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37 pages, 7066 KiB

Open AccessArticle

Identification of Modulators of HIV-1 Proviral Transcription from a Library of FDA-Approved Pharmaceuticals

by Gavin C. Sampey, Sergey Iordanskiy, Michelle L. Pleet, Catherine DeMarino, Fabio Romerio, Renaud Mahieux and Fatah Kashanchi

Viruses 2020, 12(10), 1067; https://doi.org/10.3390/v12101067 - 23 Sep 2020

Cited by 5 | Viewed by 3246

Abstract

Human immunodeficiency virus 1 (HIV-1) is the most prevalent human retrovirus. Recent data show that 34 million people are living with HIV-1 worldwide. HIV-1 infections can lead to AIDS which still causes nearly 20,000 deaths annually in the USA alone. As this retrovirus [...] Read more.

Human immunodeficiency virus 1 (HIV-1) is the most prevalent human retrovirus. Recent data show that 34 million people are living with HIV-1 worldwide. HIV-1 infections can lead to AIDS which still causes nearly 20,000 deaths annually in the USA alone. As this retrovirus leads to high morbidity and mortality conditions, more effective therapeutic regimens must be developed to treat these viral infections. A key target for intervention for which there are no current FDA-approved modulators is at the point of proviral transcription. One successful method for identifying novel therapeutics for treating infectious diseases is the repurposing of pharmaceuticals that are approved by the FDA for alternate indications. Major benefits of using FDA-approved drugs include the fact that the compounds have well established toxicity profiles, approved manufacturing processes, and immediate commercial availability to the patients. Here, we demonstrate that pharmaceuticals previously approved for other indications can be utilized to either activate or inhibit HIV-1 proviral transcription. Specifically, we found febuxostat, eltrombopag, and resveratrol to be activators of HIV-1 transcription, while mycophenolate was our lead inhibitor of HIV-1 transcription. Additionally, we observed that the infected cells of lymphoid and myeloid lineage responded differently to our lead transcriptional modulators. Finally, we demonstrated that the use of a multi-dose regimen allowed for enhanced activation with our transcriptional activators. Full article

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

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22 pages, 1773 KiB

Open AccessArticle

CBF-1 Promotes the Establishment and Maintenance of HIV Latency by Recruiting Polycomb Repressive Complexes, PRC1 and PRC2, at HIV LTR

by Adhikarimayum Lakhikumar Sharma, Joseph Hokello, Shilpa Sonti, Sonia Zicari, Lin Sun, Aseel Alqatawni, Michael Bukrinsky, Gary Simon, Ashok Chauhan, Rene Daniel and Mudit Tyagi

Viruses 2020, 12(9), 1040; https://doi.org/10.3390/v12091040 - 18 Sep 2020

Cited by 21 | Viewed by 4045

Abstract

The C-promoter binding factor-1 (CBF-1) is a potent and specific inhibitor of the human immunodeficiency virus (HIV)-1 LTR promoter. Here, we demonstrate that the knockdown of endogenous CBF-1 in latently infected primary CD4+ T cells, using specific small hairpin RNAs (shRNA), resulted in [...] Read more.

The C-promoter binding factor-1 (CBF-1) is a potent and specific inhibitor of the human immunodeficiency virus (HIV)-1 LTR promoter. Here, we demonstrate that the knockdown of endogenous CBF-1 in latently infected primary CD4+ T cells, using specific small hairpin RNAs (shRNA), resulted in the reactivation of latent HIV proviruses. Chromatin immunoprecipitation (ChIP) assays using latently infected primary T cells and Jurkat T-cell lines demonstrated that CBF-1 induces the establishment and maintenance of HIV latency by recruiting polycomb group (PcG/PRC) corepressor complexes or polycomb repressive complexes 1 and 2 (PRC1 and PRC2). Knockdown of CBF-1 resulted in the dissociation of PRCs corepressor complexes enhancing the recruitment of RNA polymerase II (RNAP II) at HIV LTR. Knockdown of certain components of PRC1 and PRC2 also led to the reactivation of latent proviruses. Similarly, the treatment of latently infected primary CD4+ T cells with the PRC2/EZH2 inhibitor, 3-deazaneplanocin A (DZNep), led to their reactivation. Full article

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

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29 pages, 11385 KiB

Open AccessArticle

Systems Biology Analysis of the Antagonizing Effects of HIV-1 Tat Expression in the Brain over Transcriptional Changes Caused by Methamphetamine Sensitization

by Liana V. Basova, James P. Kesby, Marcus Kaul, Svetlana Semenova and Maria Cecilia Garibaldi Marcondes

Viruses 2020, 12(4), 426; https://doi.org/10.3390/v12040426 - 9 Apr 2020

Cited by 9 | Viewed by 5003

Abstract

Methamphetamine (Meth) abuse is common among humans with immunodeficiency virus (HIV). The HIV-1 regulatory protein, trans-activator of transcription (Tat), has been described to induce changes in brain gene transcription that can result in impaired reward circuitry, as well as in inflammatory processes. In [...] Read more.

