Interleukin-2 Therapy Induces CD4 Downregulation, Which Decreases Circulating CD4 T Cell Counts, in African Green Monkeys

Mudd, Joseph C.; Perkins, Molly R.; DiNapoli, Sarah R.; Hirsch, Vanessa M.; Brenchley, Jason M.

doi:10.1128/jvi.00057-16

Cited by 4 publications

(4 citation statements)

References 31 publications

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“…While very little is known regarding the mechanisms of CD4 postthymic repression in AGMs, the process can be readily studied in vitro, as CD4 expression in AGMs is exceptionally unstable. Multiple stimuli can induce AGM CD4 T cells to downregulate CD4, including antigen or homeostatic cytokines ( 13 , 18 ). It is thought that events governing CD4 downregulation are inherently linked to those involved in cell division.…”

Section: Introductionmentioning

confidence: 99%

Epigenetic silencing of CD4 expression in nonpathogenic SIV infection in African green monkeys

Mudd¹,

Lai²,

Shah³

et al. 2020

JCI Insight

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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 SIV agm 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.

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Section: Introductionmentioning

confidence: 99%

Epigenetic silencing of CD4 expression in nonpathogenic SIV infection in African green monkeys

Mudd¹,

Lai²,

Shah³

et al. 2020

JCI Insight

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“…CD4 expression is lost upon activation. This post-thymic downregulation of CD4 can be achieved through TCR stimulation or cytokine signaling (8,39). CD4 downregulation in AGMs likely occurs through multiple mechanisms, including increased DNA methylation (11) and additional epigenetic pathways observed here in altered chromatin states.…”

Section: Discussionmentioning

confidence: 81%

“…The mechanisms underlying this coevolution reveal important aspects of infection responsible for progressive HIV infection of humans. We have previously shown that coevolution of AGM with SIVagm has involved downregulation of CD4 1 by CD4 T cells in this natural host species (7,8,39). The T cells that have downregulated CD4 maintain effector functions of Th cells but also accumulate some effector functions associated with CD8 1 T cells (40).…”

Section: Discussionmentioning

confidence: 99%

Epigenetic Reprogramming Leads to Downregulation of CD4 and Functional Changes in African Green Monkey Memory CD4+ T Cells

Rahmberg

Markowitz

Mudd

et al. 2022

The Journal of Immunology

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African green monkeys (AGMs), Chlorocebus pygerythrus, are a natural host for a lentivirus related to HIV, SIV. SIV-infected AGMs rarely progress to AIDS despite robust viral replication. Though multiple mechanisms are involved, a primary component is the animals' ability to downregulate CD4 expression on mature CD4 + Th cells, rendering these cells resistant to infection by SIV. These CD8aa + T cells retain functional characteristics of CD4 + Th cells while simultaneously acquiring abilities of cytotoxic CD8ab + T cells. To determine mechanisms underlying functional differences between T cell subsets in AGMs, chromatin accessibility in purified populations was determined by assay for transposase-accessible chromatin sequencing. Differences in chromatin accessibility alone were sufficient to cluster cells by subtype, and accessibility at the CD4 locus reflected changes in CD4 expression. DNA methylation at the CD4 locus also correlated with inaccessible chromatin. By associating accessible regions with nearby genes, gene expression was found to correlate with accessibility changes. T cell and immune system activation pathways were identified when comparing regions that changed accessibility from CD4 + T cells to CD8aa + T cells. Different transcription factor binding sites are revealed as chromatin accessibility changes, and these differences may elicit downstream changes in differentiation. This comprehensive description of the epigenetic landscape of AGM T cells identified genes and pathways that could have translational value in therapeutic approaches recapitulating the protective effects CD4 downregulation.

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“…These cells can avoid SIV infection while performing some CD4 + T cell-like functions in the absence or with very low levels of classical CD4 + T-cells. The conversion process is accelerated by SIV infection in AGMs in vitro and induced both in vitro and in vivo by homeostatic cytokines, such as IL-2 ( 50 , 176 ). These virus-resistant hyperfunctional T cells arise through post-thymical downregulation of CD4 by CD4 + T cells causing CD4-to-CD8αα conversion ( 120 ).…”

Section: Homeostatic Regulation Of Immune Cell Populationsmentioning

confidence: 99%

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

2023

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HIV emerged following cross-species transmissions of simian immunodeficiency viruses (SIVs) that naturally infect non-human primates (NHPs) from Africa. While HIV replication and CD4+ T-cell depletion lead to increased gut permeability, microbial translocation, chronic immune activation, and systemic inflammation, the natural hosts of SIVs generally avoid these deleterious consequences when infected with their species-specific SIVs and do not progress to AIDS despite persistent lifelong high viremia due to long-term coevolution with their SIV pathogens. The benign course of natural SIV infection in the natural hosts is in stark contrast to the experimental SIV infection of Asian macaques, which progresses to simian AIDS. The mechanisms of non-pathogenic SIV infections are studied mainly in African green monkeys, sooty mangabeys, and mandrills, while progressing SIV infection is experimentally modeled in macaques: rhesus macaques, pigtailed macaques, and cynomolgus macaques. Here, we focus on the distinctive features of SIV infection in natural hosts, particularly (1): the superior healing properties of the intestinal mucosa, which enable them to maintain the integrity of the gut barrier and prevent microbial translocation, thus avoiding excessive/pathologic immune activation and inflammation usually perpetrated by the leaking of the microbial products into the circulation; (2) the gut microbiome, the disruption of which is an important factor in some inflammatory diseases, yet not completely understood in the course of lentiviral infection; (3) cell population shifts resulting in target cell restriction (downregulation of CD4 or CCR5 surface molecules that bind to SIV), control of viral replication in the lymph nodes (expansion of natural killer cells), and anti-inflammatory effects in the gut (NKG2a/c+ CD8+ T cells); and (4) the genes and biological pathways that can shape genetic adaptations to viral pathogens and are associated with the non-pathogenic outcome of the natural SIV infection. Deciphering the protective mechanisms against SIV disease progression to immunodeficiency, which have been established through long-term coevolution between the natural hosts and their species-specific SIVs, may prompt the development of novel therapeutic interventions, such as drugs that can control gut inflammation, enhance gut healing capacities, or modulate the gut microbiome. These developments can go beyond HIV infection and open up large avenues for correcting gut damage, which is common in many diseases.

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Interleukin-2 Therapy Induces CD4 Downregulation, Which Decreases Circulating CD4 T Cell Counts, in African Green Monkeys

Cited by 4 publications

References 31 publications

Epigenetic silencing of CD4 expression in nonpathogenic SIV infection in African green monkeys

Epigenetic silencing of CD4 expression in nonpathogenic SIV infection in African green monkeys

Epigenetic Reprogramming Leads to Downregulation of CD4 and Functional Changes in African Green Monkey Memory CD4+ T Cells

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

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