scholarly journals New host factors and pathways involved in CD4 downregulation in HIV-1 infected cells

Retrovirology ◽  
2013 ◽  
Vol 10 (S1) ◽  
Author(s):  
Alessia Landi ◽  
Jolien Vermeire ◽  
Veronica Iannucci ◽  
Hanne Vanderstraeten ◽  
Evelien Naessens ◽  
...  
Keyword(s):  
Host Factors ◽  
New Host ◽  
Infected Cells ◽  
Hiv 1

scholarly journals Identification of unrecognized host factors promoting HIV-1 latency

2020 ◽  
Vol 16 (12) ◽  
pp. e1009055
Author(s):  
Zichong Li ◽  
Cyrus Hajian ◽  
Warner C. Greene
Keyword(s):  
Rna Polymerase Ii ◽  
Full Range ◽  
Screening Strategy ◽  
Host Factors ◽  
Host Cells ◽  
Hiv Latency ◽  
New Host ◽  
High Background ◽  
Hiv 1 ◽  
Host Genes

To counter HIV latency, it is important to develop a better understanding of the full range of host factors promoting latency. Their identification could suggest new strategies to reactivate latent proviruses and subsequently kill the host cells (“shock and kill”), or to permanently silence these latent proviruses (“block and lock”). We recently developed a screening strategy termed “Reiterative Enrichment and Authentication of CRISPRi Targets” (REACT) that can unambiguously identify host genes promoting HIV latency, even in the presence of high background “noise” produced by the stochastic nature of HIV reactivation. After applying this strategy in four cell lines displaying different levels of HIV inducibility, we identified FTSJ3, TMEM178A, NICN1 and the Integrator Complex as host genes promoting HIV latency. shRNA knockdown of these four repressive factors significantly enhances HIV expression in primary CD4 T cells, and active HIV infection is preferentially found in cells expressing lower levels of these four factors. Mechanistically, we found that downregulation of these newly identified host inhibitors stimulates different stages of RNA Polymerase II-mediated transcription of HIV-1. The identification and validation of these new host inhibitors provide insight into the novel mechanisms that maintain HIV latency even when cells are activated and undergo cell division.

scholarly journals A CRISPR/Cas9 screen identifies the histone demethylase MINA53 as a novel HIV-1 latency-promoting gene (LPG)

2019 ◽  
Vol 47 (14) ◽  
pp. 7333-7347 ◽  
Author(s):  
Huachao Huang ◽  
Weili Kong ◽  
Maxime Jean ◽  
Guillaume Fiches ◽  
Dawei Zhou ◽  
...  
Keyword(s):  
Local Level ◽  
Histone Demethylase ◽  
Host Factors ◽  
Epigenetic Mark ◽  
Combination Antiretroviral Therapy ◽  
Downstream Effectors ◽  
Infected Cells ◽  
Latent Hiv ◽  
Hiv 1

AbstractAlthough combination antiretroviral therapy is potent to block active replication of HIV-1 in AIDS patients, HIV-1 persists as transcriptionally inactive proviruses in infected cells. These HIV-1 latent reservoirs remain a major obstacle for clearance of HIV-1. Investigation of host factors regulating HIV-1 latency is critical for developing novel antiretroviral reagents to eliminate HIV-1 latent reservoirs. From our recently accomplished CRISPR/Cas9 sgRNA screens, we identified that the histone demethylase, MINA53, is potentially a novel HIV-1 latency-promoting gene (LPG). We next validated MINA53’s function in maintenance of HIV-1 latency by depleting MINA53 using the alternative RNAi approach. We further identified that in vitro MINA53 preferentially demethylates the histone substrate, H3K36me3 and that in cells MINA53 depletion by RNAi also increases the local level of H3K36me3 at LTR. The effort to map the downstream effectors unraveled that H3K36me3 has the cross-talk with another epigenetic mark H4K16ac, mediated by KAT8 that recognizes the methylated H3K36 and acetylated H4K16. Removing the MINA53-mediated latency mechanisms could benefit the reversal of post-integrated latent HIV-1 proviruses for purging of reservoir cells. We further demonstrated that a pan jumonji histone demethylase inhibitor, JIB-04, inhibits MINA53-mediated demethylation of H3K36me3, and JIB-04 synergizes with other latency-reversing agents (LRAs) to reactivate latent HIV-1.

