Molecular mechanisms of HIV latency

Cary, Daniele C.; Fujinaga, Koh; Peterlin, B. Matija

doi:10.1172/jci80565

Cited by 125 publications

(136 citation statements)

References 96 publications

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“…As reviewed elsewhere in this issue (5), little or no transcription of proviral DNA occurs in resting CD4 + T cells that are latently infected with HIV-1. In the absence of any expression of viral proteins, these cells evade detection and destruction by the innate and adaptive immune systems.…”

Section: Introductionmentioning

confidence: 99%

Hematopoietic stem cell transplantation for HIV cure

Kuritzkes¹

2016

Journal of Clinical Investigation

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Section: Introductionmentioning

confidence: 99%

Hematopoietic stem cell transplantation for HIV cure

Kuritzkes¹

2016

Journal of Clinical Investigation

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“…It was reported that low levels of nuclear NF-κB in resting CD4+ T cells may support the establishment of HIV latency [41]. Upon cell activation, the p50/p65 heterodimer binds to NF-κB sites in the HIV LTR, recruits Histone Acetyl Transferase (HAT) to acetylate the histone tails, opens nucleosomes to facilitate HIV transcription and recruits HDAC1 leading to the suppression of HIV expression [42]. Our data showed that, in addition to activating NF-κB p65 itself, p53 expression assists and is involved in NF-κB p65-driven reactivation of HIV-1 latently infected U1 cells.…”

Section: Resultsmentioning

confidence: 99%

p53 Expression Activation of HIV-1 Latency in U1 Cells

Wang¹,

Jiangqin²,

Christelle³

et al. 2017

Int J Virol AIDS

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“…Although other transcription factors also bind to the HIV-1 LTR promoter and regulate viral gene expression, NF-B, as a master regulator of viral and gene transcription, is one of the most critical cellular factors in regulating HIV-1 latency (7-14). Lower levels of nuclear NF-B in resting CD4 ϩ T cells than in activated cells contribute to the establishment and maintenance of HIV-1 latency (14,40). Activation of NF-B signaling has been proposed as an attractive target for the development of agents to reverse HIV-1 latency (41); however, NF-B signaling modulates multiple cellular events, and the nonspecific activation of bystander T cells by NF-B signal-activating agents should be evaluated cautiously (42).…”

Section: Discussionmentioning

confidence: 99%

“…Transcriptional inefficiency of HIV-1 gene expression is an important mechanism of viral latency (2, 6, 7). HIV-1 gene transcription and viral reactivation from latency require the activity of nuclear factor kappa B (NF-B), whose modulation by cellular factors contributes to the establishment and maintenance of HIV-1 latency (7)(8)(9)(10)(11)(12)(13)(14).…”

mentioning

confidence: 99%

Naf1 Regulates HIV-1 Latency by Suppressing Viral Promoter-Driven Gene Expression in Primary CD4 ⁺ T Cells

Wang

Kuang

et al. 2017

J Virol

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HIV-1 latency is characterized by reversible silencing of viral transcription driven by the long terminal repeat (LTR) promoter of HIV-1. Cellular and viral factors regulating LTR activity contribute to HIV-1 latency, and certain repressive cellular factors modulate viral transcription silencing. Nef-associated factor 1 (Naf1) is a host nucleocytoplasmic shuttling protein that regulates multiple cellular signaling pathways and HIV-1 production. We recently reported that nuclear Naf1 promoted nuclear export of unspliced HIV-1 gag mRNA, leading to increased Gag production. Here we demonstrate new functions of Naf1 in regulating HIV-1 persistence. We found that Naf1 contributes to the maintenance of HIV-1 latency by inhibiting LTR-driven HIV-1 gene transcription in a nuclear factor kappa B-dependent manner. Interestingly, Naf1 knockdown significantly enhanced viral reactivation in both latently HIV-1-infected Jurkat T cells and primary central memory CD4+ T cells. Furthermore, Naf1 knockdown in resting CD4+ T cells from HIV-1-infected individuals treated with antiretroviral therapy significantly increased viral reactivation upon T-cell activation, suggesting an important role of Naf1 in modulating HIV-1 latency in vivo. Our findings provide new insights for a better understanding of HIV-1 latency and suggest that inhibition of Naf1 activity to activate latently HIV-1-infected cells may be a potential therapeutic strategy. IMPORTANCE HIV-1 latency is characterized mainly by a reversible silencing of LTR promoter-driven transcription of an integrated provirus. Cellular and viral proteins regulating LTR activity contribute to the modulation of HIV-1 latency. In this study, we found that the host protein Naf1 inhibited HIV-1 LTR-driven transcription of HIV genes and contributed to the maintenance of HIV-1 latency. Our findings provide new insights into the effects of host modulation on HIV-1 latency, which may lead to a potential therapeutic strategy for HIV persistence by targeting the Naf1 protein.

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Molecular mechanisms of HIV latency

Cited by 125 publications

References 96 publications

Hematopoietic stem cell transplantation for HIV cure

Hematopoietic stem cell transplantation for HIV cure

p53 Expression Activation of HIV-1 Latency in U1 Cells

Naf1 Regulates HIV-1 Latency by Suppressing Viral Promoter-Driven Gene Expression in Primary CD4 ⁺ T Cells

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Molecular mechanisms of HIV latency

Cited by 125 publications

References 96 publications

Hematopoietic stem cell transplantation for HIV cure

Hematopoietic stem cell transplantation for HIV cure

p53 Expression Activation of HIV-1 Latency in U1 Cells

Naf1 Regulates HIV-1 Latency by Suppressing Viral Promoter-Driven Gene Expression in Primary CD4 + T Cells

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Naf1 Regulates HIV-1 Latency by Suppressing Viral Promoter-Driven Gene Expression in Primary CD4 ⁺ T Cells