Background: The multiplicity, heterogeneity, and dynamic nature of human immunodeficiency virus type-1 (HIV-1) latency mechanisms are reflected in the current lack of functional cure for HIV-1. Accordingly, all classes of latency-reversing agents (LRAs) have been reported to present variable ex vivo potencies. Here, we investigated the molecular mechanisms underlying the potency variability of one LRA: the DNA methylation inhibitor 5-aza-2'-deoxycytidine (5-AzadC).
View Article and Find Full Text PDFIntroduction of cART in 1996 has drastically increased the life expectancy of people living with HIV-1. However, this treatment has not allowed cure as cessation of cART is associated with a rapid viral rebound. The main barrier to the eradication of the virus is related to the persistence of latent HIV reservoirs.
View Article and Find Full Text PDFAmong many cellular transcriptional regulators, Bcl11b/CTIP2 and HGMA1 have been described to control the establishment and the persistence of HIV-1 latency in microglial cells, the main viral reservoir in the brain. In this present work, we identify and characterize a transcription factor i.e.
View Article and Find Full Text PDFExpert Opin Ther Targets
November 2016
Combination Antiretroviral Therapy (cART) has not allowed the cure of HIV. The main obstacle to HIV eradication is the existence of quiescent reservoirs. Several other limitations of cART have been described, such as strict life-long treatment and high costs, restricting it to Western countries, as well as the development of multidrug resistance.
View Article and Find Full Text PDFThe transcription factor CTIP2 (BCL11B) is a multifunctional protein involved in numerous cell physiological processes. To date, many molecular mechanisms underlying this process have been discovered, which highlighted the importance of the epigenetic regulation of genes and the regulation of the elongation factor P-TEFb. Furthermore studies of the deregulation of CTIP2 showed the association of CTIP2 to numerous pathologies including cancer and cardiac hypertrophy.
View Article and Find Full Text PDFActive positive transcription elongation factor b (P-TEFb) is essential for cellular and human immunodeficiency virus type 1 (HIV-1) transcription elongation. CTIP2 represses P-TEFb activity in a complex containing 7SK RNA and HEXIM1. Recently, the inactive 7SK/P-TEFb small nuclear RNP (snRNP) has been detected at the HIV-1 core promoter as well as at the promoters of cellular genes, but a recruiting mechanism still remains unknown to date.
View Article and Find Full Text PDFCTIP2 is a key transcriptional regulator involved in numerous physiological functions. Initial works have shown the importance of CTIP2 in the establishment and persistence of HIV latency in microglial cells, the main latent/quiescent viral reservoir in the brain. Recent studies have highlighted the importance of CTIP2 in several other pathologies, such as cardiac hypertrophy and various types of human malignancies.
View Article and Find Full Text PDFBackground: Anti-HIV-1 therapy depends upon multiple agents that target different phases of the viral replication cycle. Recent reports indicate that plant and human DING proteins are unique in targeting viral gene transcription as the basis of their anti-HIV-1 therapy.
Methods: Two cloned DING genes from Pseudomonas were transiently expressed in human cells, and effects on NFκB-mediated transcription, HIV-1 transcription, and HIV-1 production were measured.
The positive transcription elongation factor b (P-TEFb) is involved in physiological and pathological events including inflammation, cancer, AIDS, and cardiac hypertrophy. The balance between its active and inactive form is tightly controlled to ensure cellular integrity. We report that the transcriptional repressor CTIP2 is a major modulator of P-TEFb activity.
View Article and Find Full Text PDFJ Antimicrob Chemother
May 2012
The introduction of highly active antiretroviral therapy (HAART) in 1996 has transformed a lethal disease to a chronic pathology with a dramatic decrease in mortality and morbidity of AIDS-related symptoms in infected patients. However, HAART has not allowed the cure of HIV infection, the main obstacle to HIV eradication being the existence of quiescent reservoirs. Several other problems have been encountered with HAART (such as side effects, adherence to medication, emergence of resistance and cost of treatment), and these motivate the search for new ways to treat these patients.
View Article and Find Full Text PDFMicroglial cells are the main HIV-1 targets in the central nervous system (CNS) and constitute an important reservoir of latently infected cells. Establishment and persistence of these reservoirs rely on the chromatin structure of the integrated proviruses. We have previously demonstrated that the cellular cofactor CTIP2 forces heterochromatin formation and HIV-1 gene silencing by recruiting HDAC and HMT activities at the integrated viral promoter.
View Article and Find Full Text PDFThe Human Phosphate-Binding protein (HPBP) is a serendipitously discovered lipoprotein that binds phosphate with high affinity. HPBP belongs to the DING protein family, involved in various biological processes like cell cycle regulation. We report that HPBP inhibits HIV-1 gene transcription and replication in T cell line, primary peripherical blood lymphocytes and primary macrophages.
View Article and Find Full Text PDFThe introduction of the highly active antiretroviral therapy (HAART) has greatly improved survival. However, these treatments fail to definitively cure the patients and unveil the presence of quiescent HIV-1 reservoirs like cells from monocyte-macrophage lineage. A purge, or at least a significant reduction of these long lived HIV-1 reservoirs will be needed to raise the hope of the viral eradication.
View Article and Find Full Text PDFThe latent HIV-1 reservoirs established early during infection present a major obstacle for virus eradication. Complete eradication of the virus from infected patients may require a purge of the reservoirs. Since the development of a HIV-1 vaccine is not achieved, and therefore remains a major challenge for the immunologists, future direction towards an effective curative therapy for HIV-1 infection will rely on the development of original therapeutic strategies which take into account latency, chronic replication and accessibility to tissue-sanctuary.
View Article and Find Full Text PDFThe HIV-1 envelope glycoprotein complex (Env) is the focus of vaccine development aimed at eliciting humoral immunity. Env's extensive and heterogeneous N-linked glycosylation affects folding, binding to lectin receptors, antigenicity and immunogenicity. We characterized recombinant Env proteins and virus particles produced in mammalian cells that lack N-acetylglucosaminyltransferase I (GnTI), an enzyme necessary for the conversion of oligomannose N-glycans to complex N-glycans.
View Article and Find Full Text PDFThe introduction of the highly active antiretroviral therapy (HAART) in 1996 has greatly extended survival and raised hopes for the eradication of HIV-1. Unfortunately, the optimism declined by revealing the existence of latent HIV-1 reservoirs in cells targeted by the virus. The long-lived HIV-1 reservoirs constitute a major obstacle to the eradication of HIV-1.
View Article and Find Full Text PDFThe introduction in 1996 of the HAART raised hopes for the eradication of HIV-1. Unfortunately, the discovery of latent HIV-1 reservoirs in CD4+ T cells and in the monocyte-macrophage lineage proved the optimism to be premature. The long-lived HIV-1 reservoirs constitute a major obstacle to the eradication of HIV-1.
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