scholarly journals Implications of HIV-1 Nef for “Shock and Kill” Strategies to Eliminate Latent Viral Reservoirs

Viruses ◽  
2018 ◽  
Vol 10 (12) ◽  
pp. 677 ◽  
Author(s):  
Xiaomei Kuang ◽  
Mark Brockman
Keyword(s):  
Clinical Success ◽  
Viral Reservoirs ◽  
Hiv Reservoirs ◽  
Cytopathic Effects ◽  
Immune Mediated ◽  
Limited Effectiveness ◽  
Shock And Kill ◽  
Cell Genome ◽  
Latent Hiv ◽  
Silent State

Finding a cure for HIV is challenging because the virus is able to integrate itself into the host cell genome and establish a silent state, called latency, allowing it to evade antiviral drugs and the immune system. Various “shock and kill” strategies are being explored in attempts to eliminate latent HIV reservoirs. The goal of these approaches is to reactivate latent viruses (“shock”), thereby exposing them to clearance by viral cytopathic effects or immune-mediated responses (“kill”). To date, there has been limited clinical success using these methods. In this review, we highlight various functions of the HIV accessory protein Nef and discuss their double-edged effects that may contribute to the limited effectiveness of current “shock and kill” methods to eradicate latent HIV reservoirs in treated individuals.

scholarly journals Reactivation of latent HIV moves shock-and-kill treatments forward

Nature ◽  
2020 ◽  
Vol 578 (7793) ◽  
pp. 42-43
Author(s):  
Mathias Lichterfeld
Keyword(s):  
Shock And Kill ◽  
Latent Hiv

scholarly journals HIV-1 Vpr mediates the depletion of the cellular repressor CTIP2 to counteract viral gene silencing

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
F. Forouzanfar ◽  
S. Ali ◽  
C. Wallet ◽  
M. De Rovere ◽  
C. Ducloy ◽  
...  
Keyword(s):  
Gene Silencing ◽  
Viral Gene ◽  
Target Cells ◽  
Viral Reservoirs ◽  
Ubiquitin Ligase Complex ◽  
Latently Infected ◽  
Cellular Cofactor ◽  
Proteasome Pathway ◽  
Latent Hiv ◽  
Hiv 1

Abstract Mammals have evolved many antiviral factors impacting different steps of the viral life cycle. Associated with chromatin-modifying enzymes, the cellular cofactor CTIP2 contributes to HIV-1 gene silencing in latently infected reservoirs that constitute the major block toward an HIV cure. We report, for the first time, that the virus has developed a strategy to overcome this major transcriptional block. Productive HIV-1 infection results in a Vpr-mediated depletion of CTIP2 in microglial cells and CD4+ T cells, two of the major viral reservoirs. Associated to the Cul4A-DDB1-DCAF1 ubiquitin ligase complex, Vpr promotes CTIP2 degradation via the proteasome pathway in the nuclei of target cells and notably at the latent HIV-1 promoter. Importantly, Vpr targets CTIP2 associated with heterochromatin-promoting enzymes dedicated to HIV-1 gene silencing. Thereby, Vpr reactivates HIV-1 expression in a microglial model of HIV-1 latency. Altogether our results suggest that HIV-1 Vpr mediates the depletion of the cellular repressor CTIP2 to counteract viral gene silencing.

scholarly journals Chronic morphine administration differentially modulates viral reservoirs in SIVmac251 infected rhesus macaque model

2020 ◽  
Author(s):  
Arpan Acharya ◽  
Omalla A Olwenyi ◽  
Michellie Thurman ◽  
Kabita Pandey ◽  
Brenda M Morsey ◽  
...  
Keyword(s):  
Rhesus Macaque ◽  
Peripheral Blood ◽  
Viral Reservoir ◽  
Lymphoid Tissues ◽  
People Living With Hiv ◽  
Opioid Use ◽  
Viral Reservoirs ◽  
Chronic Morphine ◽  
Hiv Reservoirs ◽  
The Impact

