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Regulation of HIV-1 Transcription and Latency

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A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Human Virology and Viral Diseases".

Deadline for manuscript submissions: closed (30 November 2023) | Viewed by 19566

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Dr. Iván D'Orso

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Guest Editor

Department of Microbiology, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Interests: HIV-1 gene expression; transcription; chromatin; epigenetics; RNA polymerase II; CD4⁺ T cell signaling; CD4⁺ T cell biology; viral regulators; viral latency and reactivation; cancer gene expression

Special Issue Information

Dear Colleagues,

We are launching a Special Issue, entitled “Regulation of HIV-1 Transcription and Latency", with the goal of discussing established dogmas and providing an update on recent discoveries in this rapidly growing field.

At every integrated HIV-1 genome there is a transcriptional cycle regulated by viral and host factors, ultimately controlling proviral fate. Despite their critical importance, our understanding of the transcriptional mechanisms regulating HIV-1 proviral fate is limited. This lack of knowledge hampers our ability to manipulate HIV-1 transcription for translational applications. Within this framework, in this Special Issue we aim to publish review and research articles focused on the basic mechanisms of HIV-1 transcriptional regulation as well as applications for its eradication or permanent silencing.

Our understanding of the viral and/or host factors in HIV-1 transcription and their implications for latency control has evolved rapidly in the last decade. Recent studies have changed our view of HIV-1 transcriptional control in the context of latency. Thus, the time is right to have an updated view of the field, with a focus on recent discoveries and future ideas for research. The need for these reviews is further justified by the increasing recognition that both viral and host factors could be valid targets of pharmacological interventions for HIV-1 transcriptional control to manipulate proviral fate. We welcome manuscripts discussing the roles of the site of integration and viral and/or host factors in HIV-1 transcription, as well as their implications for our understanding of latency establishment, maintenance, and reactivation.

Dr. Iván D'Orso
Guest Editor

Manuscript Submission Information

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Keywords

HIV-1 transcription
HIV-1 latency and reactivation
HIV-1 latent reservoir
chromatin and epigenetics
viral and host transcriptional regulators
mechanisms and therapeutic opportunities
role of the integration site
HIV-1 eradication and cure

Published Papers (11 papers)

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Editorial

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3 pages, 159 KiB

Open AccessEditorial

HIV-1 Transcription and Latency in the Spotlight

by Iván D’Orso

Viruses 2024, 16(2), 248; https://doi.org/10.3390/v16020248 - 04 Feb 2024

Viewed by 705

Abstract

At every integrated HIV-1 genome, there is a transcriptional cycle that ultimately shapes proviral fate [...] Full article

(This article belongs to the Special Issue Regulation of HIV-1 Transcription and Latency)

Research

Jump to: Editorial, Review

18 pages, 4588 KiB

Open AccessArticle

Functional Analysis of KAP1/TRIM28 Requirements for HIV-1 Transcription Activation

by Keyera Randolph, Usman Hyder, Ashwini Challa, Erick Perez and Iván D’Orso

Viruses 2024, 16(1), 116; https://doi.org/10.3390/v16010116 - 13 Jan 2024

Viewed by 973

Abstract

HIV-1 latency maintenance and reactivation are regulated by several viral and host factors. One such factor is Krüppel-associated box (KRAB)-associated protein 1 (KAP1: also named TRIM28 or TIF1β). While initial studies have revealed KAP1 to be a positive regulator of latency reversal in transformed and primary CD4⁺ T cells, subsequent studies have proposed KAP1 to be a repressor required for latency maintenance. Given this discrepancy, in this study, we re-examine KAP1 transcription regulatory functions using a chemical genetics strategy to acutely deplete KAP1 expression to avoid the accumulation of indirect effects. Notably, KAP1 acute loss partially decreased HIV-1 promoter activity in response to activating signals, a function that can be restored upon complementation with exogenous KAP1, thus revealing that KAP1-mediated activation is on target. By combining comprehensive KAP1 domain deletion and mutagenesis in a cell-based reporter assay, we genetically defined the RING finger domain and an Intrinsically Disordered Region as key activating features. Together, our study solidifies the notion that KAP1 activates HIV-1 transcription by exploiting its multi-domain protein arrangement via previously unknown domains and functions. Full article

(This article belongs to the Special Issue Regulation of HIV-1 Transcription and Latency)