Methamphetamine (Meth) abuse is common among humans with immunodeficiency virus (HIV). The HIV-1 regulatory protein, trans-activator of transcription (Tat), has been described to induce changes in brain gene transcription that can result in impaired reward circuitry, as well as in inflammatory processes. In transgenic mice with doxycycline-induced Tat protein expression in the brain, i.e., a mouse model of neuroHIV, we tested global gene expression patterns induced by Meth sensitization. Meth-induced locomotor sensitization included repeated daily Meth or saline injections for seven days and Meth challenge after a seven-day abstinence period. Brain samples were collected 30 min after the Meth challenge. We investigated global gene expression changes in the caudate putamen, an area with relevance in behavior and HIV pathogenesis, and performed pathway and transcriptional factor usage predictions using systems biology strategies. We found that Tat expression alone had a very limited impact in gene transcription after the Meth challenge. In contrast, Meth-induced sensitization in the absence of Tat induced a global suppression of gene transcription. Interestingly, the interaction between Tat and Meth broadly prevented the Meth-induced global transcriptional suppression, by maintaining regulation pathways, and resulting in gene expression profiles that were more similar to the controls. Pathways associated with mitochondrial health, initiation of transcription and translation, as well as with epigenetic control, were heavily affected by Meth, and by its interaction with Tat in anti-directional ways. A series of systems strategies have predicted several components impacted by these interactions, including mitochondrial pathways, mTOR/RICTOR, AP-1 transcription factor, and eukaryotic initiation factors involved in transcription and translation. In spite of the antagonizing effects of Tat, a few genes identified in relevant gene networks remained downregulated, such as sirtuin 1, and the amyloid precursor protein (APP). In conclusion, Tat expression in the brain had a low acute transcriptional impact but strongly interacted with Meth sensitization, to modify effects in the global transcriptome. Full article

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

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14 pages, 3422 KiB

Open AccessArticle

Oxygen Levels Affect Macrophage HIV-1 Gene Expression and Delay Resolution of Inflammation in HIV-Tg Mice

by Marina Jerebtsova, Asrar Ahmad, Namita Kumari, Ornela Rutagarama and Sergei Nekhai

Viruses 2020, 12(3), 277; https://doi.org/10.3390/v12030277 - 1 Mar 2020

Cited by 4 | Viewed by 2983

Abstract

While antiretroviral therapy increases the longevity of people living with HIV (PLWH), about 30% of this population suffers from three or more concurrent comorbidities, whose mechanisms are not well understood. Chronic activation and dysfunction of the immune system could be one potential cause [...] Read more.

While antiretroviral therapy increases the longevity of people living with HIV (PLWH), about 30% of this population suffers from three or more concurrent comorbidities, whose mechanisms are not well understood. Chronic activation and dysfunction of the immune system could be one potential cause of these comorbidities. We recently demonstrated reduced macrophage infiltration and delayed resolution of inflammation in the lungs of HIV-transgenic mice. Additionally, trans-endothelial migration of HIV-positive macrophages was reduced in vitro. Here, we analyze macrophages’ response to LPS challenge in the kidney and peritoneum of HIV-Tg mice. In contrast to the lung infiltration, renal and peritoneal macrophage infiltrations were similar in WT and HIV-Tg mice. Higher levels of HIV-1 gene expression were detected in lung macrophages compared to peritoneal macrophages. In peritoneal macrophages, HIV-1 gene expression was increased when they were cultured at 21% O₂ compared to 5% O₂, inversely correlating with reduced trans-endothelial migration at higher oxygen levels in vitro. The resolution of macrophage infiltration was reduced in both the lung and the peritoneal cavity of HIV-Tg mice. Taken together, our study described the organ-specific alteration of macrophage dynamics in HIV-Tg mice. The delayed resolution of macrophage infiltration might constitute a risk factor for the development of multiple comorbidities in PLWH. Full article

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

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22 pages, 6504 KiB

Open AccessArticle

HIV-1 Envelope Glycoprotein Amino Acids Signatures Associated with Clade B Transmitted/Founder and Recent Viruses

by Alexis Kafando, Christine Martineau, Mohamed El-Far, Eric Fournier, Florence Doualla-Bell, Bouchra Serhir, Adama Kazienga, Mohamed Ndongo Sangaré, Mohamed Sylla, Annie Chamberland, Hugues Charest and Cécile L. Tremblay

Viruses 2019, 11(11), 1012; https://doi.org/10.3390/v11111012 - 1 Nov 2019

Cited by 4 | Viewed by 4139

Abstract

Background: HIV-1 transmitted/founder viruses (TF) are selected during the acute phase of infection from a multitude of virions present during transmission. They possess the capacity to establish infection and viral dissemination in a new host. Deciphering the discrete genetic determinant of infectivity in [...] Read more.

