HIV-1 and SIV predominantly use CCR5 expressed on a precursor population to establish infection in T follicular helper cells
<h4>Background</h4> <p>T follicular helper (Tfh) cells are increasingly recognized as a major reservoir of HIV infection that will likely need to be addressed in approaches to curing HIV. However, Tfh express minimal CCR5, the major coreceptor for HIV-1, and the mechanism by which...
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
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Frontiers Media
2017
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| _version_ | 1826303628636323840 |
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| author | Xu, Y Phetsouphanh, C Suzuki, K Aggrawal, A Graff-Dubois, S Roche, M Bailey, M Alcantara, S Cashin, K Sivasubramaniam, R Koelsch, K Autran, B Harvey, R Gorry, P Moris, A Cooper, D Turville, S Kent, S Kelleher, A Zaunders, J |
| author_facet | Xu, Y Phetsouphanh, C Suzuki, K Aggrawal, A Graff-Dubois, S Roche, M Bailey, M Alcantara, S Cashin, K Sivasubramaniam, R Koelsch, K Autran, B Harvey, R Gorry, P Moris, A Cooper, D Turville, S Kent, S Kelleher, A Zaunders, J |
| author_sort | Xu, Y |
| collection | OXFORD |
| description | <h4>Background</h4> <p>T follicular helper (Tfh) cells are increasingly recognized as a major reservoir of HIV infection that will likely need to be addressed in approaches to curing HIV. However, Tfh express minimal CCR5, the major coreceptor for HIV-1, and the mechanism by which they are infected is unclear. We have previously shown that macaque Tfh lack CCR5, but are infected in vivo with CCR5-using SIV at levels comparable to other memory CD4+ T cells. Similarly, human splenic Tfh cells are highly infected with HIV-1 DNA. Therefore, we set out to examine the mechanism of infection of Tfh cells.</p> <h4>Methodology</h4> <p>Tfh and other CD4+ T cell subsets from macaque lymph nodes and spleens, splenic Tfh from HIV+ subjects, and tonsillar Tfh from HIV-uninfected subjects were isolated by cell sorting prior to cell surface and molecular characterization. HIV proviral gp120 sequences were submitted to genotypic and phenotypic tropism assays. Entry of CCR5- and CXCR4-using viruses into Tfh from uninfected tonsillar tissue was measured using a fusion assay.</p> <h4>Results</h4> <p>Phylogenetic analysis, genotypic, and phenotypic analysis showed that splenic Tfh cells from chronic HIV+ subjects were predominantly infected with CCR5-using viruses. In macaques, purified CCR5+PD-1intermediate(int)+ memory CD4+ T cells were shown to include pre-Tfh cells capable of differentiating in vitro to Tfh by upregulation of PD-1 and Bcl6, confirmed by qRT-PCR and single-cell multiplex PCR. Infected PD-1int cells survive, carry SIV provirus, and differentiate into PD-1hi Tfh after T cell receptor stimulation, suggesting a pathway for SIV infection of Tfh. In addition, a small subset of macaque and human PD-1hi Tfh can express low levels of CCR5, which makes them susceptible to infection. Fusion assays demonstrated CCR5-using HIV-1 entry into CCR5+ Tfh and pre-Tfh cells from human tonsils.</p> <h4>Conclusion</h4> <p>The major route of infection of Tfh in macaques and humans appears to be via a CCR5-expressing pre-Tfh population. As the generation of Tfh are important for establishing effective immune responses during primary infections, Tfh are likely to be an early target of HIV-1 following transmission, creating an important component of the reservoir that has the potential to expand over time.</p> |
| first_indexed | 2024-03-07T06:05:36Z |
| format | Journal article |
| id | oxford-uuid:edbb5f4b-4e55-4907-abb2-d0927d2bec99 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T06:05:36Z |
| publishDate | 2017 |
| publisher | Frontiers Media |
| record_format | dspace |