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11 pages, 596 KiB

Open AccessCommunication

HIV-1 Remission: Accelerating the Path to Permanent HIV-1 Silencing

by Danielle E. Lyons, Priti Kumar, Nadia R. Roan, Patricia A. Defechereux, Cedric Feschotte, Ulrike C. Lange, Niren Murthy, Pauline Sameshima, Eric Verdin, Julie A. Ake, Matthew S. Parsons, Avindra Nath, Sara Gianella, Davey M. Smith, Esper G. Kallas, Thomas J. Villa, Richard Strange, Betty Mwesigwa, Robert L. Furler O’Brien, Douglas F. Nixon, Lishomwa C. Ndhlovu, Susana T. Valente and Melanie Ott Show full author list Hide full author list

Viruses 2023, 15(11), 2171; https://doi.org/10.3390/v15112171 - 28 Oct 2023

Cited by 2 | Viewed by 4459

Abstract

Despite remarkable progress, a cure for HIV-1 infection remains elusive. Rebound competent latent and transcriptionally active reservoir cells persevere despite antiretroviral therapy and rekindle infection due to inefficient proviral silencing. We propose a novel “block-lock-stop” approach, entailing long term durable silencing of viral expression towards an irreversible transcriptionally inactive latent provirus to achieve long term antiretroviral free control of the virus. A graded transformation of remnant HIV-1 in PLWH from persistent into silent to permanently defective proviruses is proposed, emulating and accelerating the natural path that human endogenous retroviruses (HERVs) take over millions of years. This hypothesis was based on research into delineating the mechanisms of HIV-1 latency, lessons from latency reversing agents and advances of Tat inhibitors, as well as expertise in the biology of HERVs. Insights from elite controllers and the availability of advanced genome engineering technologies for the direct excision of remnant virus set the stage for a rapid path to an HIV-1 cure. Full article

(This article belongs to the Special Issue Regulation of HIV-1 Transcription and Latency)

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23 pages, 2951 KiB

Open AccessArticle

A CRISPR Screen of HIV Dependency Factors Reveals That CCNT1 Is Non-Essential in T Cells but Required for HIV-1 Reactivation from Latency

by Terry L. Hafer, Abby Felton, Yennifer Delgado, Harini Srinivasan and Michael Emerman

Viruses 2023, 15(9), 1863; https://doi.org/10.3390/v15091863 - 31 Aug 2023

Cited by 1 | Viewed by 1587

Abstract

We sought to explore the hypothesis that host factors required for HIV-1 replication also play a role in latency reversal. Using a CRISPR gene library of putative HIV dependency factors, we performed a screen to identify genes required for latency reactivation. We identified several HIV-1 dependency factors that play a key role in HIV-1 latency reactivation including ELL, UBE2M, TBL1XR1, HDAC3, AMBRA1, and ALYREF. The knockout of Cyclin T1 (CCNT1), a component of the P-TEFb complex that is important for transcription elongation, was the top hit in the screen and had the largest effect on HIV latency reversal with a wide variety of latency reversal agents. Moreover, CCNT1 knockout prevents latency reactivation in a primary CD4+ T cell model of HIV latency without affecting the activation of these cells. RNA sequencing data showed that CCNT1 regulates HIV-1 proviral genes to a larger extent than any other host gene and had no significant effects on RNA transcripts in primary T cells after activation. We conclude that CCNT1 function is non-essential in T cells but is absolutely required for HIV latency reversal. Full article

(This article belongs to the Special Issue Regulation of HIV-1 Transcription and Latency)

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26 pages, 7039 KiB

Open AccessArticle

Upstream Stimulatory Factors Regulate HIV-1 Latency and Are Required for Robust T Cell Activation

by Riley M. Horvath and Ivan Sadowski

Viruses 2023, 15(7), 1470; https://doi.org/10.3390/v15071470 - 28 Jun 2023

Cited by 1 | Viewed by 1276

Abstract

HIV-1 provirus expression is controlled by signaling pathways that are responsive to T cell receptor engagement, including those involving Ras and downstream protein kinases. The induction of transcription from the HIV-1 LTR in response to Ras signaling requires binding of the Ras-responsive element binding factor (RBF-2) to conserved cis elements flanking the enhancer region, designated RBE3 and RBE1. RBF-2 is composed minimally of the USF1, USF2, and TFII-I transcription factors. We recently determined that TFII-I regulates transcriptional elongation from the LTR through recruitment of the co-activator TRIM24. However, the function of USF1 and USF2 for this effect are uncharacterized. Here, we find that genetic deletion of USF2 but not USF1 in T cells inhibits HIV-1 expression. The loss of USF2 caused a reduction in expression of the USF1 protein, an effect that was not associated with decreased USF1 mRNA abundance. USF1 and USF2 were previously shown to exist predominately as heterodimers and to cooperatively regulate target genes. To examine cooperativity between these factors, we performed RNA-seq analysis of T cell lines bearing knockouts of the genes encoding these factors. In untreated cells, we found limited evidence of coordinated global gene regulation between USF1 and USF2. In contrast, we observed a high degree of genome-wide cooperative regulation of RNA expression between these factors in cells stimulated with the combination of PMA and ionomycin. In particular, we found that the deletion of USF1 or USF2 restricted T cell activation response. These observations indicate that USF2, but not USF1, is crucial for HIV-1 expression, while the combined function of these factors is required for a robust T cell inflammatory response. Full article

