Epigenetic silencing of CD4 expression in nonpathogenic SIV infection in African green monkeys.
JCI Insight
; 5(18)2020 09 17.
Article
en En
| MEDLINE
| ID: mdl-32841214
ABSTRACT
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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Linfocitos T CD4-Positivos
/
Antígenos CD4
/
Regulación de la Expresión Génica
/
Síndrome de Inmunodeficiencia Adquirida del Simio
/
Virus de la Inmunodeficiencia de los Simios
/
Epigénesis Genética
/
Inmunidad Innata
Límite:
Animals
Idioma:
En
Revista:
JCI Insight
Año:
2020
Tipo del documento:
Article