Epigenetic alterations are associated with monocyte immune dysfunctions in HIV-1 infection

Abstract

Monocytes are key cells in the immune dysregulation observed during human immunodeficiency virus (HIV) infection. The events that take place specifically in monocytes may contribute to the systemic immune dysfunction characterized by excessive immune activation in infected individuals, which directly correlates with pathogenesis and progression of the disease. Here, we investigated the immune dysfunction in monocytes from untreated and treated HIV + patients and associated these findings with epigenetic changes. Monocytes from HIV patients showed dysfunctional ability of phagocytosis and killing, and exhibited dysregulated cytokines and reactive oxygen species production after M. tuberculosis challenge in vitro. In addition, we showed that the expression of enzymes responsible for epigenetic changes was altered during HIV infection and was more prominent in patients that had high levels of soluble CD163 (sCD163), a newly identified plasmatic HIV progression biomarker. Among the enzymes, histone acetyltransferase 1 (HAT1) was the best epigenetic biomarker correlated with HIV - sCD163 high patients. In conclusion, we confirmed that HIV impairs effector functions of monocytes and these alterations are associated with epigenetic changes that once identified could be used as targets in therapies aiming the reduction of the systemic activation state found in HIV patients.

Bisubstrate inhibitors to target histone acetyltransferase 1

“…HAT1 can be a biomarker of the disease state (Espíndola et al, 2018). These disease studies shed light on the roles that HAT1 plays in pathology and suggest that HAT1 could be a potential molecular target in the design of new therapeutics treatment.…”

“…Cancer formation and progression can occur due to the dysregulation of histone‐modifying enzymes that regulate gene transcription, cell differentiation, proliferation, and apoptosis (Gelato Kathy & Fischle, ; Miglena, Michael, & Marc, ; Sun, Man, Tan, Nimer, & Wang, ). HAT1 has been linked to various pathological conditions, such as cardiovascular diseases (Liu et al., ), colorectal cancer (Seiden‐Long et al., ), liver cancer (Pogribny, Tryndyak, Muskhelishvili, Rusyn, & Ross, ), lung cancer (Jin, Tian, & Li, ), human immunodeficiency virus (HIV; Espíndola et al., ), and the dysregulation of immune responses (Jin et al., ). Besides the aberrant expression, dys‐localization of HAT1 can also aid in disease progression (Parthun, ; Seiden‐Long et al., ).…”

“…Besides the aberrant expression, dys‐localization of HAT1 can also aid in disease progression (Parthun, ; Seiden‐Long et al., ). It has been reported in an HIV study that HAT1 can be a biomarker of the disease state (Espíndola et al., ). These disease studies shed light on the roles that HAT1 plays in pathology and suggest that HAT1 could be a potential molecular target in the design of new therapeutics treatment.…”

Efeito do tratamento com agentes hipometilantes: modulação das funções de monócitos e macrófagos e possível repercussão terapêutica

“…Como já mencionado, as alterações epigenéticas estão associadas a diversos processos fisiológicos e patológicos, e sua importância no desenvolvimento e progressão de diversas doenças constitui interesse de grupos de pesquisa, na busca de compreender os mecanismos moleculares envolvidos e determinar biomarcadores que possibilitem auxiliar no diagnóstico, progressão e tratamentos destes processos patológicos. Tais modificações tem sido estudadas no desenvolvimento e progressão tumoral (Baxter et al, 2014;Toh et al, 2017;Nebbioso et al, 2018), bem como em doenças infecciosas (Samanta et al, 2017;Espíndola et al, 2018; Grabiec e Potempa, 2018), neurológicas (Qureshi e Mehler, 2014), autoimunes (Ciechomska et al, 2014), cardiovasculares (Ordovás e Smith, 2010), metabólicascomo no diabetes e obesidade (Rosen et al, 2018), dentre várias outras .…”

“…A disfunção imune foi associada a alterações no perfil de expressão de enzimas epigenéticas induzidas pela infecção com HIV, dentre as quais, a expressão da histona acetiltrasferase 1 (HAT1). Em pacientes progressores rápidos, determinados pelos altos níveis do biomarcador plasmático sCD163, o aumento da expressão de HAT1 apresentou potencial utilização como marcador na infecção pelo HIV, podendo ser alvo de estratégias terapêuticas com objetivo de reduzir a ativação imune sistêmica observada nestes pacientes(Espíndola et al, 2018).Além de estarem diretamente envolvidas com o processo patológico, as alterações epigenéticas estão associadas com a resposta imunológica desenvolvida pelo organismo. O desenvolvimento da resposta é orquestrado por células funcionalmente especializadas, que estão sob influência direta do microambiente, e desta forma, as alterações epigenéticas constituem importante mecanismo de regulação, contribuindo para a plasticidade celular e determinação dos diferentes padrões de resposta.…”