Background: HIV-1 transmitted/founder viruses (TF) are selected during the acute phase of infection from a multitude of virions present during transmission. They possess the capacity to establish infection and viral dissemination in a new host. Deciphering the discrete genetic determinant of infectivity in their envelope may provide clues for vaccine design. Methods: One hundred twenty-six clade B HIV-1 consensus envelope sequences from untreated acute and early infected individuals were compared to 105 sequences obtained from chronically infected individuals using next generation sequencing and molecular analyses. Results: We identified an envelope amino acid signature associated with TF viruses. They are more likely to have an isoleucine (I) in position 841 instead of an arginine (R). This mutation of R to I (R841I) in the gp41 cytoplasmic tail (gp41CT), specifically in lentivirus lytic peptides segment 1 (LLP-1), is significantly enriched compared to chronic viruses (OR = 0.2, 95% CI (0.09, 0.44), p = 0.00001). Conversely, a mutation of lysine (K) to isoleucine (I) located in position six (K6I) of the envelope signal peptide was selected by chronic viruses and compared to TF (OR = 3.26, 95% CI (1.76–6.02), p = 0.0001). Conclusions: The highly conserved gp41 CT_ LLP-1 domain plays a major role in virus replication in mediating intracellular traffic and Env incorporation into virions in interacting with encoded matrix protein. The presence of an isoleucine in gp41 in the TF viruses’ envelope may sustain its role in the successful establishment of infection during the acute stage. Full article

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

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Review

Jump to: Research

19 pages, 1171 KiB

Open AccessReview

Depicting HIV-1 Transcriptional Mechanisms: A Summary of What We Know

by Antoine Dutilleul, Anthony Rodari and Carine Van Lint

Viruses 2020, 12(12), 1385; https://doi.org/10.3390/v12121385 - 3 Dec 2020

Cited by 32 | Viewed by 6695

Abstract

Despite the introduction of combinatory antiretroviral therapy (cART), HIV-1 infection cannot be cured and is still one of the major health issues worldwide. Indeed, as soon as cART is interrupted, a rapid rebound of viremia is observed. The establishment of viral latency and [...] Read more.

Despite the introduction of combinatory antiretroviral therapy (cART), HIV-1 infection cannot be cured and is still one of the major health issues worldwide. Indeed, as soon as cART is interrupted, a rapid rebound of viremia is observed. The establishment of viral latency and the persistence of the virus in cellular reservoirs constitute the main barrier to HIV eradication. For this reason, new therapeutic approaches have emerged to purge or restrain the HIV-1 reservoirs in order to cure infected patients. However, the viral latency is a multifactorial process that depends on various cellular mechanisms. Since these new therapies mainly target viral transcription, their development requires a detailed and precise understanding of the regulatory mechanism underlying HIV-1 transcription. In this review, we discuss the complex molecular transcriptional network regulating HIV-1 gene expression by focusing on the involvement of host cell factors that could be used as potential drug targets to design new therapeutic strategies and, to a larger extent, to reach an HIV-1 functional cure. Full article

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

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21 pages, 989 KiB

Open AccessReview

Experimental Systems for Measuring HIV Latency and Reactivation

by Koh Fujinaga and Daniele C. Cary

Viruses 2020, 12(11), 1279; https://doi.org/10.3390/v12111279 - 9 Nov 2020

Cited by 16 | Viewed by 4910

Abstract

The final obstacle to achieving a cure to HIV/AIDS is the presence of latent HIV reservoirs scattered throughout the body. Although antiretroviral therapy maintains plasma viral loads below the levels of detection, upon cessation of therapy, the latent reservoir immediately produces infectious progeny [...] Read more.