AbstractHIV persists in cellular reservoirs despite effective anti-retroviral therapy with rebound of viremia upon therapy interruption. Opioids modulate the immune system and suppress antiviral gene responses, which significantly impact people living with HIV (PLWH). However, the effects of opioids on viral reservoir remains elusive. Herein, we describe a morphine dependent SIVmac251 infected Rhesus macaque (RM) model to study the impact of opioids on HIV reservoirs. RMs were ramped up with morphine (n=10) or saline (n=9) for two weeks to a final dosage of 5mg/kg administered twice daily, which was maintained for seven weeks, and then infected with SIVmac251. Combined anti-retroviral therapy (cART) was initiated in approximately half the animals in each group five weeks post-infection and morphine/saline administration continued for 10 months. Among drug naïve macaques, there were no differences in plasma/CSF viral load nor in cell-associated DNA/RNA loads. However, within the cART-suppressed macaques, there was a reduction in cell-associated DNA load, intact proviral DNA copy numbers, and inducible SIV reservoir in both peripheral blood and lymph nodes (LNs) of morphine-administered RMs compared to saline controls. Further, PBMCs of morphine administered RMs, a reduction in Th1 polarized CD4+ T cells and in LNs there was a reduction in the total Tfh and Th1 like Tfh cells were observed, indicating probably have impact on reduction of viral reservoirs. In distinction to PBMC and LNs, within the CNS size of latent SIV reservoirs was higher in the CD11b+ microglia/macrophages of morphine-dependent RMs. These data suggest that morphine plays a role in modulating SIV reservoirs, reduces the CD4+ T-cell reservoir in both peripheral blood and LNs, and increases microglia/macrophage reservoirs in CNS. These findings will aid in understanding of molecular mechanism(s) of opioid-mediated differential modulation of viral reservoirs and evaluation of therapeutic strategies to reduce/eliminate HIV reservoirs in opioid-dependent PLWH.Author summaryOpioids are commonly used as well as abused by HIV infected individuals, are known to suppress immune responses. However, their effects on modulating viral reservoir dynamics is not known. Here we developed a morphine dependent SIVmac251 infected rhesus macaque (RM) model to study the impact of opioids on HIV reservoirs and immune cells. We found that there was no difference in viral loads or cell-associated DNA/RNA loads among morphine dependent vs. saline treated control macaques. On the other hand, when macaques were treated with cART, there was a reduction in SIV reservoirs both in periphery and lymphoid tissues in morphine administered RMs, and the size of latent SIV reservoir was higher in the CNS CD11b+ microglia/macrophages as compared to control macaques. Therefore, these new data form macaque models suggest that PLWH who suffering from opioid use disorders have higher reservoirs in CNS as compared to lymphoid system. Thus, through understanding these reservoirs among PLWH who uses opioids are critical for better designing HIV cure strategies.

scholarly journals HIV in the Brain: Identifying Viral Reservoirs and Addressing the Challenges of an HIV Cure

Vaccines ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 867
Author(s):  
Michelle K. Ash ◽  
Lena Al-Harthi ◽  
Jeffrey R. Schneider
Keyword(s):  
Treatment Options ◽  
Cell Types ◽  
Latent Reservoir ◽  
People Living With Hiv ◽  
Hiv Cure ◽  
Viral Reservoirs ◽  
Susceptibility To Infection ◽  
The Central Nervous System ◽  
Latent Hiv ◽  
The Brain

Advances in antiretroviral therapy have prolonged the life of people living with HIV and diminished the level of virus in these individuals. Yet, HIV quickly rebounds after disruption and/or cessation of treatment due to significant cellular and anatomical reservoirs for HIV, which underscores the challenge for HIV cure strategies. The central nervous system (CNS), in particular, is seeded with HIV within 1–2 weeks of infection and is a reservoir for HIV. In this review, we address the paradigm of HIV reservoirs in the CNS and the relevant cell types, including astrocytes and microglia, that have been shown to harbor viral infection even with antiretroviral treatment. In particular, we focus on developmental aspects of astrocytes and microglia that lead to their susceptibility to infection, and how HIV infection propagates among these cells. We also address challenges of measuring the HIV latent reservoir, advances in viral detection assays, and how curative strategies have evolved in regard to the CNS reservoir. Current curative strategies still require optimization to reduce or eliminate the HIV CNS reservoir, and may also contribute to levels of neuroinflammation that lead to cognitive decline. With this in mind, the latent HIV reservoir in the brain should remain a prominent focus when assessing treatment options and overall viral burden in the clinic, especially in the context of HIV-associated neurocognitive disorders (HAND).