(This article belongs to the Special Issue Regulation of HIV-1 Transcription and Latency)

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Review

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27 pages, 2194 KiB

Open AccessReview

HIV Expression in Infected T Cell Clones

by Jason W. Rausch, Shadab Parvez, Sachi Pathak, Adam A. Capoferri and Mary F. Kearney

Viruses 2024, 16(1), 108; https://doi.org/10.3390/v16010108 - 11 Jan 2024

Cited by 3 | Viewed by 1900

Abstract

The principal barrier to an HIV-1 cure is the persistence of infected cells harboring replication-competent proviruses despite antiretroviral therapy (ART). HIV-1 transcriptional suppression, referred to as viral latency, is foremost among persistence determinants, as it allows infected cells to evade the cytopathic effects of virion production and killing by cytotoxic T lymphocytes (CTL) and other immune factors. HIV-1 persistence is also governed by cellular proliferation, an innate and essential capacity of CD4+ T cells that both sustains cell populations over time and enables a robust directed response to immunological threats. However, when HIV-1 infects CD4+ T cells, this capacity for proliferation can enable surreptitious HIV-1 propagation without the deleterious effects of viral gene expression in latently infected cells. Over time on ART, the HIV-1 reservoir is shaped by both persistence determinants, with selective forces most often favoring clonally expanded infected cell populations harboring transcriptionally quiescent proviruses. Moreover, if HIV latency is incomplete or sporadically reversed in clonal infected cell populations that are replenished faster than they are depleted, such populations could both persist indefinitely and contribute to low-level persistent viremia during ART and viremic rebound if treatment is withdrawn. In this review, select genetic, epigenetic, cellular, and immunological determinants of viral transcriptional suppression and clonal expansion of HIV-1 reservoir T cells, interdependencies among these determinants, and implications for HIV-1 persistence will be presented and discussed. Full article

(This article belongs to the Special Issue Regulation of HIV-1 Transcription and Latency)

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27 pages, 881 KiB

Open AccessReview

Breaking the Silence: Regulation of HIV Transcription and Latency on the Road to a Cure

by Natasha N. Duggan, Tatjana Dragic, Sumit K. Chanda and Lars Pache

Viruses 2023, 15(12), 2435; https://doi.org/10.3390/v15122435 - 15 Dec 2023

Viewed by 1694

Abstract

Antiretroviral therapy (ART) has brought the HIV/AIDS epidemic under control, but a curative strategy for viral eradication is still needed. The cessation of ART results in rapid viral rebound from latently infected CD4+ T cells, showing that control of viral replication alone does not fully restore immune function, nor does it eradicate viral reservoirs. With a better understanding of factors and mechanisms that promote viral latency, current approaches are primarily focused on the permanent silencing of latently infected cells (“block and lock”) or reactivating HIV-1 gene expression in latently infected cells, in combination with immune restoration strategies to eliminate HIV infected cells from the host (“shock and kill”). In this review, we provide a summary of the current, most promising approaches for HIV-1 cure strategies, including an analysis of both latency-promoting agents (LPA) and latency-reversing agents (LRA) that have shown promise in vitro, ex vivo, and in human clinical trials to reduce the HIV-1 reservoir. Full article

(This article belongs to the Special Issue Regulation of HIV-1 Transcription and Latency)

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21 pages, 1740 KiB

Open AccessReview

Mathematical Models of HIV-1 Dynamics, Transcription, and Latency

by Iván D’Orso and Christian V. Forst

Viruses 2023, 15(10), 2119; https://doi.org/10.3390/v15102119 - 19 Oct 2023

Viewed by 1479

Abstract

HIV-1 latency is a major barrier to curing infections with antiretroviral therapy and, consequently, to eliminating the disease globally. The establishment, maintenance, and potential clearance of latent infection are complex dynamic processes and can be best described with the help of mathematical models followed by experimental validation. Here, we review the use of viral dynamics models for HIV-1, with a focus on applications to the latent reservoir. Such models have been used to explain the multi-phasic decay of viral load during antiretroviral therapy, the early seeding of the latent reservoir during acute infection and the limited inflow during treatment, the dynamics of viral blips, and the phenomenon of post-treatment control. Finally, we discuss that mathematical models have been used to predict the efficacy of potential HIV-1 cure strategies, such as latency-reversing agents, early treatment initiation, or gene therapies, and to provide guidance for designing trials of these novel interventions. Full article