The final obstacle to achieving a cure to HIV/AIDS is the presence of latent HIV reservoirs scattered throughout the body. Although antiretroviral therapy maintains plasma viral loads below the levels of detection, upon cessation of therapy, the latent reservoir immediately produces infectious progeny viruses. This results in elevated plasma viremia, which leads to clinical progression to AIDS. Thus, if a HIV cure is ever to become a reality, it will be necessary to target and eliminate the latent reservoir. To this end, tremendous effort has been dedicated to locate the viral reservoir, understand the mechanisms contributing to latency, find optimal methods to reactivate HIV, and specifically kill latently infected cells. Although we have not yet identified a therapeutic approach to completely eliminate HIV from patients, these efforts have provided many technological breakthroughs in understanding the underlying mechanisms that regulate HIV latency and reactivation in vitro. In this review, we summarize and compare experimental systems which are frequently used to study HIV latency. While none of these models are a perfect proxy for the complex systems at work in HIV+ patients, each aim to replicate HIV latency in vitro. Full article

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

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41 pages, 4555 KiB

Open AccessReview

HIV-1 Proviral Transcription and Latency in the New Era

by Ashutosh Shukla, Nora-Guadalupe P. Ramirez and Iván D’Orso

Viruses 2020, 12(5), 555; https://doi.org/10.3390/v12050555 - 18 May 2020

Cited by 35 | Viewed by 7951

Abstract

Three decades of extensive work in the HIV field have revealed key viral and host cell factors controlling proviral transcription. Various models of transcriptional regulation have emerged based on the collective information from in vitro assays and work in both immortalized and primary [...] Read more.

Three decades of extensive work in the HIV field have revealed key viral and host cell factors controlling proviral transcription. Various models of transcriptional regulation have emerged based on the collective information from in vitro assays and work in both immortalized and primary cell-based models. Here, we provide a recount of the past and current literature, highlight key regulatory aspects, and further describe potential limitations of previous studies. We particularly delve into critical steps of HIV gene expression including the role of the integration site, nucleosome positioning and epigenomics, and the transition from initiation to pausing and pause release. We also discuss open questions in the field concerning the generality of previous regulatory models to the control of HIV transcription in patients under suppressive therapy, including the role of the heterogeneous integration landscape, clonal expansion, and bottlenecks to eradicate viral persistence. Finally, we propose that building upon previous discoveries and improved or yet-to-be discovered technologies will unravel molecular mechanisms of latency establishment and reactivation in a “new era”. Full article

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

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35 pages, 2767 KiB

Open AccessReview

Key Players in HIV-1 Transcriptional Regulation: Targets for a Functional Cure

by Luisa Mori and Susana T. Valente

Viruses 2020, 12(5), 529; https://doi.org/10.3390/v12050529 - 11 May 2020

Cited by 28 | Viewed by 6377

Abstract

HIV-1 establishes a life-long infection when proviral DNA integrates into the host genome. The provirus can then either actively transcribe RNA or enter a latent state, without viral production. The switch between these two states is governed in great part by the viral [...] Read more.

HIV-1 establishes a life-long infection when proviral DNA integrates into the host genome. The provirus can then either actively transcribe RNA or enter a latent state, without viral production. The switch between these two states is governed in great part by the viral protein, Tat, which promotes RNA transcript elongation. Latency is also influenced by the availability of host transcription factors, integration site, and the surrounding chromatin environment. The latent reservoir is established in the first few days of infection and serves as the source of viral rebound upon treatment interruption. Despite effective suppression of HIV-1 replication by antiretroviral therapy (ART), to below the detection limit, ART is ineffective at reducing the latent reservoir size. Elimination of this reservoir has become a major goal of the HIV-1 cure field. However, aside from the ideal total HIV-1 eradication from the host genome, an HIV-1 remission or functional cure is probably more realistic. The “block-and-lock” approach aims at the transcriptional silencing of the viral reservoir, to render suppressed HIV-1 promoters extremely difficult to reactivate from latency. There are unfortunately no clinically available HIV-1 specific transcriptional inhibitors. Understanding the mechanisms that regulate latency is expected to provide novel targets to be explored in cure approaches. Full article

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

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12 pages, 948 KiB

Open AccessReview

Cellular Factors Targeting HIV-1 Transcription and Viral RNA Transcripts

by Rayhane Nchioua, Matteo Bosso, Dorota Kmiec and Frank Kirchhoff

Viruses 2020, 12(5), 495; https://doi.org/10.3390/v12050495 - 29 Apr 2020

Cited by 24 | Viewed by 6705

Abstract

Restriction factors are structurally and functionally diverse cellular proteins that constitute a first line of defense against viral pathogens. Exceptions exist, but typically these proteins are upregulated by interferons (IFNs), target viral components, and are rapidly evolving due to the continuous virus–host arms [...] Read more.