dCas9 targeted chromatin and histone enrichment for mass spectrometry (Catchet-MS) identifies IKZF1 as a novel drug-able target for HIV-1 latency reversal

2021 ◽  
Author(s):  
Enrico Ne ◽  
Raquel Crespo ◽  
Ray Izquierdo-Lara ◽  
Selin Kocer ◽  
Alicja Gorszka ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Transcriptional Repression ◽  
Host Factors ◽  
Hiv Cure ◽  
Polycomb Repressive Complex 2 ◽  
Infected Cells ◽  
Latent Hiv ◽  
Novel Drug ◽  
Enrichment Strategy ◽  
Hiv 1

SummaryA major pharmacological strategy toward HIV cure aims to reverse latency in infected cells as a first step leading to their elimination. While the unbiased identification of molecular targets physically associated with the latent HIV-1 provirus would be highly valuable to unravel the molecular correlates of HIV-1 transcriptional repression and latency reversal, due to technical limitations, this has not been possible. Here we use dCas9 targeted chromatin and histone enrichment strategy coupled to mass spectrometry (Catchet-MS) to isolate the latent and activated HIV-1 5’LTR, followed by MS identification of the differentially locus-bound proteins. Catchet-MS identified known and novel latent 5’LTR-associated host factors. Among these, IKZF1 is a novel HIV-1 transcriptional repressor, required for Polycomb Repressive Complex 2 recruitment to the LTR. We find the drug iberdomide, which targets IKZF1 for degradation, to be a clinically advanced novel LRA that reverses HIV-1 latency in CD4+T-cells isolated from virally suppressed HIV-1 infected participants.

scholarly journals HIV-1 Virus Interactions With Host Proteins: Interaction of the N-terminal Domain of the HIV-1 Capsid Protein With Human Calmodulin

2019 ◽  
Vol 14 (5) ◽  
pp. 1934578X1984919
Author(s):  
Ywh-Min Tzou ◽  
Ronald Shin ◽  
N. Rama Krishna
Keyword(s):  
Capsid Protein ◽  
Host Factors ◽  
Host Proteins ◽  
Terminal Domain ◽  
Immunodeficiency Virus ◽  
Infected Cells ◽  
Virus Interactions ◽  
Precise Role ◽  
Hiv 1

The human immunodeficiency virus (HIV-1 virus) exploits several host factors for assembly, infection, and replication within the infected cells. In this work, we describe the evidence for an interaction of the N-terminal domain of the HIV-1 capsid protein with human calmodulin. The precise role of this interaction within the life cycle of the HIV-1 virus is yet to be defined. Potential roles for this interaction in the viral capsid uncoating are discussed.

scholarly journals HIV-1 Capsid Core: A Bullet to the Heart of the Target Cell

2021 ◽  
Vol 12 ◽  
Author(s):  
Elenia Toccafondi ◽  
Daniela Lener ◽  
Matteo Negroni
Keyword(s):  
Genetic Material ◽  
Host Factors ◽  
Retroviral Infection ◽  
Infectious Process ◽  
Infected Cells ◽  
Material Translocation ◽  
Infectious Cycle ◽  
Hiv 1 ◽  
Genomic Material

The first step of the intracellular phase of retroviral infection is the release of the viral capsid core in the cytoplasm. This structure contains the viral genetic material that will be reverse transcribed and integrated into the genome of infected cells. Up to recent times, the role of the capsid core was considered essentially to protect this genetic material during the earlier phases of this process. However, increasing evidence demonstrates that the permanence inside the cell of the capsid as an intact, or almost intact, structure is longer than thought. This suggests its involvement in more aspects of the infectious cycle than previously foreseen, particularly in the steps of viral genomic material translocation into the nucleus and in the phases preceding integration. During the trip across the infected cell, many host factors are brought to interact with the capsid, some possessing antiviral properties, others, serving as viral cofactors. All these interactions rely on the properties of the unique component of the capsid core, the capsid protein CA. Likely, the drawback of ensuring these multiple functions is the extreme genetic fragility that has been shown to characterize this protein. Here, we recapitulate the busy agenda of an HIV-1 capsid in the infectious process, in particular in the light of the most recent findings.