scholarly journals The African natural product knipholone anthrone and its analogue anthralin (dithranol) enhance HIV-1 latency reversal

2020 ◽  
Vol 295 (41) ◽  
pp. 14084-14099
Author(s):  
Khumoekae Richard ◽  
Cole Schonhofer ◽  
Leila B. Giron ◽  
Jocelyn Rivera-Ortiz ◽  
Silven Read ◽  
...  
Keyword(s):  
Natural Product ◽  
Histone Deacetylases ◽  
Global Gene Expression ◽  
Viral Reservoirs ◽  
Reversal Agent ◽  
Hiv Rna ◽  
Functional Classes ◽  
Natural Product Library ◽  
Shock And Kill ◽  
Multiple Cell

A sterilizing or functional cure for HIV is currently precluded by resting CD4+ T cells that harbor latent but replication-competent provirus. The “shock-and-kill” pharmacological ap-proach aims to reactivate provirus expression in the presence of antiretroviral therapy and target virus-expressing cells for elimination. However, no latency reversal agent (LRA) to date effectively clears viral reservoirs in humans, suggesting a need for new LRAs and LRA combinations. Here, we screened 216 compounds from the pan-African Natural Product Library and identified knipholone anthrone (KA) and its basic building block anthralin (dithranol) as novel LRAs that reverse viral latency at low micromolar concentrations in multiple cell lines. Neither agent's activity depends on protein kinase C; nor do they inhibit class I/II histone deacetylases. However, they are differentially modulated by oxidative stress and metal ions and induce distinct patterns of global gene expression from established LRAs. When applied in combination, both KA and anthralin synergize with LRAs representing multiple functional classes. Finally, KA induces both HIV RNA and protein in primary cells from HIV-infected donors. Taken together, we describe two novel LRAs that enhance the activities of multiple “shock-and-kill” agents, which in turn may inform ongoing LRA combination therapy efforts.

scholarly journals Designed, synthetically accessible bryostatin analogues potently induce activation of latent HIV reservoirs in vitro

2012 ◽  
Vol 4 (9) ◽  
pp. 705-710 ◽  
Author(s):  
Brian A. DeChristopher ◽  
Brian A. Loy ◽  
Matthew D. Marsden ◽  
Adam J. Schrier ◽  
Jerome A. Zack ◽  
...  
Keyword(s):  
Hiv Reservoirs ◽  
Latent Hiv

scholarly journals Enhanced antitumoral activity of TLR7 agonists via activation of human endogenous retroviruses by HDAC inhibitors

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
David Díaz-Carballo ◽  
Sahitya Saka ◽  
Ali H. Acikelli ◽  
Ekaterina Homp ◽  
Julia Erwes ◽  
...  
Keyword(s):  
Hdac Inhibitors ◽  
Ovarian Tumour ◽  
Endogenous Retroviruses ◽  
Antitumoral Activity ◽  
Cancer Therapies ◽  
Simultaneous Application ◽  
Human Endogenous Retroviruses ◽  
Shock And Kill ◽  
Latent Hiv

AbstractIn this work, we are reporting that “Shock and Kill”, a therapeutic approach designed to eliminate latent HIV from cell reservoirs, is extrapolatable to cancer therapy. This is based on the observation that malignant cells express a spectrum of human endogenous retroviral elements (HERVs) which can be transcriptionally boosted by HDAC inhibitors. The endoretroviral gene HERV-V2 codes for an envelope protein, which resembles syncytins. It is significantly overexpressed upon exposure to HDAC inhibitors and can be effectively targeted by simultaneous application of TLR7/8 agonists, triggering intrinsic apoptosis. We demonstrated that this synergistic cytotoxic effect was accompanied by the functional disruption of the TLR7/8-NFκB, Akt/PKB, and Ras-MEK-ERK signalling pathways. CRISPR/Cas9 ablation of TLR7 and HERV-V1/V2 curtailed apoptosis significantly, proving the pivotal role of these elements in driving cell death. The effectiveness of this new approach was confirmed in ovarian tumour xenograft studies, revealing a promising avenue for future cancer therapies.

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