scholarly journals SMAC Mimetics as Therapeutic Agents in HIV Infection

2021 ◽  
Vol 12 ◽  
Author(s):  
Bengisu Molyer ◽  
Ashok Kumar ◽  
Jonathan B. Angel
Keyword(s):  
Hiv Cure ◽  
Apoptosis Pathway ◽  
Persistently Infected ◽  
Hiv Rna ◽  
Current State ◽  
Latently Infected ◽  
Smac Mimetics ◽  
Inhibitors Of Apoptosis Proteins ◽  
Infected Cells ◽  
Apoptosis Proteins

Although combination antiretroviral therapy is extremely effective in lowering HIV RNA to undetectable levels in the blood, HIV persists in latently infected CD4+ T-cells and persistently infected macrophages. In latently/persistently infected cells, HIV proteins have shown to affect the expression of proteins involved in the apoptosis pathway, notably the inhibitors of apoptosis proteins (IAPs), and thereby influence cell survival. IAPs, which are inhibited by endogenous second mitochondrial-derived activators of caspases (SMAC), can serve as targets for SMAC mimetics, synthetic compounds capable of inducing apoptosis. There is increasing evidence that SMAC mimetics can be used to reverse HIV latency and/or kill cells that are latently/persistently infected with HIV. Here, we review the current state of knowledge of SMAC mimetics as an approach to eliminate HIV infected cells and discuss the potential future use of SMAC mimetics as part of an HIV cure strategy.

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 Relationship between Measures of HIV Reactivation and Decline of the Latent Reservoir under Latency-Reversing Agents

2017 ◽  
Vol 91 (9) ◽  
Author(s):  
Janka Petravic ◽  
Thomas A. Rasmussen ◽  
Sharon R. Lewin ◽  
Stephen J. Kent ◽  
Miles P. Davenport
Keyword(s):  
Clinical Trials ◽  
Life Span ◽  
Substantial Reduction ◽  
Latent Reservoir ◽  
Hiv Rna ◽  
Hiv Transcription ◽  
Latently Infected ◽  
Infected Cells ◽  
The Impact ◽  
Reversing Agents

ABSTRACT Antiretroviral-free HIV remission requires substantial reduction of the number of latently infected cells and enhanced immune control of viremia. Latency-reversing agents (LRAs) aim to eliminate latently infected cells by increasing the rate of reactivation of HIV transcription, which exposes these cells to killing by the immune system. As LRAs are explored in clinical trials, it becomes increasingly important to assess the effect of an increased HIV reactivation rate on the decline of latently infected cells and to estimate LRA efficacy in increasing virus reactivation. However, whether the extent of HIV reactivation is a good predictor of the rate of decline of the number of latently infected cells is dependent on a number of factors. Our modeling shows that the mechanisms of maintenance and clearance of the reservoir, the life span of cells with reactivated HIV, and other factors may significantly impact the relationship between measures of HIV reactivation and the decline in the number of latently infected cells. The usual measures of HIV reactivation are the increase in cell-associated HIV RNA (CA RNA) and/or plasma HIV RNA soon after administration. We analyze two recent studies where CA RNA was used to estimate the impact of two novel LRAs, panobinostat and romidepsin. Both drugs increased the CA RNA level 3- to 4-fold in clinical trials. However, cells with panobinostat-reactivated HIV appeared long-lived (half-life > 1 month), suggesting that the HIV reactivation rate increased by approximately 8%. With romidepsin, the life span of cells that reactivated HIV was short (2 days), suggesting that the HIV reactivation rate may have doubled under treatment. IMPORTANCE Long-lived latently infected cells that persist on antiretroviral treatment (ART) are thought to be the source of viral rebound soon after ART interruption. The elimination of latently infected cells is an important step in achieving antiretroviral-free HIV remission. Latency-reversing agents (LRAs) aim to activate HIV expression in latently infected cells, which could lead to their death. Here, we discuss the possible impact of the LRAs on the reduction of the number of latently infected cells, depending on the mechanisms of their loss and self-renewal and on the life span of the cells that have HIV transcription activated by the LRAs.