scholarly journals A Two-Color Haploid Genetic Screen Identifies Novel Host Factors Involved in HIV-1 Latency

mBio ◽  
2021 ◽  
Author(s):  
Michael Röling ◽  
Mahsa Mollapour Sisakht ◽  
Enrico Ne ◽  
Panagiotis Moulos ◽  
Raquel Crespo ◽  
...  
Keyword(s):  
Antiretroviral Therapy ◽  
Genetic Screen ◽  
Host Factors ◽  
Major Obstacle ◽  
Combination Antiretroviral Therapy ◽  
Viral Eradication ◽  
Novel Host ◽  
Infected Cells ◽  
Latent Hiv ◽  
Hiv 1

A reservoir of latently HIV-1-infected cells persists in the presence of combination antiretroviral therapy (cART), representing a major obstacle for viral eradication. Reactivation of the latent HIV-1 provirus is part of curative strategies which aim to promote clearance of the infected cells.

scholarly journals Induction of Autophagy to Achieve a Human Immunodeficiency Virus Type 1 Cure

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1798
Author(s):  
Grant R. Campbell ◽  
Stephen A. Spector
Keyword(s):  
Human Immunodeficiency Virus ◽  
Antiretroviral Therapy ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Functional Cure ◽  
Immunodeficiency Virus ◽  
Latently Infected ◽  
Infected Cells ◽  
Hiv 1

Effective antiretroviral therapy has led to significant human immunodeficiency virus type 1 (HIV-1) suppression and improvement in immune function. However, the persistence of integrated proviral DNA in latently infected reservoir cells, which drive viral rebound post-interruption of antiretroviral therapy, remains the major roadblock to a cure. Therefore, the targeted elimination or permanent silencing of this latently infected reservoir is a major focus of HIV-1 research. The most studied approach in the development of a cure is the activation of HIV-1 expression to expose latently infected cells for immune clearance while inducing HIV-1 cytotoxicity—the “kick and kill” approach. However, the complex and highly heterogeneous nature of the latent reservoir, combined with the failure of clinical trials to reduce the reservoir size casts doubt on the feasibility of this approach. This concern that total elimination of HIV-1 from the body may not be possible has led to increased emphasis on a “functional cure” where the virus remains but is unable to reactivate which presents the challenge of permanently silencing transcription of HIV-1 for prolonged drug-free remission—a “block and lock” approach. In this review, we discuss the interaction of HIV-1 and autophagy, and the exploitation of autophagy to kill selectively HIV-1 latently infected cells as part of a cure strategy. The cure strategy proposed has the advantage of significantly decreasing the size of the HIV-1 reservoir that can contribute to a functional cure and when optimised has the potential to eradicate completely HIV-1.

scholarly journals PCIP-seq: simultaneous sequencing of integrated viral genomes and their insertion sites with long reads

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Maria Artesi ◽  
Vincent Hahaut ◽  
Basiel Cole ◽  
Laurens Lambrechts ◽  
Fereshteh Ashrafi ◽  
...  
Keyword(s):  
Viral Genome ◽  
Clonal Expansion ◽  
Endogenous Retroviruses ◽  
Viral Genomes ◽  
Short Read Sequencing ◽  
Long Reads ◽  
Infected Cells ◽  
Insertion Sites ◽  
Viral Insertion ◽  
Hiv 1

AbstractThe integration of a viral genome into the host genome has a major impact on the trajectory of the infected cell. Integration location and variation within the associated viral genome can influence both clonal expansion and persistence of infected cells. Methods based on short-read sequencing can identify viral insertion sites, but the sequence of the viral genomes within remains unobserved. We develop PCIP-seq, a method that leverages long reads to identify insertion sites and sequence their associated viral genome. We apply the technique to exogenous retroviruses HTLV-1, BLV, and HIV-1, endogenous retroviruses, and human papillomavirus.

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