Genetic, structural, and functional exploration of the restrictive capacity of TRIM proteins against immunodeficiency viruses
<p>HIV-2 differs from HIV-1 in that many infected people experience normal survival, whilst only 20% progress rapidly to AIDS. Understanding mechanisms of delayed HIV-2 disease progression could provide new insights into HIV control. The Caio Community Cohort was established in Guinea-Bissau i...
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| Format: | Thesis |
| Language: | English |
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2017
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| _version_ | 1817932446167990272 |
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| author | Simpson, S |
| author2 | Rowland-Jones, S |
| author_facet | Rowland-Jones, S Simpson, S |
| author_sort | Simpson, S |
| collection | OXFORD |
| description | <p>HIV-2 differs from HIV-1 in that many infected people experience normal survival, whilst only 20% progress rapidly to AIDS. Understanding mechanisms of delayed HIV-2 disease progression could provide new insights into HIV control. The Caio Community Cohort was established in Guinea-Bissau in the setting of high HIV-2 prevalence. This thesis investigates the role of polymorphic host restriction factors of the TRIM family in HIV-2 outcome. TRIM proteins are a family of E3 ubiquitin-ligases, where closely-related TRIM5α and TRIM22 are thought to inhibit HIV-1 transcription, uncoating and budding. </p> <p>There was an association between TRIM5α amino acid substitution R136Q and reduced HIV-2 viral load/prolonged survival. Conversely, P479L was enriched among HIV-2 infected participants and progressors with CD4+ T cell decline. TRIM22 was highly polymorphic in this cohort, revealing three novel coding variants. Although most substitutions were located in the putative virus-interacting PRYSPRY domain, two in the coiled-coil, D155N and R242T, showed significant and divergent associations with survival. R242T was enriched in HIV-2 infected participants, who progressed to death at twice the rate of wild-type controls. <em>In silico</em> studies predicted D282, D360, and R321 of TRIM22 to be highly conserved, exposed residues, for which polymorphisms would be deleterious. When aligned with sequences from the potent HIV-1 restriction factor, rhesus macaque TRIM5α, TRIM22 substitutions R321K, T415I, and D360Y were spatially relevant to residues involved in HIV-1 restriction. The role of TRIM22 in HIV restriction was supported by <em>in vitro</em> pilot studies showing that TRIM22 was upregulated by HIV-1 infection in a lymphoid cell line and co-localised with the HIV-1 capsid protein p24. Overexpression of TRIM22 resulted in the restriction of VSV-G pseudotyped HIV-1 and SIVmac. The R242T substitution diminished TRIM22's restriction of HIV-1 and SIVmac: protein analysis suggested that this may be due to the inability of the R242T mutant to fully dimerise. </p> |
| first_indexed | 2024-03-06T19:23:37Z |
| format | Thesis |
| id | oxford-uuid:1af588ba-603a-4f39-9443-bb1a95d983f5 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-12-09T03:38:02Z |
| publishDate | 2017 |
| record_format | dspace |
| spelling | oxford-uuid:1af588ba-603a-4f39-9443-bb1a95d983f52024-12-06T08:09:37ZGenetic, structural, and functional exploration of the restrictive capacity of TRIM proteins against immunodeficiency virusesThesishttp://purl.org/coar/resource_type/c_db06uuid:1af588ba-603a-4f39-9443-bb1a95d983f5Global HealthHost Restriction FactorsInfectious DiseaseMedicinePopulation GeneticsImmunogeneticsEnglishORA Deposit2017Simpson, SRowland-Jones, SCarrington, M<p>HIV-2 differs from HIV-1 in that many infected people experience normal survival, whilst only 20% progress rapidly to AIDS. Understanding mechanisms of delayed HIV-2 disease progression could provide new insights into HIV control. The Caio Community Cohort was established in Guinea-Bissau in the setting of high HIV-2 prevalence. This thesis investigates the role of polymorphic host restriction factors of the TRIM family in HIV-2 outcome. TRIM proteins are a family of E3 ubiquitin-ligases, where closely-related TRIM5α and TRIM22 are thought to inhibit HIV-1 transcription, uncoating and budding. </p> <p>There was an association between TRIM5α amino acid substitution R136Q and reduced HIV-2 viral load/prolonged survival. Conversely, P479L was enriched among HIV-2 infected participants and progressors with CD4+ T cell decline. TRIM22 was highly polymorphic in this cohort, revealing three novel coding variants. Although most substitutions were located in the putative virus-interacting PRYSPRY domain, two in the coiled-coil, D155N and R242T, showed significant and divergent associations with survival. R242T was enriched in HIV-2 infected participants, who progressed to death at twice the rate of wild-type controls. <em>In silico</em> studies predicted D282, D360, and R321 of TRIM22 to be highly conserved, exposed residues, for which polymorphisms would be deleterious. When aligned with sequences from the potent HIV-1 restriction factor, rhesus macaque TRIM5α, TRIM22 substitutions R321K, T415I, and D360Y were spatially relevant to residues involved in HIV-1 restriction. The role of TRIM22 in HIV restriction was supported by <em>in vitro</em> pilot studies showing that TRIM22 was upregulated by HIV-1 infection in a lymphoid cell line and co-localised with the HIV-1 capsid protein p24. Overexpression of TRIM22 resulted in the restriction of VSV-G pseudotyped HIV-1 and SIVmac. The R242T substitution diminished TRIM22's restriction of HIV-1 and SIVmac: protein analysis suggested that this may be due to the inability of the R242T mutant to fully dimerise. </p> |
| spellingShingle | Global Health Host Restriction Factors Infectious Disease Medicine Population Genetics Immunogenetics Simpson, S Genetic, structural, and functional exploration of the restrictive capacity of TRIM proteins against immunodeficiency viruses |
| title | Genetic, structural, and functional exploration of the restrictive capacity of TRIM proteins against immunodeficiency viruses |
| title_full | Genetic, structural, and functional exploration of the restrictive capacity of TRIM proteins against immunodeficiency viruses |
| title_fullStr | Genetic, structural, and functional exploration of the restrictive capacity of TRIM proteins against immunodeficiency viruses |
| title_full_unstemmed | Genetic, structural, and functional exploration of the restrictive capacity of TRIM proteins against immunodeficiency viruses |
| title_short | Genetic, structural, and functional exploration of the restrictive capacity of TRIM proteins against immunodeficiency viruses |
| title_sort | genetic structural and functional exploration of the restrictive capacity of trim proteins against immunodeficiency viruses |
| topic | Global Health Host Restriction Factors Infectious Disease Medicine Population Genetics Immunogenetics |
| work_keys_str_mv | AT simpsons geneticstructuralandfunctionalexplorationoftherestrictivecapacityoftrimproteinsagainstimmunodeficiencyviruses |