scholarly journals Mechanisms of HIV Transcriptional Regulation and Their Contribution to Latency

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Gillian M. Schiralli Lester ◽  
Andrew J. Henderson
Keyword(s):  
Transcription Initiation ◽  
Antiretroviral Treatment ◽  
Potential Role ◽  
Treatment Interruption ◽  
Major Barrier ◽  
Biochemical Processes ◽  
Hiv Transcription ◽  
Infected Cells ◽  
Multiple Levels ◽  
Latent Hiv

Long-lived latent HIV-infected cells lead to the rebound of virus replication following antiretroviral treatment interruption and present a major barrier to eliminating HIV infection. These latent reservoirs, which include quiescent memory T cells and tissue-resident macrophages, represent a subset of cells with decreased or inactive proviral transcription. HIV proviral transcription is regulated at multiple levels including transcription initiation, polymerase recruitment, transcription elongation, and chromatin organization. How these biochemical processes are coordinated and their potential role in repressing HIV transcription along with establishing and maintaining latency are reviewed.

scholarly journals Block-And-Lock Strategies to Cure HIV Infection

Viruses ◽  
2020 ◽  
Vol 12 (1) ◽  
pp. 84 ◽  
Author(s):  
Gerlinde Vansant ◽  
Anne Bruggemans ◽  
Julie Janssens ◽  
Zeger Debyser
Keyword(s):  
Hiv Infection ◽  
Treatment Interruption ◽  
Latent Reservoir ◽  
Hiv Cure ◽  
Major Barrier ◽  
Hiv Transcription ◽  
Latently Infected ◽  
Shock And Kill ◽  
Infected Cells ◽  
Underlying Mechanisms

Today HIV infection cannot be cured due to the presence of a reservoir of latently infected cells inducing a viral rebound upon treatment interruption. Hence, the latent reservoir is considered as the major barrier for an HIV cure. So far, efforts to completely eradicate the reservoir via a shock-and-kill approach have proven difficult and unsuccessful. Therefore, more research has been done recently on an alternative block-and-lock functional cure strategy. In contrast to the shock-and-kill strategy that aims to eradicate the entire reservoir, block-and-lock aims to permanently silence all proviruses, even after treatment interruption. HIV silencing can be achieved by targeting different factors of the transcription machinery. In this review, we first describe the underlying mechanisms of HIV transcription and silencing. Next, we give an overview of the different block-and-lock strategies under investigation.

scholarly journals COMMD1/Murr1 Reinforces HIV-1 Latent Infection through IκB-α Stabilization

2014 ◽  
Vol 89 (5) ◽  
pp. 2643-2658 ◽  
Author(s):  
Manabu Taura ◽  
Eriko Kudo ◽  
Ryusho Kariya ◽  
Hiroki Goto ◽  
Kouki Matsuda ◽  
...  
Keyword(s):  
Transcription Initiation ◽  
Primary Infection ◽  
Latent Infection ◽  
Myeloid Cells ◽  
Innate Immune ◽  
Lymphoid Cells ◽  
Inhibition Mechanism ◽  
Major Barrier ◽  
Infected Cells ◽  
Hiv 1

ABSTRACTThe transcription factor NF-κB is important for HIV-1 transcription initiation in primary HIV-1 infection and reactivation in latently HIV-1-infected cells. However, comparative analysis of the regulation and function of NF-κB in latently HIV-1-infected cells has not been done. Here we show that the expression of IκB-α, an endogenous inhibitor of NF-κB, is enhanced by latent HIV-1 infection via induction of the host-derived factor COMMD1/Murr1 in myeloid cells but not in lymphoid cells by using four sets of latently HIV-1-infected cells and the respective parental cells. IκB-α protein was stabilized by COMMD1, which attenuated NF-κB signaling during Toll-like receptor ligand and tumor necrosis factor alpha treatment and enhanced HIV-1 latency in latently HIV-1-infected cells. Activation of the phosphoinositol 3-kinase (PI3K)–JAK pathway is involved in COMMD1 induction in latently HIV-1-infected cells. Our findings indicate that COMMD1 induction is the NF-κB inhibition mechanism in latently HIV-1-infected cells that contributes to innate immune deficiency and reinforces HIV-1 latency. Thus, COMMD1 might be a double-edged sword that is beneficial in primary infection but not beneficial in latent infection when HIV-1 eradication is considered.IMPORTANCEHIV-1 latency is a major barrier to viral eradication in the era of combination antiretroviral therapy. In this study, we found that COMMD1/Murr1, previously identified as an HIV-1 restriction factor, inhibits the proteasomal degradation of IκB-α by increasing the interaction with IκB-α in latently HIV-1-infected myeloid cells. IκB-α protein was stabilized by COMMD1, which attenuated NF-κB signaling during the innate immune response and enhanced HIV-1 latency in latently HIV-1-infected cells. Activation of the PI3K-JAK pathway is involved in COMMD1 induction in latently HIV-1-infected cells. Thus, the host-derived factor COMMD1 is beneficial in suppressing primary infection but enhances latent infection, indicating that it may be a double-edged sword in HIV-1 eradication.

