HBV antigens quantity: duration and effect on functional cure

Gut ◽  
2021 ◽  
pp. gutjnl-2021-326258
Author(s):  
Antonio Bertoletti ◽  
Carolina Boni
Keyword(s):  
Functional Cure

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 human Acyl-CoA:cholesterol acyltransferase as a dual viral and T cell metabolic checkpoint

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Nathalie M. Schmidt ◽  
Peter A. C. Wing ◽  
Mariana O. Diniz ◽  
Laura J. Pallett ◽  
Leo Swadling ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Human Liver ◽  
Lipid Droplets ◽  
Ex Vivo ◽  
Functional Cure ◽  
Carcinogenic Activity ◽  
Attractive Therapeutic Target ◽  
Tcr Signalling

AbstractDetermining divergent metabolic requirements of T cells, and the viruses and tumours they fail to combat, could provide new therapeutic checkpoints. Inhibition of acyl-CoA:cholesterol acyltransferase (ACAT) has direct anti-carcinogenic activity. Here, we show that ACAT inhibition has antiviral activity against hepatitis B (HBV), as well as boosting protective anti-HBV and anti-hepatocellular carcinoma (HCC) T cells. ACAT inhibition reduces CD8+ T cell neutral lipid droplets and promotes lipid microdomains, enhancing TCR signalling and TCR-independent bioenergetics. Dysfunctional HBV- and HCC-specific T cells are rescued by ACAT inhibitors directly ex vivo from human liver and tumour tissue respectively, including tissue-resident responses. ACAT inhibition enhances in vitro responsiveness of HBV-specific CD8+ T cells to PD-1 blockade and increases the functional avidity of TCR-gene-modified T cells. Finally, ACAT regulates HBV particle genesis in vitro, with inhibitors reducing both virions and subviral particles. Thus, ACAT inhibition provides a paradigm of a metabolic checkpoint able to constrain tumours and viruses but rescue exhausted T cells, rendering it an attractive therapeutic target for the functional cure of HBV and HBV-related HCC.

scholarly journals Advances toward Curing HIV-1 Infection in Tissue Reservoirs

2019 ◽  
Vol 94 (3) ◽  
Author(s):  
Lisa J. Henderson ◽  
Lauren B. Reoma ◽  
Joseph A. Kovacs ◽  
Avindra Nath
Keyword(s):  
Checkpoint Inhibitors ◽  
Functional Cure ◽  
Viral Transcript ◽  
Curative Therapy ◽  
Gene Therapies ◽  
Recent Developments ◽  
The Central Nervous System ◽  
Effector Response ◽  
Hiv 1 ◽  
Cell Effector

ABSTRACT A disease of more than 39.6 million people worldwide, HIV-1 infection has no curative therapy. To date, one man has achieved a sterile cure, with millions more hoping to avoid the potential pitfalls of lifelong antiretroviral therapy and other HIV-related disorders, including neurocognitive decline. Recent developments in immunotherapies and gene therapies provide renewed hope in advancing efforts toward a sterilizing or functional cure. On the horizon is research concentrated in multiple separate but potentially complementary domains: vaccine research, viral transcript editing, T-cell effector response targeting including checkpoint inhibitors, and gene editing. Here, we review the concept of targeting the HIV-1 tissue reservoirs, with an emphasis on the central nervous system, and describe relevant new work in functional cure research and strategies for HIV-1 eradication.

scholarly journals Moving Toward a Functional Cure for HIV-1

2021 ◽  
Vol Publish Ahead of Print ◽  
Author(s):  
Wen Kang ◽  
Yongtao Sun
Keyword(s):  
Functional Cure ◽  
Hiv 1

scholarly journals Impact of a decade of successful antiretroviral therapy initiated at HIV-1 seroconversion on blood and rectal reservoirs

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Eva Malatinkova ◽  
Ward De Spiegelaere ◽  
Pawel Bonczkowski ◽  
Maja Kiselinova ◽  
Karen Vervisch ◽  
...  
Keyword(s):  
Antiretroviral Therapy ◽  
Treatment Initiation ◽  
Cross Sectional Study ◽  
Functional Cure ◽  
Cross Sectional ◽  
Polymerase Chain ◽  
Low Levels ◽  
Rectal Biopsies ◽  
Hiv 1

Persistent reservoirs remain the major obstacles to achieve an HIV-1 cure. Prolonged early antiretroviral therapy (ART) may reduce the extent of reservoirs and allow for virological control after ART discontinuation. We compared HIV-1 reservoirs in a cross-sectional study using polymerase chain reaction-based techniques in blood and tissue of early-treated seroconverters, late-treated patients, ART-naïve seroconverters, and long-term non-progressors (LTNPs) who have spontaneous virological control without treatment. A decade of early ART reduced the total and integrated HIV-1 DNA levels compared with later treatment initiation, but not reaching the low levels found in LTNPs. Total HIV-1 DNA in rectal biopsies did not differ between cohorts. Importantly, lower viral transcription (HIV-1 unspliced RNA) and enhanced immune preservation (CD4/CD8), reminiscent of LTNPs, were found in early compared to late-treated patients. This suggests that early treatment is associated with some immunovirological features of LTNPs that may improve the outcome of future interventions aimed at a functional cure.

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.

Sign in / Sign up

Export Citation Format

Share Document