Immunotherapy with Cell-Based Biological Drugs to Cure HIV-1 Infection

Since its discovery 35 years ago, there have been no therapeutic interventions shown to enable full HIV-1 remission. Combined antiretroviral therapy (cART) has achieved the sustained control of HIV-1 replication, however, the life-long treatment does not eradicate long-lived latently infected reservoirs and can result in multiple side effects including the development of multidrug-resistant escape mutants. Antibody-based treatments have emerged as alternative approaches for a HIV-1 cure. Here, we will review clinical advances in coreceptor-targeting antibodies, with respect to anti-CCR5 antibodies in particular, which are currently being generated to target the early stages of infection. Among the Env-specific antibodies widely accepted as relevant in cure strategies, the potential role of those targeting CD4-induced (CD4i) epitopes of the CD4-binding site (CD4bs) in eliminating HIV-1 infected cells has gained increasing interest and will be presented. Together, with approaches targeting the HIV-1 replication cycle, we will discuss the strategies aimed at boosting and modulating specific HIV-1 immune responses, highlighting the harnessing of TLR agonists for their dual role as latency reverting agents (LRAs) and immune-modulatory compounds. The synergistic combinations of different approaches have shown promising results to ultimately enable a HIV-1 cure.

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

Frontiers in Microbiology ◽

10.3389/fmicb.2021.636276 ◽

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.

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New Latency Reversing Agents for HIV-1 Cure: Insights from Nonhuman Primate Models

Viruses ◽

10.3390/v13081560 ◽

2021 ◽

Vol 13 (8) ◽

pp. 1560

Author(s):

Katherine M. Bricker ◽

Ann Chahroudi ◽

Maud Mavigner

Keyword(s):

Nonhuman Primate ◽

Immune Checkpoint Blockade ◽

Tlr Agonists ◽

Latently Infected ◽

Shock And Kill ◽

Infected Cells ◽

Main Barrier ◽

Hiv 1 ◽

Reversing Agents

Antiretroviral therapy (ART) controls human immunodeficiency virus 1 (HIV-1) replication and prevents disease progression but does not eradicate HIV-1. The persistence of a reservoir of latently infected cells represents the main barrier to a cure. “Shock and kill” is a promising strategy involving latency reversing agents (LRAs) to reactivate HIV-1 from latently infected cells, thus exposing the infected cells to killing by the immune system or clearance agents. Here, we review advances to the “shock and kill” strategy made through the nonhuman primate (NHP) model, highlighting recently identified latency reversing agents and approaches such as mimetics of the second mitochondrial activator of caspase (SMACm), experimental CD8+ T cell depletion, immune checkpoint blockade (ICI), and toll-like receptor (TLR) agonists. We also discuss the advantages and limits of the NHP model for HIV cure research and methods developed to evaluate the efficacy of in vivo treatment with LRAs in NHPs.

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Induction of Autophagy to Achieve a Human Immunodeficiency Virus Type 1 Cure

Cells ◽

10.3390/cells10071798 ◽

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.

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

Virus Research ◽

10.1016/j.virusres.2018.11.012 ◽

2019 ◽

Vol 260 ◽

pp. 86-93 ◽

Cited By ~ 5

Author(s):

Mika Okamoto ◽

Akemi Hidaka ◽

Masaaki Toyama ◽

Masanori Baba

Keyword(s):

Latently Infected ◽

Galectin 3 ◽

Infected Cells ◽

Hiv 1

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The bromodomain and extraterminal domain inhibitor bromosporine synergistically reactivates latent HIV-1 in latently infected cells

Oncotarget ◽

10.18632/oncotarget.21585 ◽

2017 ◽

Vol 8 (55) ◽

pp. 94104-94116 ◽

Cited By ~ 5

Author(s):

Hanyu Pan ◽

Panpan Lu ◽

Yinzhong Shen ◽

Yanan Wang ◽

Zhengtao Jiang ◽

...