Exploring HIV latency using transcription profiling

2017 ◽  
Vol 38 (3) ◽  
pp. 137
Author(s):  
Sushama Telwatte ◽  
Steven A Yukl
Keyword(s):  
Transcriptional Profiling ◽  
Cell Types ◽  
Hiv Latency ◽  
Dna Viruses ◽  
Major Barrier ◽  
Hiv Transcription ◽  
Latently Infected ◽  
Infected Cells ◽  
Mechanisms Of Persistence

The major barrier to a cure for HIV is the existence of reservoirs consisting predominantly of latently infected CD4+ T cells, which do not produce virus constitutively but can be induced to produce infectious virus on activation. HIV latency research has largely focused on peripheral blood, yet most HIV-infected cells reside in tissues, especially the gut, where differences in drug penetration, cell types, and immune responses may impact mechanisms of persistence. Exploring the differences between the gut and the blood in transcriptional blocks may reveal fundamental insights into mechanisms that contribute to HIV latency. Our novel transcriptional profiling assays enable us to determine where blocks to HIV transcription occur in various tissues and the magnitude of their contribution. These assays could also be adapted to investigate latency established by other retroviridae or even DNA viruses such as herpesviridae with a view to pinpointing mechanisms underlying latency in vivo and ultimately contribute to designing a cure.

scholarly journals Targeted Chromatinization and Repression of HIV-1 Provirus Transcription with Repurposed CRISPR/Cas9

Viruses ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 1154
Author(s):  
Alex Olson ◽  
Binita Basukala ◽  
Seunghee Lee ◽  
Matthew Gagne ◽  
Wilson W. Wong ◽  
...  
Keyword(s):  
Transcriptional Repression ◽  
Major Barrier ◽  
Guide Rnas ◽  
Immunodeficiency Virus ◽  
Shock And Kill ◽  
Infected Cells ◽  
Latent Hiv ◽  
Transcriptional Repressor Domain ◽  
Hiv 1 ◽  
Latent Provirus

The major barrier to HIV-1 cure is the persistence of latent provirus, which is not eradicated by antiretroviral therapy. The “shock and kill” approach entails stimulating viral production with latency-reversing agents followed by the killing of cells actively producing the virus by immune clearance. However, this approach does not induce all intact proviruses, leaving a residual reservoir. CRISPR/Cas9 has been utilized to excise integrated Human Immunodeficiency Virus (HIV) DNA from infected cells in an RNA-guided, sequence-specific manner. Here, we seek to epigenetically silence the proviral DNA by introducing nuclease-deficient disabled Cas9 (dCas9) coupled with a transcriptional repressor domain derived from Kruppel-associated box (KRAB). We show that specific guide RNAs (gRNAs) and dCas9-KRAB repress HIV-1 transcription and reactivation of latent HIV-1 provirus. This repression is correlated with chromatin changes, including decreased H3 histone acetylation and increased histone H3 lysine 9 trimethylation, histone marks that are associated with transcriptional repression. dCas9-KRAB-mediated inhibition of HIV-1 transcription suggests that CRISPR can be engineered as a tool for block-and-lock strategies.

scholarly journals Epigenetic Silencing of Human Immunodeficiency Virus (HIV) Transcription by Formation of Restrictive Chromatin Structures at the Viral Long Terminal Repeat Drives the Progressive Entry of HIV into Latency

2008 ◽  
Vol 82 (24) ◽  
pp. 12291-12303 ◽  
Author(s):  
Richard Pearson ◽  
Young Kyeung Kim ◽  
Joseph Hokello ◽  
Kara Lassen ◽  
Julia Friedman ◽  
...  
Keyword(s):  
Gene Expression ◽  
Human Immunodeficiency Virus ◽  
Transcription Initiation ◽  
Molecular Mechanisms ◽  
Lentiviral Vectors ◽  
Hiv Transcription ◽  
Wide Range ◽  
Immunodeficiency Virus ◽  
Latently Infected ◽  
Infected Cells