Restriction factors are structurally and functionally diverse cellular proteins that constitute a first line of defense against viral pathogens. Exceptions exist, but typically these proteins are upregulated by interferons (IFNs), target viral components, and are rapidly evolving due to the continuous virus–host arms race. Restriction factors may target HIV replication at essentially each step of the retroviral replication cycle, and the suppression of viral transcription and the degradation of viral RNA transcripts are emerging as major innate immune defense mechanisms. Recent data show that some antiviral factors, such as the tripartite motif-containing protein 22 (TRIM22) and the γ-IFN-inducible protein 16 (IFI16), do not target HIV-1 itself but limit the availability of the cellular transcription factor specificity protein 1 (Sp1), which is critical for effective viral gene expression. In addition, several RNA-interacting cellular factors including RNAse L, the NEDD4-binding protein 1 (N4BP1), and the zinc finger antiviral protein (ZAP) have been identified as important immune effectors against HIV-1 that may be involved in the maintenance of the latent viral reservoirs, representing the major obstacle against viral elimination and cure. Here, we review recent findings on specific cellular antiviral factors targeting HIV-1 transcription or viral RNA transcripts and discuss their potential role in viral latency. Full article

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

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25 pages, 1163 KiB

Open AccessReview

Role of Divalent Cations in HIV-1 Replication and Pathogenicity

by Nabab Khan, Xuesong Chen and Jonathan D. Geiger

Viruses 2020, 12(4), 471; https://doi.org/10.3390/v12040471 - 21 Apr 2020

Cited by 19 | Viewed by 4928

Abstract

Divalent cations are essential for life and are fundamentally important coordinators of cellular metabolism, cell growth, host-pathogen interactions, and cell death. Specifically, for human immunodeficiency virus type-1 (HIV-1), divalent cations are required for interactions between viral and host factors that govern HIV-1 replication [...] Read more.

Divalent cations are essential for life and are fundamentally important coordinators of cellular metabolism, cell growth, host-pathogen interactions, and cell death. Specifically, for human immunodeficiency virus type-1 (HIV-1), divalent cations are required for interactions between viral and host factors that govern HIV-1 replication and pathogenicity. Homeostatic regulation of divalent cations’ levels and actions appear to change as HIV-1 infection progresses and as changes occur between HIV-1 and the host. In people living with HIV-1, dietary supplementation with divalent cations may increase HIV-1 replication, whereas cation chelation may suppress HIV-1 replication and decrease disease progression. Here, we review literature on the roles of zinc (Zn²⁺), iron (Fe²⁺), manganese (Mn²⁺), magnesium (Mg²⁺), selenium (Se²⁺), and copper (Cu²⁺) in HIV-1 replication and pathogenicity, as well as evidence that divalent cation levels and actions may be targeted therapeutically in people living with HIV-1. Full article

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

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18 pages, 812 KiB

Open AccessReview

Tat-Based Therapies as an Adjuvant for an HIV-1 Functional Cure

by Hongping Jin, Dongsheng Li, Min-Hsuan Lin, Li Li and David Harrich

Viruses 2020, 12(4), 415; https://doi.org/10.3390/v12040415 - 8 Apr 2020

Cited by 21 | Viewed by 4934

Abstract

The human immunodeficiency virus type 1 (HIV) establishes a chronic infection that can be well controlled, but not cured, by combined antiretroviral therapy (cART). Interventions have been explored to accomplish a functional cure, meaning that a patient remains infected but HIV is undetectable [...] Read more.

The human immunodeficiency virus type 1 (HIV) establishes a chronic infection that can be well controlled, but not cured, by combined antiretroviral therapy (cART). Interventions have been explored to accomplish a functional cure, meaning that a patient remains infected but HIV is undetectable in the blood, with the aim of allowing patients to live without cART. Tat, the viral transactivator of transcription protein, plays a critical role in controlling HIV transcription, latency, and viral rebound following the interruption of cART treatment. Therefore, a logical approach for controlling HIV would be to block Tat. Tackling Tat with inhibitors has been a difficult task, but some recent discoveries hold promise. Two anti-HIV proteins, Nullbasic (a mutant of Tat) and HT1 (a fusion of HEXIM1 and Tat functional domains) inhibit viral transcription by interfering with the interaction of Tat and cellular factors. Two small molecules, didehydro-cortistatin A (dCA) and triptolide, inhibit Tat by different mechanisms: dCA through direct binding and triptolide through enhanced proteasomal degradation. Finally, two Tat-based vaccines under development elicit Tat-neutralizing antibodies. These vaccines have increased the levels of CD4⁺ cells and reduced viral loads in HIV-infected people, suggesting that the new vaccines are therapeutic. This review summarizes recent developments of anti-Tat agents and how they could contribute to a functional cure for HIV. Full article

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

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