scholarly journals Phenotypic analysis of the unstimulated in vivo HIV CD4 T cell reservoir

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Jason Neidleman ◽  
Xiaoyu Luo ◽  
Julie Frouard ◽  
Guorui Xie ◽  
Feng Hsiao ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Cd4 T Cell ◽  
Latent Reservoir ◽  
Hiv Cure ◽  
Phenotypic Analysis ◽  
Major Barrier ◽  
Hiv Persistence ◽  
Latently Infected ◽  
Infected Cells

The latent reservoir is a major barrier to HIV cure. As latently infected cells cannot be phenotyped directly, the features of the in vivo reservoir have remained elusive. Here, we describe a method that leverages high-dimensional phenotyping using CyTOF to trace latently infected cells reactivated ex vivo to their original pre-activation states. Our results suggest that, contrary to common assumptions, the reservoir is not randomly distributed among cell subsets, and is remarkably conserved between individuals. However, reservoir composition differs between tissues and blood, as do cells successfully reactivated by different latency reversing agents. By selecting 8–10 of our 39 original CyTOF markers, we were able to isolate highly purified populations of unstimulated in vivo latent cells. These purified populations were highly enriched for replication-competent and intact provirus, transcribed HIV, and displayed clonal expansion. The ability to isolate unstimulated latent cells from infected individuals enables previously impossible studies on HIV persistence.

scholarly journals Targeting the latent reservoir to achieve functional HIV cure

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 1009 ◽  
Author(s):  
Daniele C. Cary ◽  
B. Matija Peterlin
Keyword(s):  
Defense Mechanisms ◽  
Viral Reactivation ◽  
Latent Reservoir ◽  
Hiv Cure ◽  
Functional Cure ◽  
Knock Out ◽  
Highly Active ◽  
Latently Infected ◽  
Infected Cells ◽  
Latent Hiv

While highly active anti-retroviral therapy has greatly improved the lives of HIV-infected individuals, current treatments are unable to completely eradicate the virus. This is due to the presence of HIV latently infected cells which harbor transcriptionally silent HIV. Latent HIV does not replicate or produce viral proteins, thereby preventing efficient targeting by anti-retroviral drugs. Strategies to target the HIV latent reservoir include viral reactivation, enhancing host defense mechanisms, keeping latent HIV silent, and using gene therapy techniques to knock out or reactivate latent HIV. While research into each of these areas has yielded promising results, currently no one mechanism eradicates latent HIV. Instead, combinations of these approaches should be considered for a potential HIV functional cure.

scholarly journals HIV RNA Suppression and Immune Restoration: Can We Do Better?

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Marilia Rita Pinzone ◽  
Michelino Di Rosa ◽  
Bruno Cacopardo ◽  
Giuseppe Nunnari
Keyword(s):  
Residual Viremia ◽  
Immune Restoration ◽  
Viral Reservoirs ◽  
Hiv Rna ◽  
All Cause Mortality ◽  
Immunologic Factors ◽  
Latently Infected ◽  
History Of ◽  
Infected Cells ◽  
Low Levels

HAART has significantly changed the natural history of HIV infection: patients receiving antiretrovirals are usually able to control viremia, even though not all virological responders adequately recover their CD4+ count. The reasons for poor immune restoration are only partially known and they include genetic, demographic and immunologic factors. A crucial element affecting immune recovery is immune activation, related to residual viremia; indeed, a suboptimal virological control (i.e., low levels of plasma HIV RNA) has been related with higher levels of chronic inflammation and all-cause mortality. The sources of residual viremia are not yet completely known, even though the most important one is represented by latently infected cells. Several methods, including 2-LTR HIV DNA and unspliced HIV RNA measurement, have been developed to estimate residual viremia and predict the outcome of antiretroviral therapy. Considering that poor immunologic responders are exposed to a higher risk of both AIDS-related and non-AIDS-related diseases, there is a need of new therapeutic strategies, including immunomodulators and drugs targeting the latent viral reservoirs, in order to face residual viremia but also to “drive” the host immunologic responses.

scholarly journals Exonic Disruption Facilitates Antiviral CRISPR-Cas9 Activity for Multistrain HIV-1 Elimination