ABSTRACT The molecular mechanisms utilized by human immunodeficiency virus (HIV) to enter latency are poorly understood. Following the infection of Jurkat T cells with lentiviral vectors that express Tat in cis, gene expression is progressively silenced. Silencing is greatly enhanced when the lentiviral vectors carry an attenuated Tat gene with the H13L mutation. Individual clones of lentivirus-infected cells showed a wide range of shutdown rates, with the majority showing a 50% silencing frequency between 30 to 80 days. The silenced clones characteristically contained a small fraction (0 to 15%) of activated cells that continued to express d2EGFP. When d2EGFP+ and d2EGFP− cell populations were isolated from the shutdown clones, they quickly reverted to the original distribution of inactive and active cells, suggesting that the d2EGFP+ cells arise from stochastic fluctuations in gene expression. The detailed analysis of transcription initiation and elongation using chromatin immunoprecipitation (ChIP) assays confirms that Tat levels are restricted in the latently infected cells but gradually rise during proviral reactivation. ChIP assays using clones of latently infected cells demonstrate that the latent proviruses carry high levels of deacetylated histones and trimethylated histones. In contrast, the cellular genes IκBα and GAPDH had high levels of acetylated histones and no trimethylated histones. The levels of trimethylated histone H3 and HP1-α associated with HIV proviruses fell rapidly after tumor necrosis factor alpha activation. The progressive shutdown of HIV transcription following infection suggests that epigenetic mechanisms targeting chromatin structures selectively restrict HIV transcription initiation. This decreases Tat production below the levels that are required to sustain HIV gene expression.

scholarly journals A Productive Expression Platform Derived from Host-Restricted Eilat Virus: Its Extensive Validation and Novel Strategy

Viruses ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 660
Author(s):  
Lu Tan ◽  
Yiwen Zhang ◽  
Xingxing Wang ◽  
Dal Young Kim
Keyword(s):  
Expression Vectors ◽  
Structural Genes ◽  
Host Restriction ◽  
Expression Platform ◽  
Mosquito Cells ◽  
Wide Range ◽  
Restriction Property ◽  
Infected Cells ◽  
Multiple Levels ◽  
Novel Strategy

Most alphaviruses are transmitted by mosquitoes and infect a wide range of insects and vertebrates. However, Eilat virus (EILV) is defective for infecting vertebrate cells at multiple levels of the viral life cycle. This host-restriction property renders EILV an attractive expression platform since it is not infectious for vertebrates and therefore provides a highly advantageous safety profile. Here, we investigated the feasibility of versatile EILV-based expression vectors. By replacing the structural genes of EILV with those of other alphaviruses, we generated seven different chimeras. These chimeras were readily rescued in the original mosquito cells and were able to reach high titers, suggesting that EILV is capable of packaging the structural proteins of different lineages. We also explored the ability of EILV to express authentic antigens via double subgenomic (SG) RNA vectors. Four foreign genetic materials of varied length were introduced into the EILV genome, and the expressed heterologous genetic materials were readily detected in the infected cells. By inserting an additional SG promoter into the chimera genome containing the structural genes of Chikungunya virus (CHIKV), we developed a bivalent vaccine candidate against CHIKV and Zika virus. These data demonstrate the outstanding compatibility of the EILV genome. The produced recombinants can be applied to vaccine and diagnostic tool development, but more investigations are required.

scholarly journals Excision of Latent HIV-1 from Infected Cells In Vivo: An Important Step Forward

2017 ◽  
Vol 25 (5) ◽  
pp. 1062-1064 ◽  
Author(s):  
Harshana S. De Silva Feelixge ◽  
Keith R. Jerome
Keyword(s):  
Infected Cells ◽  
Latent Hiv ◽  
Hiv 1

scholarly journals ABX464 decreases the total HIV reservoir and HIV transcription initiation in CD4 + T cells from HIV-infected ART-suppressed individuals

2021 ◽  
Author(s):  
Sara Moron-Lopez ◽  
Silvia Bernal ◽  
Joseph K Wong ◽  
Javier Martinez-Picado ◽  
Steven A Yukl
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Transcription Initiation ◽  
Digital Pcr ◽  
Fold Change ◽  
Hiv Rna ◽  
Hiv Transcription ◽  
Hiv Dna ◽  
Median Level ◽  
Term Administration

Abstract Background Antiretroviral therapy (ART) intensification and disruption of latency have been suggested as strategies to eradicate HIV. ABX464 is a novel antiviral that inhibits HIV RNA biogenesis. We investigated the effect of ABX464 on HIV transcription and total and intact HIV DNA in CD4 + T cells from ART-suppressed participants enrolled in the ABIVAX-005 clinical trial (NCT02990325). Methods Peripheral CD4 + T cells were available for analysis from nine ART-suppressed participants who were treated daily with 150mg of ABX464 for 4 weeks. Total and intact HIV DNA, and initiated, 5’elongated, unspliced, polyadenylated and multiply-spliced HIV transcripts, were quantified at weeks 0, 4 and 8 using droplet digital PCR. Results We observed a significant decrease in total HIV DNA (p=0.008, median fold-change=0.8) and a lower median level of intact HIV DNA (p=n.s., median fold-change=0.8) after ABX464 treatment (wk 0 vs. 4). Moreover, we observed a decrease in initiated HIV RNA per million CD4 + T cells and per provirus (p=0.05, median fold-change=0.7; p=0.004, median fold-change=0.5, respectively), a trend towards a decrease in the 5’elongated HIV RNA per provirus (p=0.07, median fold-change=0.5), and a lower median level of unspliced HIV RNA (p=n.s., median fold-change=0.6), but no decrease in polyadenylated or multiply-spliced HIV RNA. Conclusion In this substudy, ABX464 had a dual effect of decreasing total HIV DNA (and possibly intact proviruses) and decreasing the amount of HIV transcription per provirus. To further characterize its specific mechanism of inhibiting HIV transcription, long-term administration of ABX464 should be studied in a larger cohort.

