scholarly journals Naturally Occurring Compounds Elicit HIV-1 Replication in Chronically Infected Promonocytic Cells

2014 ◽  
Vol 2014 ◽  
pp. 1-6 ◽  
Author(s):  
Andrea Alejandra Barquero ◽  
María Eugenia Dávola ◽  
Diego Ariel Riva ◽  
Susana Esther Mersich ◽  
Laura Edith Alché
Keyword(s):  
Viral Genome ◽  
Nordihydroguaiaretic Acid ◽  
Hiv Replication ◽  
Viral Reservoirs ◽  
Naturally Occurring ◽  
Latently Infected ◽  
Infected Cells ◽  
P24 Antigen ◽  
Hiv 1 ◽  
Promonocytic Cells

Since antiretroviral therapy suppresses but does not eradicate HIV-1 infection, methods to purge viral reservoirs are required. Many strategies involve the reactivation of chronically HIV infected cells to induce the expression of integrated viral genome. In this study, five bioactive compounds, the plant derivatives 1-cinnamoyl-3,11-dihydroxymeliacarpin (CDM), nordihydroguaiaretic acid (NDGA), and curcumin (Cur) and the synthetic stigmasterol analogs (22S,23S)-22,23-dihydroxystigmast-4-en-3-one (compound1) and (22S,23S)-3β-bromo-5α,22,23-trihydroxystigmastan-6-one (compound2), were evaluated for their ability to elicit HIV replication in promonocytic (U1) and lymphocytic (H9+) HIV-1 chronically infected cells. The results revealed that natural compounds CDM, NDGA, and Cur were able to increase HIV-1 p24 antigen, determined by ELISA, only in latently infected promonocytic cells. CDM would reactivate HIV from latency by modulating the release of IL-6 and TNF-α, since the amount of both cytokines measured through ELISA significantly increased in U1 treated cells. Besides, NDGA increased ROS production, which might be related to the increase on p24 level observed in NDGA treated U1. These findings suggest that CDM, NDGA, and Cur might be candidates for further studies on latency-reversing therapeutics to eliminate latently HIV-1 reservoirs.

scholarly journals The Dual-Specificity Kinase DYRK1A Modulates the Levels of Cyclin L2 To Control HIV Replication in Macrophages

2019 ◽  
Vol 94 (6) ◽  
Author(s):  
Javan K. Kisaka ◽  
Lee Ratner ◽  
George B. Kyei
Keyword(s):  
Public Health Problem ◽  
Critical Factor ◽  
Major Public Health Problem ◽  
Hiv Replication ◽  
Viral Reservoirs ◽  
Dual Specificity ◽  
Cellular Factors ◽  
Latently Infected ◽  
Hiv Eradication ◽  
Hiv 1

ABSTRACT HIV replication in macrophages contributes to the latent viral reservoirs, which are considered the main barrier to HIV eradication. Few cellular factors that facilitate HIV replication in latently infected cells are known. We previously identified cyclin L2 as a critical factor required by HIV-1 and found that depletion of cyclin L2 attenuates HIV-1 replication in macrophages. Here we demonstrate that cyclin L2 promotes HIV-1 replication through interactions with the dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A). Cyclin L2 and DYRK1A were colocalized in the nucleus and were found together in immunoprecipitation experiments. Knockdown or inhibition of DYRK1A increased HIV-1 replication in macrophages, while depletion of cyclin L2 decreased HIV-1 replication. Furthermore, depletion of DYRK1A increased expression levels of cyclin L2. DYRK1A is a proline-directed kinase that phosphorylates cyclin L2 at serine residues. Mutations of cyclin L2 at serine residues preceding proline significantly stabilized cyclin L2 and increased HIV-1 replication in macrophages. Thus, we propose that DYRK1A controls cyclin L2 expression, leading to restriction of HIV replication in macrophages. IMPORTANCE HIV continues to be a major public health problem worldwide, with over 36 million people living with the virus. Although antiretroviral therapy (ART) can control the virus, it does not provide cure. The virus hides in the genomes of long-lived cells, such as resting CD4+ T cells and differentiated macrophages. To get a cure for HIV, it is important to identify and characterize the cellular factors that control HIV multiplication in these reservoir cells. Previous work showed that cyclin L2 is required for HIV replication in macrophages. However, how cyclin L2 is regulated in macrophages is unknown. Here we show that the protein DYRK1A interacts with and phosphorylates cyclin L2. Phosphorylation makes cyclin L2 amenable to cellular degradation, leading to restriction of HIV replication in macrophages.

scholarly journals Low-Level Ionizing Radiation Induces Selective Killing of HIV-1-Infected Cells with Reversal of Cytokine Induction Using mTOR Inhibitors

