New Approaches to Dendritic Cell-Based Therapeutic Vaccines Against HIV-1 Infection

Due to the success of combined antiretroviral therapy (cART) in recent years, the pathological outcome of Human Immunodeficiency Virus type 1 (HIV-1) infection has improved substantially, achieving undetectable viral loads in most cases. Nevertheless, the presence of a viral reservoir formed by latently infected cells results in patients having to maintain treatment for life. In the absence of effective eradication strategies against HIV-1, research efforts are focused on obtaining a cure. One of these approaches is the creation of therapeutic vaccines. In this sense, the most promising one up to now is based on the establishing of the immunological synapse between dendritic cells (DCs) and T lymphocytes (TL). DCs are one of the first cells of the immune system to encounter HIV-1 by acting as antigen presenting cells, bringing about the interaction between innate and adaptive immune responses mediated by TL. Furthermore, TL are the end effector, and their response capacity is essential in the adaptive elimination of cells infected by pathogens. In this review, we summarize the knowledge of the interaction between DCs with TL, as well as the characterization of the specific T-cell response against HIV-1 infection. The use of nanotechnology in the design and improvement of vaccines based on DCs has been researched and presented here with a special emphasis.

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

mBio ◽

10.1128/mbio.00560-21 ◽

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.

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Low-Level Ionizing Radiation Induces Selective Killing of HIV-1-Infected Cells with Reversal of Cytokine Induction Using mTOR Inhibitors

Viruses ◽

10.3390/v12080885 ◽

2020 ◽

Vol 12 (8) ◽

pp. 885

Author(s):

Daniel O. Pinto ◽

Catherine DeMarino ◽

Thy T. Vo ◽

Maria Cowen ◽

Yuriy Kim ◽

...

Keyword(s):

Ionizing Radiation ◽

Mtor Inhibitors ◽

Viral Reservoirs ◽

Viral Loads ◽

Viral Spread ◽

Novel Approach ◽

Latently Infected ◽

Shock And Kill ◽

Infected Cells ◽

Hiv 1

HIV-1 infects 39.5 million people worldwide, and cART is effective in preventing viral spread by reducing HIV-1 plasma viral loads to undetectable levels. However, viral reservoirs persist by mechanisms, including the inhibition of autophagy by HIV-1 proteins (i.e., Nef and Tat). HIV-1 reservoirs can be targeted by the “shock and kill” strategy, which utilizes latency-reversing agents (LRAs) to activate latent proviruses and immunotarget the virus-producing cells. Yet, limitations include reduced LRA permeability across anatomical barriers and immune hyper-activation. Ionizing radiation (IR) induces effective viral activation across anatomical barriers. Like other LRAs, IR may cause inflammation and modulate the secretion of extracellular vesicles (EVs). We and others have shown that cells may secrete cytokines and viral proteins in EVs and, therefore, LRAs may contribute to inflammatory EVs. In the present study, we mitigated the effects of IR-induced inflammatory EVs (i.e., TNF-α), through the use of mTOR inhibitors (mTORi; Rapamycin and INK128). Further, mTORi were found to enhance the selective killing of HIV-1-infected myeloid and T-cell reservoirs at the exclusion of uninfected cells, potentially via inhibition of viral transcription/translation and induction of autophagy. Collectively, the proposed regimen using cART, IR, and mTORi presents a novel approach allowing for the targeting of viral reservoirs, prevention of immune hyper-activation, and selectively killing latently infected HIV-1 cells.

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Blockage of CD59 Function Restores Activities of Neutralizing and Nonneutralizing Antibodies in Triggering Antibody-Dependent Complement-Mediated Lysis of HIV-1 Virions and Provirus-Activated Latently Infected Cells

Journal of Virology ◽

10.1128/jvi.01614-15 ◽

2015 ◽

Vol 89 (18) ◽

pp. 9393-9406 ◽

Cited By ~ 8

Author(s):

Kai Yang ◽

Jie Lan ◽

Nicole Shepherd ◽

Ningjie Hu ◽

Yanyan Xing ◽

...

Keyword(s):

