DNA methylation changes in metabolic and immune-regulatory pathways in blood and lymph node CD4 + T cells in response to SIV infections

Abstract

The molecular mechanisms underlying HIV-induced inflammation, which persists even during effective long-term treatment, remain incompletely defined. Here, we studied pathogenic and nonpathogenic simian immunodeficiency virus (SIV) infections in macaques and African green monkeys, respectively. We longitudinally analyzed genome-wide DNA methylation changes in CD4 + T cells from lymph node and blood, using arrays. DNA methylation changes after SIV infection were more pronounced in lymph nodes than blood and already detected in primary infection. Differentially methylated genes in pathogenic SIV infection were enriched for Th1-signaling (e.g., RUNX3, STAT4, NFKB1) and metabolic pathways (e.g., PRKCZ). In contrast, nonpathogenic SIVagm infection induced DNA methylation in genes coding for regulatory proteins such as LAG-3, arginase-2, interleukin-21 and interleukin-31. Between 15 and 18% of genes with DNA methylation changes were differentially expressed in CD4 + T cells in vivo. Selected identified sites were validated using bisulfite pyrosequencing in an independent cohort of uninfected, viremic and SIV controller macaques. Altered DNA methylation was confirmed in blood and lymph node CD4 + T cells in viremic macaques but was notably absent from SIV controller macaques. Our study identified key genes differentially methylated already in primary infection and in tissues that could contribute to the persisting metabolic disorders and inflammation in HIV-infected individuals despite effective treatment.

Butyrate administration is not sufficient to improve immune reconstitution in antiretroviral-treated SIV-infected macaques

“…Although lentiviral infections have been shown to specifically alter these parameters 54 – 57 , disruptions to butyrate-responsive pathways may not be the primary roadblock to complete immune restoration. Lentiviral infections induce widespread epigenetic changes 58 , 59 , many of which persist or rise anew after the initiation of ARV therapy 60 – 63 . Although HDAC inhibitors have been successfully used to reactivate viral reservoirs in latency reversal studies 64 – 66 , sodium butyrate treatment was not associated with increased viremia in our study (Fig.…”

Understanding LAG-3 Signaling

“…Nonpathogenic simian immunodeficiency virus (SIV) primary infections induce DNA methylation in the LAG-3 coding gene. A similar mechanism may be occurring in HIV-infected patients, which could contribute to persisting metabolic and inflammation disorders [106].…”

Walk on the wild side: SIV infection in African non-human primate hosts—from the field to the laboratory

“…SIV infection has a different influence on DNA methylation patterns in CD4 + T cells purified from circulation and lymphoid tissue in non-pathogenic SIVagm infection of AGMs and pathogenic SIV infection of Chinese RMs ( 192 ). Non-pathogenic SIV infection of AGMs is characterized by the enrichment for methylation signals in regulatory proteins, while pathogenic infection in macaques is associated with Th1-signaling and metabolic pathways, suggesting that epigenetic mechanism may contribute to the risk of metabolic diseases during progressing infection ( 192 ).…”