scholarly journals Efficient Transendothelial Migration of Latently HIV-1-Infected Cells

Viruses ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1589
Author(s):  
Reou Tanabe ◽  
Yuko Morikawa
Keyword(s):  
Lymph Nodes ◽  
Stromal Cells ◽  
Cell Subset ◽  
Transendothelial Migration ◽  
The Body ◽  
Lymphoid Tissues ◽  
Latently Infected ◽  
Infected Cells ◽  
Hiv 1

A small fraction of HIV-1-infected T cells forms populations of latently infected cells when they are a naive T-cell subset or in transit to a resting memory state. Latently HIV-1-infected cells reside in lymphoid tissues and serve as viral reservoirs. However, whether they systemically recirculate in the body and re-enter the lymphoid nodes are unknown. Here, we employed two in-vitro cell coculture systems mimicking the lymphatic endothelium in lymph nodes and investigated the homing potential, specifically the transendothelial migration (TEM), of two latently HIV-1-infected cell lines (J1.1 and ACH-2). In trans-well coculture systems, J1.1 and ACH-2 showed higher TEM efficiencies than their parental uninfected and acutely infected cells. The efficiency of TEM was enhanced by the presence of stromal cells, such as HS-5 and fibroblastic reticular cells. In an in-vitro reconstituted, three-dimensional coculture system in which stromal cells are embedded in collagen matrices, J1.1 showed slightly higher TEM efficiency in the presence of HS-5. In accordance with these phenotypes, latently infected cells adhered to the endothelial cells more efficiently than uninfected cells. Together, our study showed that latently HIV-1-infected cells enhanced cell adhesion and TEM abilities, suggesting their potential for efficient homing to lymph nodes.

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 A Therapeutic Strategy to Combat HIV-1 Latently Infected Cells With a Combination of Latency-Reversing Agents Containing DAG-Lactone PKC Activators

2021 ◽  
Vol 12 ◽  
Author(s):  
Kouki Matsuda ◽  
Takuya Kobayakawa ◽  
Ryusho Kariya ◽  
Kiyoto Tsuchiya ◽  
Shoraku Ryu ◽  
...  
Keyword(s):  
Whole Body ◽  
Therapeutic Effects ◽  
Combined Antiretroviral Therapy ◽  
Latently Infected ◽  
Shock And Kill ◽  
Infected Cells ◽  
Hiv 1 ◽  
Reversing Agents

Advances in antiviral therapy have dramatically improved the therapeutic effects on HIV type 1 (HIV-1) infection. However, even with potent combined antiretroviral therapy, HIV-1 latently infected cells cannot be fully eradicated. Latency-reversing agents (LRAs) are considered a potential tool for eliminating such cells; however, recent in vitro and in vivo studies have raised serious concerns regarding the efficacy and safety of the “shock and kill” strategy using LRAs. In the present study, we examined the activity and safety of a panel of protein kinase C (PKC) activators with a diacylglycerol (DAG)-lactone structure that mimics DAG, an endogenous ligand for PKC isozymes. YSE028, a DAG-lactone derivative, reversed HIV-1 latency in vitro when tested using HIV-1 latently infected cells (e.g., ACH2 and J-Lat cells) and primary cells from HIV-1-infected individuals. The activity of YSE028 in reversing HIV-1 latency was synergistically enhanced when combined with JQ1, a bromodomain and extra-terminal inhibitor LRA. DAG-lactone PKC activators also induced caspase-mediated apoptosis, specifically in HIV-1 latently infected cells. In addition, these DAG-lactone PKC activators showed minimal toxicity in vitro and in vivo. These data suggest that DAG-lactone PKC activators may serve as potential candidates for combination therapy against HIV-1 latently infected cells, especially when combined with other LRAs with a different mechanism, to minimize side effects and achieve maximum efficacy in various reservoir cells of the whole body.

scholarly journals Quantifying the turnover of transcriptional subclasses of HIV-1-infected cells

2013 ◽  
Author(s):  
Christian L Althaus ◽  
Beda Joos ◽  
Alan S Perelson ◽  
Huldrych F Günthard
Keyword(s):  
Peripheral Blood ◽  
Chronic Infection ◽  
Burst Size ◽  
Acute Infection ◽  
The Body ◽  
Latent Reservoir ◽  
Published Data ◽  
Latently Infected ◽  
Infected Cells ◽  
Hiv 1