Complement Activation ◽

Biological Function ◽

Membrane Attack Complex ◽

Enzyme Linked Immunosorbent Assay ◽

Therapeutic Vaccines ◽

Novel Approach ◽

Regulators Of Complement Activation ◽

Latently Infected ◽

Infected Cells ◽

Hiv 1

ABSTRACTBoth HIV-1 virions and infected cells use their surface regulators of complement activation (RCA) to resist antibody-dependent complement-mediated lysis (ADCML). Blockage of the biological function of RCA members, particularly CD59 (a key RCA member that controls formation of the membrane attack complex at the terminal stage of the complement activation cascades via all three activation pathways), has rendered both HIV-1 virions and infected cells sensitive to ADCML mediated by anti-Env antibodies (Abs) or sera/plasma from patients at different stages of viral infection. In the current study, we used the well-characterized anti-HIV-1 neutralizing Abs (nAbs), including 2G12, 2F5, and 4E10, and non-nAbs, including 2.2C, A32, N5-i5, and N12-i15, to investigate whether the enhancement of ADCML by blockage of CD59 function is mediated by nAbs, non-nAbs, or both. We found that all nAbs and two non-nAbs (N5-i5 and A32) strongly reacted to three HIV-1 laboratory strains (R5, X4, and R5/X4), six primary isolates, and provirus-activated ACH-2 cells examined. In contrast, two non-nAbs, 2.2C and N12-i15, reacted weakly and did not react to these targets, respectively. After blockage of CD59 function, the reactive Abs, regardless of their neutralizing activities, significantly enhanced specific ADCML of HIV-1 virions (both laboratory strains and primary isolates) and provirus-activated latently infected cells. The ADMCL efficacy positively correlated with the enzyme-linked immunosorbent assay-reactive intensity of those Abs with their targets. Thus, blockage of RCA function represents a novel approach to restore activities of both nAbs and non-nAbs in triggering ADCML of HIV-1 virions and provirus-activated latently infected cells.IMPORTANCEThere is a renewed interest in the potential role of non-nAbs in the control of HIV-1 infection. Our data, for the first time, demonstrated that blockage of the biological function of RCA members rendered both HIV-1 virions and infected cells sensitive to ADCML mediated by not only nAbs but also non-nAbs. Our results are significant in developing novel immune-based approaches to restore the functions of nAbs and non-nAbs in the circulation of HIV-1-infected individuals to specifically target and clear HIV-1 virions and infected cells. Our data also provide new insights into the mechanisms by which HIV-1 virions and infected cells escape Ab-mediated immunity and could aid in the design and/or development of therapeutic HIV-1 vaccines. In addition, a combination of antiretroviral therapy with RCA blockage, provirus activators, and therapeutic vaccines may represent a novel approach to eliminate HIV-1 reservoirs, i.e., the infected cells harboring replication-competent proviruses and residual viremia.

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An amphipathic peptide targeting the gp41 cytoplasmic tail kills HIV-1 virions and infected cells

Science Translational Medicine ◽

10.1126/scitranslmed.aaz2254 ◽

2020 ◽

Vol 12 (546) ◽

pp. eaaz2254 ◽

Cited By ~ 1

Author(s):

Qian Wang ◽

Shan Su ◽

Jing Xue ◽

Fei Yu ◽

Jing Pu ◽

...

Keyword(s):

Limit Of Detection ◽

Cytoplasmic Tail ◽

Hiv Treatment ◽

Drug Candidate ◽

Amphipathic Peptide ◽

Viral Loads ◽

Latently Infected ◽

Infected Cells ◽

Peptide Targeting ◽

Hiv 1

HIV-associated morbidity and mortality have markedly declined because of combinational antiretroviral therapy, but HIV readily mutates to develop drug resistance. Developing antivirals against previously undefined targets is essential to treat existing drug-resistant HIV strains. Some peptides derived from HIV-1 envelope glycoprotein (Env, gp120-gp41) have been shown to be effective in inhibiting HIV-1 infection. Therefore, we screened a peptide library from HIV-1 Env and identified a peptide from the cytoplasmic region, designated F9170, able to effectively inactivate HIV-1 virions and induce necrosis of HIV-1–infected cells, and reactivated latently infected cells. F9170 specifically targeted the conserved cytoplasmic tail of HIV-1 Env and effectively disrupted the integrity of the viral membrane. Short-term monoadministration of F9170 controlled viral loads to below the limit of detection in chronically SHIV-infected macaques. F9170 can enter the brain and lymph nodes, anatomic reservoirs for HIV latency. Therefore, F9170 shows promise as a drug candidate for HIV treatment.

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A humanized mouse-based HIV-1 viral outgrowth assay with higher sensitivity than in vitro qVOA in detecting latently infected cells from individuals on ART with undetectable viral loads

Virology ◽

10.1016/j.virol.2017.04.011 ◽

2017 ◽

Vol 507 ◽

pp. 135-139 ◽

Cited By ~ 29

Author(s):

Paige Charlins ◽

Kimberly Schmitt ◽

Leila Remling-Mulder ◽

Louise E. Hogan ◽

Emily Hanhauser ◽

...

Keyword(s):

Humanized Mouse ◽

Viral Loads ◽

Latently Infected ◽

Infected Cells ◽

Hiv 1 ◽

Viral Outgrowth Assay ◽

Higher Sensitivity

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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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Latently KSHV-Infected Cells Promote Further Establishment of Latency upon Superinfection with KSHV

International Journal of Molecular Sciences ◽

10.3390/ijms222111994 ◽

2021 ◽

Vol 22 (21) ◽

pp. 11994

Author(s):

Chen Gam ze Letova ◽

Inna Kalt ◽

Meir Shamay ◽

Ronit Sarid

Keyword(s):

Latent Infection ◽

Fluorescent Proteins ◽

Cell Types ◽

Lytic Cycle ◽

Viral Reservoir ◽

Virus Spread ◽

Viral Genomes ◽

Latently Infected ◽

Infected Cells

Kaposi’s sarcoma-associated herpesvirus (KSHV) is a cancer-related virus which engages in two forms of infection: latent and lytic. Latent infection allows the virus to establish long-term persistent infection, whereas the lytic cycle is needed for the maintenance of the viral reservoir and for virus spread. By using recombinant KSHV viruses encoding mNeonGreen and mCherry fluorescent proteins, we show that various cell types that are latently-infected with KSHV can be superinfected, and that the new incoming viruses establish latent infection. Moreover, we show that latency establishment is enhanced in superinfected cells compared to primary infected ones. Further analysis revealed that cells that ectopically express the major latency protein of KSHV, LANA-1, prior to and during infection exhibit enhanced establishment of latency, but not cells expressing LANA-1 fragments. This observation supports the notion that the expression level of LANA-1 following infection determines the efficiency of latency establishment and avoids loss of viral genomes. These findings imply that a host can be infected with more than a single viral genome and that superinfection may support the maintenance of long-term latency.

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