Macrophage-CD4+ T cell interactions in HIV-1 spread
<p>Macrophages and CD4+ T cells are the main targets for productive human immunodeficiency virus-1 (HIV-1) infection in vivo. HIV-1 transmission at immune cell synapses, such as the multi-molecular HIV-1-induced virological synapse (VS) formed between T cells, is a more efficient method of vir...
| Main Authors: | , |
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| Format: | Thesis |
| Language: | English |
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2013
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| _version_ | 1826315718485868544 |
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| author | Duncan, C Christopher Duncan |
| author2 | Sattentau, Q |
| author_facet | Sattentau, Q Duncan, C Christopher Duncan |
| author_sort | Duncan, C |
| collection | OXFORD |
| description | <p>Macrophages and CD4+ T cells are the main targets for productive human immunodeficiency virus-1 (HIV-1) infection in vivo. HIV-1 transmission at immune cell synapses, such as the multi-molecular HIV-1-induced virological synapse (VS) formed between T cells, is a more efficient method of viral dissemination than infection by cell-free virus, with important implications for HIV-1 prophylaxis and eradication. Infected macrophages can transfer HIV-1 to CD4+ T cells in a contact- dependent manner. However, the mechanism(s) of intercellular HIV-1 transmission between primary macrophages and CD4+ T cells are poorly defined.</p> <p>Here I investigate the organisation of the macrophage-T cell VS, which like the VS formed between T cells is dependent on envelope glycoprotein (Env) binding to CD4, and is stabilised by ICAM-1/LFA-1 interactions. However, unlike the T cell VS, where polarised budding of virions occurs at the donor cell membrane, VS-transmission from macrophages involves actin-dependent relocation of HIV-1 contained within the macrophage virus-containing compartment. Macrophage VS-mediated transmission results in highly efficient productive T cell infection at multiplicities capable of largely overcoming antiretroviral inhibition. Compared with cell-free infection of T cells, VS-transmission by macrophages is equally susceptible to broadly neutralising antibodies (bNAbs) against gp120, but relatively resistant to bNAbs targeting the membrane-proximal external region of gp41, probably via steric hindrance.</p> <p>In a related project, I investigated how HIV-1-infected CD4+ T cells might infect macrophages. Interaction of macrophages with HIV-1-infected CD4+ T cells resulted in rapid phagocytic uptake of the infected T cells, which correlated with efficient productive macrophage infection. This route of transmission also permitted macrophage infection with transmitted/founder HIV-1 clones that inefficiently replicate in macrophages following cell-free inoculation, potentially implicating macrophages in the mucosal amplification of transmitted HIV-1.</p> <p>Overall, these data indicate an important role for cell-to-cell transmission between macrophages and CD4+ T cells in various aspects of HIV-1 pathogenesis.</p> |
| first_indexed | 2024-03-06T19:05:32Z |
| format | Thesis |
| id | oxford-uuid:14fc6445-a001-4f6d-9d90-b69f80626f15 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-12-09T03:31:10Z |
| publishDate | 2013 |
| record_format | dspace |
| spelling | oxford-uuid:14fc6445-a001-4f6d-9d90-b69f80626f152024-12-01T14:31:36ZMacrophage-CD4+ T cell interactions in HIV-1 spreadThesishttp://purl.org/coar/resource_type/c_db06uuid:14fc6445-a001-4f6d-9d90-b69f80626f15Medical SciencesLife SciencesHIV/AIDSEnglish2013Duncan, CChristopher DuncanSattentau, QMcMichael, AMoore, R<p>Macrophages and CD4+ T cells are the main targets for productive human immunodeficiency virus-1 (HIV-1) infection in vivo. HIV-1 transmission at immune cell synapses, such as the multi-molecular HIV-1-induced virological synapse (VS) formed between T cells, is a more efficient method of viral dissemination than infection by cell-free virus, with important implications for HIV-1 prophylaxis and eradication. Infected macrophages can transfer HIV-1 to CD4+ T cells in a contact- dependent manner. However, the mechanism(s) of intercellular HIV-1 transmission between primary macrophages and CD4+ T cells are poorly defined.</p> <p>Here I investigate the organisation of the macrophage-T cell VS, which like the VS formed between T cells is dependent on envelope glycoprotein (Env) binding to CD4, and is stabilised by ICAM-1/LFA-1 interactions. However, unlike the T cell VS, where polarised budding of virions occurs at the donor cell membrane, VS-transmission from macrophages involves actin-dependent relocation of HIV-1 contained within the macrophage virus-containing compartment. Macrophage VS-mediated transmission results in highly efficient productive T cell infection at multiplicities capable of largely overcoming antiretroviral inhibition. Compared with cell-free infection of T cells, VS-transmission by macrophages is equally susceptible to broadly neutralising antibodies (bNAbs) against gp120, but relatively resistant to bNAbs targeting the membrane-proximal external region of gp41, probably via steric hindrance.</p> <p>In a related project, I investigated how HIV-1-infected CD4+ T cells might infect macrophages. Interaction of macrophages with HIV-1-infected CD4+ T cells resulted in rapid phagocytic uptake of the infected T cells, which correlated with efficient productive macrophage infection. This route of transmission also permitted macrophage infection with transmitted/founder HIV-1 clones that inefficiently replicate in macrophages following cell-free inoculation, potentially implicating macrophages in the mucosal amplification of transmitted HIV-1.</p> <p>Overall, these data indicate an important role for cell-to-cell transmission between macrophages and CD4+ T cells in various aspects of HIV-1 pathogenesis.</p> |
| spellingShingle | Medical Sciences Life Sciences HIV/AIDS Duncan, C Christopher Duncan Macrophage-CD4+ T cell interactions in HIV-1 spread |
| title | Macrophage-CD4+ T cell interactions in HIV-1 spread |
| title_full | Macrophage-CD4+ T cell interactions in HIV-1 spread |
| title_fullStr | Macrophage-CD4+ T cell interactions in HIV-1 spread |
| title_full_unstemmed | Macrophage-CD4+ T cell interactions in HIV-1 spread |
| title_short | Macrophage-CD4+ T cell interactions in HIV-1 spread |
| title_sort | macrophage cd4 t cell interactions in hiv 1 spread |
| topic | Medical Sciences Life Sciences HIV/AIDS |
| work_keys_str_mv | AT duncanc macrophagecd4tcellinteractionsinhiv1spread AT christopherduncan macrophagecd4tcellinteractionsinhiv1spread |