2021 ◽  
Author(s):  
Jonathan Herskovitz ◽  
Mahmudul Hasan ◽  
Milankumar Patel ◽  
Wilson R. Blomberg ◽  
Jacob D. Cohen ◽  
...  
Keyword(s):  
T Cells ◽  
Consensus Sequence ◽  
Hiv Cure ◽  
Proviral Dna ◽  
Guide Rnas ◽  
Antiretroviral Drug Resistance ◽  
Antiretroviral Drug ◽  
Latently Infected ◽  
Infected Cells ◽  
Hiv 1

AbstractA barrier to HIV-1 cure rests in the persistence of proviral DNA in infected CD4+ leukocytes. The high mutation rate of HIV-1 gives rise to numerous circulating strains with increased capacity for immune evasion and antiretroviral drug resistance. To facilitate viral elimination while accounting for this diversity, we propose genetic inactivation of proviral DNA with CRISPR-spCas9. We designed a library of “mosaic gRNAs” against a HIV-1 consensus sequence constructed from 4004 clinical strains, targeting the viral transcriptional regulator tat. Testing in 7 HIV-1 transmitted founder strains led, on average, to viral reductions of 82% with tandem TatD and TatE (TatDE) treatment. No off-target cleavages were recorded. Lentiviral transduction of TatDE attenuated latency reversal by 94% in HIV-infected, transcriptionally silent ACH2 T cells. In all, TatDE guide RNAs successfully disrupted 5 separate HIV-1 exons (tat1-2/rev1-2/gp41) providing a pathway for CRISPR-directed HIV-1 cure therapies.Significance StatementOver 38 million individuals worldwide are infected with HIV-1, which necessitates lifelong dependence on antiretroviral therapy (ART) to prevent viral replication that leads to AIDS. Efforts to rid hosts of HIV-1 are limited by the virus’ abilities to integrate proviral DNA in nuclei, mutate their genomes, and lay dormant for decades during ART treatment. We developed mosaic guide RNAs, TatD and TatE, for CRISPR-Cas9 that recognize the majority of known HIV-1 strains and inactivate 94% of proviral DNA in latently infected cells. Tandem TatDE-CRISPR inactivation of 5 viral exons (tat1-2, rev1-2, and gp41), which blocked HIV-1 replication for 28 days in CD4+ T cells without unwanted editing to the host genome, may serve as a viable strategy for HIV cure.

Infective substructures of measles virus from acutely and persistently infected cells.

1979 ◽  
Vol 32 (1) ◽  
pp. 329-333 ◽  
Author(s):  
S Rozenblatt ◽  
T Koch ◽  
O Pinhasi ◽  
S Bratosin
Keyword(s):  
Measles Virus ◽  
Persistently Infected ◽  
Infected 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 Targeting the latent human cytomegalovirus reservoir for T-cell-mediated killing with virus-specific nanobodies

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Timo W. M. De Groof ◽  
Elizabeth G. Elder ◽  
Eleanor Y. Lim ◽  
Raimond Heukers ◽  
Nick D. Bergkamp ◽  
...  
Keyword(s):  
Gene Expression ◽  
Human Cytomegalovirus ◽  
Early Gene ◽  
Latent Reservoir ◽  
Solid Organ ◽  
Cell Transplant ◽  
Viral Receptor ◽  
Transplant Patients ◽  
Latently Infected ◽  
Infected Cells

AbstractLatent human cytomegalovirus (HCMV) infection is characterized by limited gene expression, making latent HCMV infections refractory to current treatments targeting viral replication. However, reactivation of latent HCMV in immunosuppressed solid organ and stem cell transplant patients often results in morbidity. Here, we report the killing of latently infected cells via a virus-specific nanobody (VUN100bv) that partially inhibits signaling of the viral receptor US28. VUN100bv reactivates immediate early gene expression in latently infected cells without inducing virus production. This allows recognition and killing of latently infected monocytes by autologous cytotoxic T lymphocytes from HCMV-seropositive individuals, which could serve as a therapy to reduce the HCMV latent reservoir of transplant patients.

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