Viruses ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 885
Author(s):  
Daniel O. Pinto ◽  
Catherine DeMarino ◽  
Thy T. Vo ◽  
Maria Cowen ◽  
Yuriy Kim ◽  
...  
Keyword(s):  
Ionizing Radiation ◽  
Mtor Inhibitors ◽  
Viral Reservoirs ◽  
Viral Loads ◽  
Viral Spread ◽  
Novel Approach ◽  
Latently Infected ◽  
Shock And Kill ◽  
Infected Cells ◽  
Hiv 1

HIV-1 infects 39.5 million people worldwide, and cART is effective in preventing viral spread by reducing HIV-1 plasma viral loads to undetectable levels. However, viral reservoirs persist by mechanisms, including the inhibition of autophagy by HIV-1 proteins (i.e., Nef and Tat). HIV-1 reservoirs can be targeted by the “shock and kill” strategy, which utilizes latency-reversing agents (LRAs) to activate latent proviruses and immunotarget the virus-producing cells. Yet, limitations include reduced LRA permeability across anatomical barriers and immune hyper-activation. Ionizing radiation (IR) induces effective viral activation across anatomical barriers. Like other LRAs, IR may cause inflammation and modulate the secretion of extracellular vesicles (EVs). We and others have shown that cells may secrete cytokines and viral proteins in EVs and, therefore, LRAs may contribute to inflammatory EVs. In the present study, we mitigated the effects of IR-induced inflammatory EVs (i.e., TNF-α), through the use of mTOR inhibitors (mTORi; Rapamycin and INK128). Further, mTORi were found to enhance the selective killing of HIV-1-infected myeloid and T-cell reservoirs at the exclusion of uninfected cells, potentially via inhibition of viral transcription/translation and induction of autophagy. Collectively, the proposed regimen using cART, IR, and mTORi presents a novel approach allowing for the targeting of viral reservoirs, prevention of immune hyper-activation, and selectively killing latently infected HIV-1 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.

Galectin-3 is involved in HIV-1 expression through NF-κB activation and associated with Tat in latently infected cells

2019 ◽  
Vol 260 ◽  
pp. 86-93 ◽  
Author(s):  
Mika Okamoto ◽  
Akemi Hidaka ◽  
Masaaki Toyama ◽  
Masanori Baba
Keyword(s):  
Latently Infected ◽  
Galectin 3 ◽  
Infected Cells ◽  
Hiv 1

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 HIV-1 DNA predicts disease progression and post-treatment virological control

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
James P Williams ◽  
Jacob Hurst ◽  
Wolfgang Stöhr ◽  
Nicola Robinson ◽  
Helen Brown ◽  
...  
Keyword(s):  
Disease Progression ◽  
Treatment Interruption ◽  
Viral Rebound ◽  
Clinical Progression ◽  
Clinical Trial Registration ◽  
Plasma Virus ◽  
Latently Infected ◽  
Infected Cells ◽  
Multivariable Analyses ◽  
Hiv 1

In HIV-1 infection, a population of latently infected cells facilitates viral persistence despite antiretroviral therapy (ART). With the aim of identifying individuals in whom ART might induce a period of viraemic control on stopping therapy, we hypothesised that quantification of the pool of latently infected cells in primary HIV-1 infection (PHI) would predict clinical progression and viral replication following ART. We measured HIV-1 DNA in a highly characterised randomised population of individuals with PHI. We explored associations between HIV-1 DNA and immunological and virological markers of clinical progression, including viral rebound in those interrupting therapy. In multivariable analyses, HIV-1 DNA was more predictive of disease progression than plasma viral load and, at treatment interruption, predicted time to plasma virus rebound. HIV-1 DNA may help identify individuals who could safely interrupt ART in future HIV-1 eradication trials.Clinical trial registration: ISRCTN76742797 and EudraCT2004-000446-20

A new small-molecule compound, Q308, silences latent HIV-1 provirus by suppressing Tat- and FACT-mediated transcription

2021 ◽  
Author(s):  
Chen-liang Zhou ◽  
Yi-fan Huang ◽  
Yi-bin Li ◽  
Tai-zhen Liang ◽  
Teng-yi Zheng ◽  
...  
Keyword(s):  
Small Molecule ◽  
Difficult Problem ◽  
Viral Reservoir ◽  
Functional Cure ◽  
Latently Infected ◽  
Small Molecule Compound ◽  
Infected Cells ◽  
Latent Hiv ◽  
Anti Hiv ◽  
Hiv 1

