell interactions that contribute to efficient HIV-1 entry into macrophages, particularly via CXCR4, are not well understood. Here, we ch...
| Main Authors: | , , , , , , , , |
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| Format: | Journal Article |
| Published: |
2011
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| Online Access: | http://hdl.handle.net/20.500.11937/46739 |
| _version_ | 1848757644145197056 |
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| author | Cashin, K. Roche, M. Sterjovski, J. Ellett, A. Gray, L. Cunningham, A. Ramsland, Paul Churchill, M. Gorry, P. |
| author_facet | Cashin, K. Roche, M. Sterjovski, J. Ellett, A. Gray, L. Cunningham, A. Ramsland, Paul Churchill, M. Gorry, P. |
| author_sort | Cashin, K. |
| building | Curtin Institutional Repository |
| collection | Online Access |
| description | Macrophage tropism of human immunodeficiency virus type 1 (HIV-1) is distinct from coreceptor specificity of the viral envelope glycoproteins (Env), but the virus-cell interactions that contribute to efficient HIV-1 entry into macrophages, particularly via CXCR4, are not well understood. Here, we characterized a panel of HIV-1 Envs that use CCR5 (n = 14) or CXCR4 (n = 6) to enter monocyte-derived macrophages (MDM) with various degrees of efficiency. Our results show that efficient CCR5-mediated MDM entry by Env-pseudotyped reporter viruses is associated with increased tolerance of several mutations within the CCR5 N terminus. In contrast, efficient CXCR4-mediated MDM entry was associated with reduced tolerance of a large deletion within the CXCR4 N terminus. Env sequence analysis and structural modeling identified amino acid variants at positions 261 and 263 within the gp41-interactive region of gp120 and a variant at position 326 within the gp120 V3 loop that were associated with efficient CXCR4-mediated MDM entry. Mutagenesis studies showed that the gp41 interaction domain variants exert a significant but strain-specific influence on CXCR4-mediated MDM entry, suggesting that the structural integrity of the gp120-gp41 interface is important for efficient CXCR4-mediated MDM entry of certain HIV-1 strains. However, the presence of Ile326 in the gp120 V3 loop stem, which we show by molecular modeling is located at the gp120-coreceptor interface and predicted to interact with the CXCR4 N terminus, was found to be critical for efficient CXCR4-mediated MDM entry of divergent CXCR4-using Envs. Together, the results of our study provide novel insights into alternative mechanisms of Env-coreceptor engagement that are associated with efficient CCR5- and CXCR4-mediated HIV-1 entry into macrophages. |
| first_indexed | 2025-11-14T09:31:22Z |
| format | Journal Article |
| id | curtin-20.500.11937-46739 |
| institution | Curtin University Malaysia |
| institution_category | Local University |
| last_indexed | 2025-11-14T09:31:22Z |
| publishDate | 2011 |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | curtin-20.500.11937-467392023-02-22T06:24:21Z Alternative coreceptor requirements for efficient CCR5- and CXCR4-mediated HIV-1 entry into macrophages Cashin, K. Roche, M. Sterjovski, J. Ellett, A. Gray, L. Cunningham, A. Ramsland, Paul Churchill, M. Gorry, P. Macrophage tropism of human immunodeficiency virus type 1 (HIV-1) is distinct from coreceptor specificity of the viral envelope glycoproteins (Env), but the virus-cell interactions that contribute to efficient HIV-1 entry into macrophages, particularly via CXCR4, are not well understood. Here, we characterized a panel of HIV-1 Envs that use CCR5 (n = 14) or CXCR4 (n = 6) to enter monocyte-derived macrophages (MDM) with various degrees of efficiency. Our results show that efficient CCR5-mediated MDM entry by Env-pseudotyped reporter viruses is associated with increased tolerance of several mutations within the CCR5 N terminus. In contrast, efficient CXCR4-mediated MDM entry was associated with reduced tolerance of a large deletion within the CXCR4 N terminus. Env sequence analysis and structural modeling identified amino acid variants at positions 261 and 263 within the gp41-interactive region of gp120 and a variant at position 326 within the gp120 V3 loop that were associated with efficient CXCR4-mediated MDM entry. Mutagenesis studies showed that the gp41 interaction domain variants exert a significant but strain-specific influence on CXCR4-mediated MDM entry, suggesting that the structural integrity of the gp120-gp41 interface is important for efficient CXCR4-mediated MDM entry of certain HIV-1 strains. However, the presence of Ile326 in the gp120 V3 loop stem, which we show by molecular modeling is located at the gp120-coreceptor interface and predicted to interact with the CXCR4 N terminus, was found to be critical for efficient CXCR4-mediated MDM entry of divergent CXCR4-using Envs. Together, the results of our study provide novel insights into alternative mechanisms of Env-coreceptor engagement that are associated with efficient CCR5- and CXCR4-mediated HIV-1 entry into macrophages. 2011 Journal Article http://hdl.handle.net/20.500.11937/46739 10.1128/JVI.05510-11 unknown |
| spellingShingle | Cashin, K. Roche, M. Sterjovski, J. Ellett, A. Gray, L. Cunningham, A. Ramsland, Paul Churchill, M. Gorry, P. Alternative coreceptor requirements for efficient CCR5- and CXCR4-mediated HIV-1 entry into macrophages |
| title | Alternative coreceptor requirements for efficient CCR5- and CXCR4-mediated HIV-1 entry into macrophages |
| title_full | Alternative coreceptor requirements for efficient CCR5- and CXCR4-mediated HIV-1 entry into macrophages |
| title_fullStr | Alternative coreceptor requirements for efficient CCR5- and CXCR4-mediated HIV-1 entry into macrophages |
| title_full_unstemmed | Alternative coreceptor requirements for efficient CCR5- and CXCR4-mediated HIV-1 entry into macrophages |
| title_short | Alternative coreceptor requirements for efficient CCR5- and CXCR4-mediated HIV-1 entry into macrophages |
| title_sort | alternative coreceptor requirements for efficient ccr5- and cxcr4-mediated hiv-1 entry into macrophages |
| url | http://hdl.handle.net/20.500.11937/46739 |