Background: HIV-1-infected cells in peripheral blood can be grouped into different transcriptional subclasses. Quantifying the turnover of these cellular subclasses can provide important insights into the viral life cycle and the generation and maintenance of latently infected cells. Results: We used previously published data from five patients chronically infected with HIV-1 that initiated combination antiretroviral therapy (cART). Patient-matched PCR for unspliced and multiply spliced viral RNAs combined with limiting dilution analysis provided measurements of transcriptional profiles at the single cell level. Furthermore, measurement of intracellular transcripts and extracellular virion-enclosed HIV-1 RNA allowed us to distinguish productive from non-productive cells. We developed a mathematical model describing the dynamics of plasma virus and the transcriptional subclasses of HIV-1-infected cells. Fitting the model to the data allowed us to better understand the phenotype of different transcriptional subclasses and their contribution to the overall turnover of HIV-1 before and during cART. The average number of virus-producing cells in peripheral blood is small during chronic infection (25.7 cells per ml). We find that 14.0%, 0.3% and 21.2% of infected cells become defectively, latently and persistently infected cells, respectively. Assuming that the infection is homogenous throughout the body, we estimate an average in vivo viral burst size of 2.1 x 10^4 virions per cell. Conclusions: Our study provides novel quantitative insights into the turnover and development of different subclasses of HIV-1-infected cells. The model predicts that the pool of latently infected cells becomes rapidly established during the first months of acute infection and continues to increase slowly during the first years of chronic infection. Having a detailed understanding of this process will be useful for the evaluation of viral eradication strategies that aim to deplete the latent reservoir of HIV-1.

scholarly journals Effect of Xanthium Strumarium on HIV-1 5′-LTR Transcriptional Activity and Viral Reactivation in Latently Infected Cells

2021 ◽  
Vol 12 ◽  
Author(s):  
Chao-Jung Chen ◽  
Mu-Lin Chiu ◽  
Chien-Hui Hung ◽  
Wen-Miin Liang ◽  
Mao-Wang Ho ◽  
...  
Keyword(s):  
Host Cell ◽  
Transcriptional Activity ◽  
Regulatory Protein ◽  
Regulatory Proteins ◽  
Viral Reactivation ◽  
Xanthium Strumarium ◽  
Latently Infected ◽  
Infected Cells ◽  
Hiv 1

Chinese herbal medicines (CHMs) are widely used in Asian countries. They show multiple pharmacological activities, including antiviral activities. The 5′-long terminal repeat (LTR) region of HIV-1, required for viral transcription, is a potential drug target for HIV-1 reactivation and intrinsic cell death induction of infected or latently infected cells. Modulation of HIV-1 reactivation requires interactions between host cell proteins and viral 5′-LTR elements. By evaluation of two CHMs- Xanthium strumarium and Pueraria montana, we found that 1) X. strumarium reactivated HIV-1 latently infected cells in J-Lat 8.4, J-Lat 9.2, U1, and ACH-2 cells in vitro; 2) 27 nuclear regulatory proteins were associated with HIV-1 5′-LTR using deoxyribonucleic acid affinity pull-down and LC-MS/MS analyses; and 3) among them, silencing of XRCC6 reactivated HIV-1 5′-LTR transcriptional activity. We found that X. strumarium inhibits the 5′-LTR associated XRCC6 nuclear regulatory proteins, increases its viral 5′-LTR promoter transcriptional activity, and reactivates HIV-1 latently infected cells in vitro. These findings may contribute to understanding the 5′-LTR activity and the host cell nuclear regulatory protein machinery for reactivating HIV-1 and for future investigations to eradicate and cure HIV-1 infection.

scholarly journals VIP-SPOT: an Innovative Assay To Quantify the Productive HIV-1 Reservoir in the Monitoring of Cure Strategies

mBio ◽  
2021 ◽  
Author(s):  
Maria C. Puertas ◽  
Ángel Bayón-Gil ◽  
Maria C. Garcia-Guerrero ◽  
Maria Salgado ◽  
Víctor Urrea ◽  
...  
Keyword(s):  
The Body ◽  
Continuous Treatment ◽  
Viral Reservoir ◽  
Functional Cure ◽  
Viral Eradication ◽  
Latently Infected ◽  
Infected Cells ◽  
Hiv 1

Current efforts aimed at finding a definitive cure for HIV-1 infection are hampered mainly by the persistence of a viral reservoir in latently infected cells. While complete viral eradication from the body remains elusive, finding a functional cure to enable control of viremia without the need for continuous treatment is a key goal.

scholarly journals Induction of HIV-1 Replication in Latently Infected CD4+ T Cells Using a Combination of Cytokines

1998 ◽  
Vol 188 (1) ◽  
pp. 83-91 ◽  
Author(s):  
Tae-Wook Chun ◽  
Delphine Engel ◽  
Stephanie B. Mizell ◽  
Linda A. Ehler ◽  
Anthony S. Fauci
Keyword(s):  
T Cells ◽  
Antiretroviral Therapy ◽  
Viral Replication ◽  
Proinflammatory Cytokines ◽  
Cd4 T Cells ◽  
Lymphoid Tissues ◽  
Tnf Α ◽  
Latently Infected ◽  
Hiv 1

