Epigenetic silencing of CD4 expression in nonpathogenic SIV infection in African green monkeys
African green monkeys (AGMs) are natural hosts of SIV that postthymically downregulate CD4 to maintain a large population of CD4–CD8aa+ virus-resistant cells with Th functionality, which can result in AGMs becoming apparently cured of SIVagm infection. To understand the mechanisms of this process, w...
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
American Society for Clinical investigation
2020-09-01
|
| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.139043 |
| _version_ | 1818723215192621056 |
|---|---|
| author | Joseph C. Mudd Stephen Lai Sanjana Shah Andrew Rahmberg Jacob K. Flynn Carly E. Starke Molly R. Perkins Amy Ransier Sam Darko Daniel C. Douek Vanessa M. Hirsch Mark Cameron Jason M. Brenchley |
| author_facet | Joseph C. Mudd Stephen Lai Sanjana Shah Andrew Rahmberg Jacob K. Flynn Carly E. Starke Molly R. Perkins Amy Ransier Sam Darko Daniel C. Douek Vanessa M. Hirsch Mark Cameron Jason M. Brenchley |
| author_sort | Joseph C. Mudd |
| collection | DOAJ |
| description | African green monkeys (AGMs) are natural hosts of SIV that postthymically downregulate CD4 to maintain a large population of CD4–CD8aa+ virus-resistant cells with Th functionality, which can result in AGMs becoming apparently cured of SIVagm infection. To understand the mechanisms of this process, we performed genome-wide transcriptional analysis on T cells induced to downregulate CD4 in vitro from AGMs and closely related patas monkeys and T cells that maintain CD4 expression from rhesus macaques. In T cells that downregulated CD4, pathway analysis revealed an atypical regulation of the DNA methylation machinery, which was reversible when pharmacologically targeted with 5-aza-2 deoxycytidine. This signature was driven largely by the dioxygenase TET3, which became downregulated with loss of CD4 expression. CpG motifs within the AGM CD4 promoter region became methylated during CD4 downregulation in vitro and were stably imprinted in AGM CD4–CD8aa+ T cells sorted directly ex vivo. These results suggest that AGMs use epigenetic mechanisms to durably silence the CD4 gene. Manipulation of these mechanisms could provide avenues for modulating SIV and HIV-1 entry receptor expression in hosts that become progressively infected with SIV, which could lead to novel therapeutic interventions aimed to reduce HIV viremia in vivo. |
| first_indexed | 2024-12-17T21:06:58Z |
| format | Article |
| id | doaj.art-275efb05e70845b9940e8ac35717c5a1 |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-12-17T21:06:58Z |
| publishDate | 2020-09-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-275efb05e70845b9940e8ac35717c5a12022-12-21T21:32:33ZengAmerican Society for Clinical investigationJCI Insight2379-37082020-09-01518Epigenetic silencing of CD4 expression in nonpathogenic SIV infection in African green monkeysJoseph C. MuddStephen LaiSanjana ShahAndrew RahmbergJacob K. FlynnCarly E. StarkeMolly R. PerkinsAmy RansierSam DarkoDaniel C. DouekVanessa M. HirschMark CameronJason M. BrenchleyAfrican green monkeys (AGMs) are natural hosts of SIV that postthymically downregulate CD4 to maintain a large population of CD4–CD8aa+ virus-resistant cells with Th functionality, which can result in AGMs becoming apparently cured of SIVagm infection. To understand the mechanisms of this process, we performed genome-wide transcriptional analysis on T cells induced to downregulate CD4 in vitro from AGMs and closely related patas monkeys and T cells that maintain CD4 expression from rhesus macaques. In T cells that downregulated CD4, pathway analysis revealed an atypical regulation of the DNA methylation machinery, which was reversible when pharmacologically targeted with 5-aza-2 deoxycytidine. This signature was driven largely by the dioxygenase TET3, which became downregulated with loss of CD4 expression. CpG motifs within the AGM CD4 promoter region became methylated during CD4 downregulation in vitro and were stably imprinted in AGM CD4–CD8aa+ T cells sorted directly ex vivo. These results suggest that AGMs use epigenetic mechanisms to durably silence the CD4 gene. Manipulation of these mechanisms could provide avenues for modulating SIV and HIV-1 entry receptor expression in hosts that become progressively infected with SIV, which could lead to novel therapeutic interventions aimed to reduce HIV viremia in vivo.https://doi.org/10.1172/jci.insight.139043AIDS/HIVImmunology |
| spellingShingle | Joseph C. Mudd Stephen Lai Sanjana Shah Andrew Rahmberg Jacob K. Flynn Carly E. Starke Molly R. Perkins Amy Ransier Sam Darko Daniel C. Douek Vanessa M. Hirsch Mark Cameron Jason M. Brenchley Epigenetic silencing of CD4 expression in nonpathogenic SIV infection in African green monkeys JCI Insight AIDS/HIV Immunology |
| title | Epigenetic silencing of CD4 expression in nonpathogenic SIV infection in African green monkeys |
| title_full | Epigenetic silencing of CD4 expression in nonpathogenic SIV infection in African green monkeys |
| title_fullStr | Epigenetic silencing of CD4 expression in nonpathogenic SIV infection in African green monkeys |
| title_full_unstemmed | Epigenetic silencing of CD4 expression in nonpathogenic SIV infection in African green monkeys |
| title_short | Epigenetic silencing of CD4 expression in nonpathogenic SIV infection in African green monkeys |
| title_sort | epigenetic silencing of cd4 expression in nonpathogenic siv infection in african green monkeys |
| topic | AIDS/HIV Immunology |
| url | https://doi.org/10.1172/jci.insight.139043 |
| work_keys_str_mv | AT josephcmudd epigeneticsilencingofcd4expressioninnonpathogenicsivinfectioninafricangreenmonkeys AT stephenlai epigeneticsilencingofcd4expressioninnonpathogenicsivinfectioninafricangreenmonkeys AT sanjanashah epigeneticsilencingofcd4expressioninnonpathogenicsivinfectioninafricangreenmonkeys AT andrewrahmberg epigeneticsilencingofcd4expressioninnonpathogenicsivinfectioninafricangreenmonkeys AT jacobkflynn epigeneticsilencingofcd4expressioninnonpathogenicsivinfectioninafricangreenmonkeys AT carlyestarke epigeneticsilencingofcd4expressioninnonpathogenicsivinfectioninafricangreenmonkeys AT mollyrperkins epigeneticsilencingofcd4expressioninnonpathogenicsivinfectioninafricangreenmonkeys AT amyransier epigeneticsilencingofcd4expressioninnonpathogenicsivinfectioninafricangreenmonkeys AT samdarko epigeneticsilencingofcd4expressioninnonpathogenicsivinfectioninafricangreenmonkeys AT danielcdouek epigeneticsilencingofcd4expressioninnonpathogenicsivinfectioninafricangreenmonkeys AT vanessamhirsch epigeneticsilencingofcd4expressioninnonpathogenicsivinfectioninafricangreenmonkeys AT markcameron epigeneticsilencingofcd4expressioninnonpathogenicsivinfectioninafricangreenmonkeys AT jasonmbrenchley epigeneticsilencingofcd4expressioninnonpathogenicsivinfectioninafricangreenmonkeys |