(This article belongs to the Special Issue Regulation of HIV-1 Transcription and Latency)

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21 pages, 4348 KiB

Open AccessReview

Transcriptional Stochasticity as a Key Aspect of HIV-1 Latency

by Alexia Damour, Vera Slaninova, Ovidiu Radulescu, Edouard Bertrand and Eugenia Basyuk

Viruses 2023, 15(9), 1969; https://doi.org/10.3390/v15091969 - 21 Sep 2023

Cited by 3 | Viewed by 1265

Abstract

This review summarizes current advances in the role of transcriptional stochasticity in HIV-1 latency, which were possible in a large part due to the development of single-cell approaches. HIV-1 transcription proceeds in bursts of RNA production, which stem from the stochastic switching of the viral promoter between ON and OFF states. This switching is caused by random binding dynamics of transcription factors and nucleosomes to the viral promoter and occurs at several time scales from minutes to hours. Transcriptional bursts are mainly controlled by the core transcription factors TBP, SP1 and NF-κb, the chromatin status of the viral promoter and RNA polymerase II pausing. In particular, spontaneous variability in the promoter chromatin creates heterogeneity in the response to activators such as TNF-α, which is then amplified by the Tat feedback loop to generate high and low viral transcriptional states. This phenomenon is likely at the basis of the partial and stochastic response of latent T cells from HIV-1 patients to latency-reversing agents, which is a barrier for the development of shock-and-kill strategies of viral eradication. A detailed understanding of the transcriptional stochasticity of HIV-1 and the possibility to precisely model this phenomenon will be important assets to develop more effective therapeutic strategies. Full article

(This article belongs to the Special Issue Regulation of HIV-1 Transcription and Latency)

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12 pages, 657 KiB

Open AccessReview

IL-15 and N-803 for HIV Cure Approaches

by J. Natalie Howard and Alberto Bosque

Viruses 2023, 15(9), 1912; https://doi.org/10.3390/v15091912 - 12 Sep 2023

Cited by 3 | Viewed by 1595

Abstract

In spite of the advances in antiretroviral therapy to treat HIV infection, the presence of a latent reservoir of HIV-infected cells represents the largest barrier towards finding a cure. Among the different strategies being pursued to eliminate or reduce this latent reservoir, the γc-cytokine IL-15 or its superagonist N-803 are currently under clinical investigation, either alone or with other interventions. They have been shown to reactivate latent HIV and enhance immune effector function, both of which are potentially required for effective reduction of latent reservoirs. In here, we present a comprehensive literature review of the different in vitro, ex vivo, and in vivo studies conducted to date that are aimed at targeting HIV reservoirs using IL-15 and N-803. Full article

(This article belongs to the Special Issue Regulation of HIV-1 Transcription and Latency)

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17 pages, 1013 KiB

Open AccessReview

New Concepts in Therapeutic Manipulation of HIV-1 Transcription and Latency: Latency Reversal versus Latency Prevention

by Catherine A. Lewis, David M. Margolis and Edward P. Browne

Viruses 2023, 15(8), 1677; https://doi.org/10.3390/v15081677 - 31 Jul 2023

Cited by 3 | Viewed by 1529

Abstract

Antiretroviral therapy (ART) has dramatically improved the prognosis for people living with HIV-1, but a cure remains elusive. The largest barrier to a cure is the presence of a long-lived latent reservoir that persists within a heterogenous mix of cell types and anatomical compartments. Efforts to eradicate the latent reservoir have primarily focused on latency reversal strategies. However, new work has demonstrated that the majority of the long-lived latent reservoir is established near the time of ART initiation, suggesting that it may be possible to pair an intervention with ART initiation to prevent the formation of a sizable fraction of the latent reservoir. Subsequent treatment with latency reversal agents, in combination with immune clearance agents, may then be a more tractable strategy for fully clearing the latent reservoir in people newly initiating ART. Here, we summarize molecular mechanisms of latency establishment and maintenance, ongoing efforts to develop effective latency reversal agents, and newer efforts to design latency prevention agents. An improved understanding of the molecular mechanisms involved in both the establishment and maintenance of latency will aid in the development of new latency prevention and reversal approaches to ultimately eradicate the latent reservoir. Full article

(This article belongs to the Special Issue Regulation of HIV-1 Transcription and Latency)

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