scholarly journals The bromodomain and extraterminal domain inhibitor bromosporine synergistically reactivates latent HIV-1 in latently infected cells

Oncotarget ◽  
2017 ◽  
Vol 8 (55) ◽  
pp. 94104-94116 ◽  
Author(s):  
Hanyu Pan ◽  
Panpan Lu ◽  
Yinzhong Shen ◽  
Yanan Wang ◽  
Zhengtao Jiang ◽  
...  
Keyword(s):  
Latently Infected ◽  
Infected Cells ◽  
Latent Hiv ◽  
Hiv 1

scholarly journals A Randomized Placebo-Controlled Efficacy Study of a Prime Boost Therapeutic Vaccination Strategy in HIV-1-Infected Individuals: VRI02 ANRS 149 LIGHT Phase II Trial

2021 ◽  
Vol 95 (9) ◽  
Author(s):  
Y. Lévy ◽  
C. Lacabaratz ◽  
E. Lhomme ◽  
A. Wiedemann ◽  
C. Bauduin ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Phase Ii ◽  
Antiretroviral Treatment ◽  
Treatment Interruption ◽  
Viral Rebound ◽  
Vaccine Strategy ◽  
Cell Responses ◽  
Hiv 1

ABSTRACT In this placebo-controlled phase II randomized clinical trial, 103 human immunodeficiency virus type 1 (HIV-1)-infected patients under cART (combined antiretroviral treatment) were randomized 2:1 to receive either 3 doses of DNA GTU-MultiHIV B (coding for Rev, Nef, Tat, Gag, and gp160) at week 0 (W0), W4, and W12, followed by 2 doses of LIPO-5 vaccine containing long peptides from Gag, Pol, and Nef at W20 and W24, or placebo. Analytical treatment interruption (ATI) was performed between W36 to W48. At W28, vaccinees experienced an increase in functional CD4+ T-cell responses (P < 0.001 for each cytokine compared to W0) measured, predominantly against Gag and Pol/Env, and an increase in HIV-specific CD8+ T cells producing interleukin 2 (IL-2) and tumor necrosis factor alpha (TNF-α) (P = 0.001 and 0.013, respectively), predominantly against Pol/Env and Nef. However, analysis of T-cell subsets by mass cytometry in a subpopulation showed an increase in the W28/W0 ratio for memory CD8+ T cells coexpressing exhaustion and senescence markers such as PD-1/TIGIT (P = 0.004) and CD27/CD57 (P = 0.044) in vaccinees compared to the placebo group. During ATI, all patients experienced viral rebound, with the maximum observed HIV RNA level at W42 (median, 4.63 log10 copies [cp]/ml; interquartile range [IQR], 4.00 to 5.09), without any difference between arms. No patient resumed cART for CD4 cell count drop. Globally, the vaccine strategy was safe. However, a secondary HIV transmission during ATI was observed. These data show that the prime-boost combination of DNA and LIPO-5 vaccines elicited broad and polyfunctional T cells. The contrast between the quality of immune responses and the lack of potent viral control underscores the need for combined immunomodulatory strategies. (This study has been registered at ClinicalTrials.gov under registration no. NCT01492985.) IMPORTANCE In this placebo-controlled phase II randomized clinical trial, we evaluated the safety and immunogenicity of a therapeutic prime-boost vaccine strategy using a recombinant DNA vaccine (GTU-MultiHIV B clade) followed by a boost vaccination with a lipopeptide vaccine (HIV-LIPO-5) in HIV-infected patients on combined antiretroviral therapy. We show here that this prime-boost strategy is well tolerated, consistently with previous studies in HIV-1-infected individuals and healthy volunteers who received each vaccine component individually. Compared to the placebo group, vaccinees elicited strong and polyfunctional HIV-specific CD4+ and CD8+ T-cell responses. However, these immune responses presented some qualitative defects and were not able to control viremia following antiretroviral treatment interruption, as no difference in HIV viral rebound was observed in the vaccine and placebo groups. Several lessons were learned from these results, pointing out the urgent need to combine vaccine strategies with other immune-based interventions.

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