Keyword(s):

Latently Infected ◽

Infected Cells ◽

Latent Hiv ◽

Hiv 1

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

eLife ◽

10.7554/elife.03821 ◽

2014 ◽

Vol 3 ◽

Cited By ~ 183

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

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

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00470-21 ◽

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.

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

The Journal of Infectious Diseases ◽

10.1093/infdis/jiaa736 ◽

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

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eCD4-Ig Variants That More Potently Neutralize HIV-1

Journal of Virology ◽

10.1128/jvi.02011-17 ◽

2018 ◽

Vol 92 (12) ◽

Cited By ~ 13

Author(s):

Ina Fetzer ◽

Matthew R. Gardner ◽

Meredith E. Davis-Gardner ◽

Neha R. Prasad ◽

Barnett Alfant ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Entry Inhibitor ◽

Immune Effector ◽

Effector Cells ◽

Antibody Recognition ◽

Immunodeficiency Virus ◽

Latently Infected ◽

Infected Cells ◽

Prophylaxis Therapy ◽

Hiv 1

ABSTRACTThe human immunodeficiency virus type 1 (HIV-1) entry inhibitor eCD4-Ig is a fusion of CD4-Ig and a coreceptor-mimetic peptide. eCD4-Ig is markedly more potent than CD4-Ig, with neutralization efficiencies approaching those of HIV-1 broadly neutralizing antibodies (bNAbs). However, unlike bNAbs, eCD4-Ig neutralized all HIV-1, HIV-2, and simian immunodeficiency virus (SIV) isolates that it has been tested against, suggesting that it may be useful in clinical settings, where antibody escape is a concern. Here, we characterize three new eCD4-Ig variants, each with a different architecture and each utilizing D1.22, a stabilized form of CD4 domain 1. These variants were 10- to 20-fold more potent than our original eCD4-Ig variant, with a construct bearing four D1.22 domains (eD1.22-HL-Ig) exhibiting the greatest potency. However, this variant mediated less efficient antibody-dependent cell-mediated cytotoxicity (ADCC) activity than eCD4-Ig itself or several other eCD4-Ig variants, including the smallest variant (eD1.22-Ig). A variant with the same architecture as the original eCD4-Ig (eD1.22-D2-Ig) showed modestly higher thermal stability and best prevented the promotion of infection of CCR5-positive, CD4-negative cells. All three variants, and eCD4-Ig itself, mediated more efficient shedding of the HIV-1 envelope glycoprotein gp120 than did CD4-Ig. Finally, we show that only three D1.22 mutations contributed to the potency of eD1.22-D2-Ig and that introduction of these changes into eCD4-Ig resulted in a variant 9-fold more potent than eCD4-Ig and 2-fold more potent than eD1.22-D2-Ig. These studies will assist in developing eCD4-Ig variants with properties optimized for prophylaxis, therapy, and cure applications.IMPORTANCEHIV-1 bNAbs have properties different from those of antiretroviral compounds. Specifically, antibodies can enlist immune effector cells to eliminate infected cells, whereas antiretroviral compounds simply interfere with various steps in the viral life cycle. Unfortunately, HIV-1 is adept at evading antibody recognition, limiting the utility of antibodies as a treatment for HIV-1 infection or as part of an effort to eradicate latently infected cells. eCD4-Ig is an antibody-like entry inhibitor that closely mimics HIV-1's obligate receptors. eCD4-Ig appears to be qualitatively different from antibodies, since it neutralizes all HIV-1, HIV-2, and SIV isolates. Here, we characterize three new structurally distinct eCD4-Ig variants and show that each excels in a key property useful to prevent, treat, or cure an HIV-1 infection. For example, one variant neutralized HIV-1 most efficiently, while others best enlisted natural killer cells to eliminate infected cells. These observations will help generate eCD4-Ig variants optimized for different clinical applications.

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