Eliminating the latent HIV reservoir remains a difficult problem for creating an HIV functional cure or achieving remission. The “block-and-lock” strategy aims to steadily suppress transcription of the viral reservoir and lock the HIV promoter in deep latency using latency-promoting agents (LPAs). However, to date, most of the investigated LPA candidates are not available for clinical trials, and some of them exhibit immune-related adverse reactions. The discovery and development of new, active, and safe LPA candidates for an HIV cure are necessary to eliminate residual HIV-1 viremia through the “block-and-lock” strategy. In this study, we demonstrated that a new small-molecule compound, Q308, silenced the HIV-1 provirus by inhibiting Tat-mediated gene transcription and selectively downregulating the expression levels of the facilitated chromatin transcription (FACT) complex. Strikingly, Q308 induced the preferential apoptosis in HIV-1 latently infected cells, indicating that Q308 may reduce the size of the viral reservoir and thus further prevent viral rebound. These findings highlight that Q308 is a novel and safe anti-HIV-1 inhibitor candidate for a functional cure.

scholarly journals Similar frequency and inducibility of intact HIV-1 proviruses in blood and lymph nodes

2020 ◽  
Author(s):  
Alyssa R Martin ◽  
Alexandra M Bender ◽  
Jada Hackman ◽  
Kyungyoon J Kwon ◽  
Briana A Lynch ◽  
...  
Keyword(s):  
T Cells ◽  
Lymph Nodes ◽  
Cd4 T Cells ◽  
Viral Rna ◽  
Latent Reservoir ◽  
Similar Frequency ◽  
Latently Infected ◽  
Infected Cells ◽  
Secondary Lymphoid Organs ◽  
Hiv 1

Abstract Background The HIV-1 latent reservoir (LR) in resting CD4 + T cells is a barrier to cure. LR measurements are commonly performed on blood samples and therefore may miss latently infected cells residing in tissues, including lymph nodes. Methods We determined the frequency of intact HIV-1 proviruses and proviral inducibility in matched peripheral blood (PB) and lymph node (LN) samples from ten HIV-1-infected patients on ART using the intact proviral DNA assay and a novel quantitative viral induction assay. Prominent viral sequences from induced viral RNA were characterized using a next-generation sequencing assay. Results The frequencies of CD4 + T cells with intact proviruses were not significantly different in PB vs LN (61vs104/10 6CD4 + cells), and were substantially lower than frequencies of CD4 + T cells with defective proviruses. The frequencies of CD4 + T cells induced to produce high levels of viral RNA were not significantly different in PB vs LN (4.3/10 6 vs 7.9/10 6), but were 14-fold lower than the frequencies of cells with intact proviruses. Sequencing of HIV-1 RNA from induced proviruses revealed comparable sequences in paired PB and LN samples. Conclusions These results further support the use of PB as an appropriate proxy for the HIV-1 LR in secondary lymphoid organs

scholarly journals Impact of Y143 HIV-1 Integrase Mutations on Resistance to Raltegravir In Vitro and In Vivo

2009 ◽  
Vol 54 (1) ◽  
pp. 491-501 ◽  
Author(s):  
Olivier Delelis ◽  
Sylvain Thierry ◽  
Frédéric Subra ◽  
Françoise Simon ◽  
Isabelle Malet ◽  
...  
Keyword(s):  
Viral Genome ◽  
Effective Concentration ◽  
Coding Region ◽  
Delayed Emergence ◽  
Infected Cells ◽  
High Level ◽  
Emergence Of Resistance ◽  
Hiv 1

ABSTRACT Integrase (IN), the HIV-1 enzyme responsible for the integration of the viral genome into the chromosomes of infected cells, is the target of the recently approved antiviral raltegravir (RAL). Despite this drug's activity against viruses resistant to other antiretrovirals, failures of raltegravir therapy were observed, in association with the emergence of resistance due to mutations in the integrase coding region. Two pathways involving primary mutations on residues N155 and Q148 have been characterized. It was suggested that mutations at residue Y143 might constitute a third primary pathway for resistance. The aims of this study were to investigate the susceptibility of HIV-1 Y143R/C mutants to raltegravir and to determine the effects of these mutations on the IN-mediated reactions. Our observations demonstrate that Y143R/C mutants are strongly impaired for both of these activities in vitro. However, Y143R/C activity can be kinetically restored, thereby reproducing the effect of the secondary G140S mutation that rescues the defect associated with the Q148R/H mutants. A molecular modeling study confirmed that Y143R/C mutations play a role similar to that determined for Q148R/H mutations. In the viral replicative context, this defect leads to a partial block of integration responsible for a weak replicative capacity. Nevertheless, the Y143 mutant presented a high level of resistance to raltegravir. Furthermore, the 50% effective concentration (EC50) determined for Y143R/C mutants was significantly higher than that obtained with G140S/Q148R mutants. Altogether our results not only show that the mutation at position Y143 is one of the mechanisms conferring resistance to RAL but also explain the delayed emergence of this mutation.

Sign in / Sign up

Export Citation Format

Share Document