Although it has been demonstrated that certain cytokines, particularly proinflammatory cytokines, can enhance ongoing viral replication in peripheral blood mononuclear cells (PBMCs) of HIV-1–infected individuals, it is unclear what role these cytokines play in the induction of HIV-1 replication in latently infected, resting CD4+ T cells. This study demonstrates that the in vitro combination of the proinflammatory cytokines interleukin (IL)-6 and tumor necrosis factor (TNF)-α together with the immunoregulatory cytokine IL-2 are potent inducers of viral replication in highly purified, latently infected, resting CD4+ T cells derived from HIV-infected individuals who are antiretroviral therapy–naive as well as those who are receiving highly active antiretroviral therapy (HAART). Viral replication induced by this combination of cytokines was completely suppressed in the presence of HAART in vitro. Given that an array of cytokines, including IL-6, TNF-α, and IL-2, are copiously expressed in the microenvironment of the lymphoid tissues, which harbor the latent viral reservoirs, induction of HIV by this combination of cytokines may in part explain the commonly observed reappearance of detectable plasma viremia in HIV-infected individuals in whom HAART was discontinued. Moreover, since it is likely that these infected cells die upon activation of virus and that HAART prevents spread of virus to adjacent cells, the observation that this combination of cytokines can markedly induce viral replication in this reservoir may have important implications for the activation-mediated diminution of the latent reservoir of HIV in patients receiving HAART.

scholarly journals A Critical Review of the Evidence Concerning the HIV Latency Reversing Effect of Disulfiram, the Possible Explanations for Its Inability to Reduce the Size of the Latent Reservoir In Vivo, and the Caveats Associated with Its Use in Practice

2017 ◽  
Vol 2017 ◽  
pp. 1-7 ◽  
Author(s):  
Harry D. J. Knights
Keyword(s):  
Immune Deficiency Syndrome ◽  
Deficiency Syndrome ◽  
Latent Reservoir ◽  
Major Barrier ◽  
Latently Infected ◽  
Shock And Kill ◽  
Infected Cells ◽  
Hiv 1

Combination antiretroviral therapy (cART) effectively suppresses the replication of human immunodeficiency virus type 1 (HIV-1), improves immune function, and decreases the morbidity of acquired immune deficiency syndrome (AIDS). However, it is unable to eradicate the virus because it does not eliminate latently infected cells. The latent reservoir poses the major barrier to an HIV-1 cure. The “shock and kill” strategy aims to reactivate the virus and destroy latently infected cells. Many latency reversing agents (LRAs) reactivate HIV in vitro, but the absence of damaging side-effects and efficacy in vivo make disulfiram particularly promising. However, in clinical trials to date, disulfiram treatment has not resulted in a reduction in the size of the latent reservoir. In this article I will therefore discuss the evidence for the latency reversing effect of disulfiram, the possible explanations for its inability to reduce the size of the latent reservoir in vivo, and the caveats associated with its use in practice. These considerations will help to inform judgements about the prospect of an HIV cure from disulfiram based treatments.

scholarly journals Expression of CircRNAs in HIV-1 latently infected cells from an in vitro model

2019 ◽  
Vol 5 ◽  
pp. 11
Author(s):  
L. Iniguez ◽  
D.C. Copertino ◽  
D.F. Nixon ◽  
M. De Mulder Rougvie
Keyword(s):  
In Vitro Model ◽  
Latently Infected ◽  
Infected Cells ◽  
Vitro Model ◽  
Hiv 1

scholarly journals Targeting and Understanding HIV Latency: The CRISPR System against the Provirus

Pathogens ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 1257
Author(s):  
Gloria Magro ◽  
Arianna Calistri ◽  
Cristina Parolin
Keyword(s):  
Viral Latency ◽  
In Vivo Studies ◽  
Latently Infected ◽  
Infected Cells ◽  
Specific Factors ◽  
The One ◽  
Cellular Dna ◽  
Hiv 1

The presence of latently infected cells and reservoirs in HIV-1 infected patients constitutes a significant obstacle to achieve a definitive cure. Despite the efforts dedicated to solve these issues, the mechanisms underlying viral latency are still under study. Thus, on the one hand, new strategies are needed to elucidate which factors are involved in latency establishment and maintenance. On the other hand, innovative therapeutic approaches aimed at eradicating HIV infection are explored. In this context, advances of the versatile CRISPR-Cas gene editing technology are extremely promising, by providing, among other advantages, the possibility to target the HIV-1 genome once integrated into cellular DNA (provirus) and/or host-specific genes involved in virus infection/latency. This system, up to now, has been employed with success in numerous in vitro and in vivo studies, highlighting its increasing significance in the field. In this review, we focus on the progresses made in the use of different CRISPR-Cas strategies to target the HIV-1 provirus, and we then discuss recent advancements in the use of CRISPR screens to elucidate the role of host-specific factors in viral latency.

In vitro antiviral activity of Mentha cordifolia plant extract in HIV-1 latently infected cells using an established human cell line

2021 ◽  
Author(s):  
Sheriah Laine Maasin de Paz-Silava ◽  
Ann Florence B. Victoriano-Belvis ◽  
Nina G. Gloriani ◽  
Yurina Hibi ◽  
Kaori Asamitsu ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Cell Line ◽  
Plant Extract ◽  
Human Cell ◽  
Human Cell Line ◽  
Latently Infected ◽  
Infected Cells ◽  
Hiv 1
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