| spelling | oxford-uuid:edbb5f4b-4e55-4907-abb2-d0927d2bec992022-03-27T11:27:23ZHIV-1 and SIV predominantly use CCR5 expressed on a precursor population to establish infection in T follicular helper cellsJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:edbb5f4b-4e55-4907-abb2-d0927d2bec99EnglishSymplectic Elements at OxfordFrontiers Media2017Xu, YPhetsouphanh, CSuzuki, KAggrawal, AGraff-Dubois, SRoche, MBailey, MAlcantara, SCashin, KSivasubramaniam, RKoelsch, KAutran, BHarvey, RGorry, PMoris, ACooper, DTurville, SKent, SKelleher, AZaunders, J <h4>Background</h4> <p>T follicular helper (Tfh) cells are increasingly recognized as a major reservoir of HIV infection that will likely need to be addressed in approaches to curing HIV. However, Tfh express minimal CCR5, the major coreceptor for HIV-1, and the mechanism by which they are infected is unclear. We have previously shown that macaque Tfh lack CCR5, but are infected in vivo with CCR5-using SIV at levels comparable to other memory CD4+ T cells. Similarly, human splenic Tfh cells are highly infected with HIV-1 DNA. Therefore, we set out to examine the mechanism of infection of Tfh cells.</p> <h4>Methodology</h4> <p>Tfh and other CD4+ T cell subsets from macaque lymph nodes and spleens, splenic Tfh from HIV+ subjects, and tonsillar Tfh from HIV-uninfected subjects were isolated by cell sorting prior to cell surface and molecular characterization. HIV proviral gp120 sequences were submitted to genotypic and phenotypic tropism assays. Entry of CCR5- and CXCR4-using viruses into Tfh from uninfected tonsillar tissue was measured using a fusion assay.</p> <h4>Results</h4> <p>Phylogenetic analysis, genotypic, and phenotypic analysis showed that splenic Tfh cells from chronic HIV+ subjects were predominantly infected with CCR5-using viruses. In macaques, purified CCR5+PD-1intermediate(int)+ memory CD4+ T cells were shown to include pre-Tfh cells capable of differentiating in vitro to Tfh by upregulation of PD-1 and Bcl6, confirmed by qRT-PCR and single-cell multiplex PCR. Infected PD-1int cells survive, carry SIV provirus, and differentiate into PD-1hi Tfh after T cell receptor stimulation, suggesting a pathway for SIV infection of Tfh. In addition, a small subset of macaque and human PD-1hi Tfh can express low levels of CCR5, which makes them susceptible to infection. Fusion assays demonstrated CCR5-using HIV-1 entry into CCR5+ Tfh and pre-Tfh cells from human tonsils.</p> <h4>Conclusion</h4> <p>The major route of infection of Tfh in macaques and humans appears to be via a CCR5-expressing pre-Tfh population. As the generation of Tfh are important for establishing effective immune responses during primary infections, Tfh are likely to be an early target of HIV-1 following transmission, creating an important component of the reservoir that has the potential to expand over time.</p> |
| spellingShingle | Xu, Y Phetsouphanh, C Suzuki, K Aggrawal, A Graff-Dubois, S Roche, M Bailey, M Alcantara, S Cashin, K Sivasubramaniam, R Koelsch, K Autran, B Harvey, R Gorry, P Moris, A Cooper, D Turville, S Kent, S Kelleher, A Zaunders, J HIV-1 and SIV predominantly use CCR5 expressed on a precursor population to establish infection in T follicular helper cells |
| title | HIV-1 and SIV predominantly use CCR5 expressed on a precursor population to establish infection in T follicular helper cells |
| title_full | HIV-1 and SIV predominantly use CCR5 expressed on a precursor population to establish infection in T follicular helper cells |
| title_fullStr | HIV-1 and SIV predominantly use CCR5 expressed on a precursor population to establish infection in T follicular helper cells |
| title_full_unstemmed | HIV-1 and SIV predominantly use CCR5 expressed on a precursor population to establish infection in T follicular helper cells |
| title_short | HIV-1 and SIV predominantly use CCR5 expressed on a precursor population to establish infection in T follicular helper cells |
| title_sort | hiv 1 and siv predominantly use ccr5 expressed on a precursor population to establish infection in t follicular helper cells |
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