Therapeutic strategies to fight HIV-1 latency: progress and challenges

AbstractThe life-long persistence of human immunodeficiency virus type-1 (HIV-1) in latent reservoirs is a major hurdle in the eradication of HIV-1, even though highly active antiretroviral therapy (HAART) can be effective in reducing the plasma HIV-1 RNA to less than 50 copies per mL, which is below the detection limit of most clinical assays. In the latent reservoirs the provirus is integrated in the host genome but does not actively replicate and thus is not inhibited by HAART or recognized by the host immune system. There has been increasing scientific interest and investment into research towards HIV cure due to the challenges and limitation of life long treatment. The various strategies that have been developed aim to activate gene expression in HIV latent cells which might lead to the elimination of the virus by HAART or the immune system. In this review we discuss latency and therapeutic approaches that are being evaluated to eradicate HIV latently infected cells to overcome the burden of life long HAART. In addition, we explore the possibility of delivering HAART in latently infected cells using femtosecond laser pulses, a topic closely studied in our research.

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Fighting HIV-1 Persistence: At the Crossroads of “Shoc-K and B-Lock”

Pathogens ◽

10.3390/pathogens10111517 ◽

2021 ◽

Vol 10 (11) ◽

pp. 1517

Author(s):

Chiara Acchioni ◽

Enrico Palermo ◽

Silvia Sandini ◽

Marta Acchioni ◽

John Hiscott ◽

...

Keyword(s):

Immune System ◽

Highly Active Antiretroviral Therapy ◽

Infected Individual ◽

Highly Active ◽

Immune Mediated ◽

Latently Infected ◽

Infected Cells ◽

Hiv 1

Despite the success of highly active antiretroviral therapy (HAART), integrated HIV-1 proviral DNA cannot be eradicated from an infected individual. HAART is not able to eliminate latently infected cells that remain invisible to the immune system. Viral sanctuaries in specific tissues and immune-privileged sites may cause residual viral replication that contributes to HIV-1 persistence. The “Shock or Kick, and Kill” approach uses latency reversing agents (LRAs) in the presence of HAART, followed by cell-killing due to viral cytopathic effects and immune-mediated clearance. Different LRAs may be required for the in vivo reactivation of HIV-1 in different CD4+ T cell reservoirs, leading to the activation of cellular transcription factors acting on the integrated proviral HIV-1 LTR. An important requirement for LRA drugs is the reactivation of viral transcription and replication without causing a generalized immune activation. Toll-like receptors, RIG-I like receptors, and STING agonists have emerged recently as a new class of LRAs that augment selective apoptosis in reactivated T lymphocytes. The challenge is to extend in vitro observations to HIV-1 positive patients. Further studies are also needed to overcome the mechanisms that protect latently infected cells from reactivation and/or elimination by the immune system. The Block and Lock alternative strategy aims at using latency promoting/inducing agents (LPAs/LIAs) to block the ability of latent proviruses to reactivate transcription in order to achieve a long term lock down of potential residual virus replication. The Shock and Kill and the Block and Lock approaches may not be only alternative to each other, but, if combined together (one after the other), or given all at once [namely “Shoc-K(kill) and B(block)-Lock”], they may represent a better approach to a functional cure.

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Resting CD4+ T Lymphocytes but Not Thymocytes Provide a Latent Viral Reservoir in a Simian Immunodeficiency Virus-Macaca nemestrina Model of Human Immunodeficiency Virus Type 1-Infected Patients on Highly Active Antiretroviral Therapy

Journal of Virology ◽

10.1128/jvi.77.8.4938-4949.2003 ◽

2003 ◽

Vol 77 (8) ◽

pp. 4938-4949 ◽

Cited By ~ 81

Author(s):

Anding Shen ◽

M. Christine Zink ◽

Joseph L. Mankowski ◽

Karen Chadwick ◽

Joseph B. Margolick ◽

...

Keyword(s):

T Lymphocytes ◽

Highly Active Antiretroviral Therapy ◽

Limit Of Detection ◽

Macaca Nemestrina ◽

Viral Reservoir ◽

Highly Active ◽

Latent Viral Reservoir ◽

Immunodeficiency Virus ◽

Latently Infected ◽

Infected Cells

ABSTRACT Despite suppression of viremia in patients on highly active antiretroviral therapy (HAART), human immunodeficiency virus type 1 persists in a latent reservoir in the resting memory CD4+ T lymphocytes and possibly in other reservoirs. To better understand the mechanisms of viral persistence, we established a simian immunodeficiency virus (SIV)-macaque model to mimic the clinical situation of patients on suppressive HAART and developed assays to detect latently infected cells in the SIV-macaque system. In this model, treatment of SIV-infected pig-tailed macaques (Macaca nemestrina) with the combination of 9-R-(2-phosphonomethoxypropyl)adenine (PMPA; tenofovir) and beta-2′,3′-dideoxy-3′-thia-5-fluorocytidine (FTC) suppressed the levels of plasma virus to below the limit of detection (100 copies of viral RNA per ml). In treated animals, levels of viremia remained close to or below the limit of detection for up to 6 months except for an isolated “blip” of detectable viremia in each animal. Latent virus was measured in blood, spleen, lymph nodes, and thymus by several different methods. Replication-competent virus was recovered after activation of a 99.5% pure population of resting CD4+ T lymphocytes from a lymph node of a treated animal. Integrated SIV DNA was detected in resting CD4+ T cells from spleen, peripheral blood, and various lymph nodes including those draining the gut, the head, and the limbs. In contrast to the wide distribution of latently infected cells in peripheral lymphoid tissues, neither replication-competent virus nor integrated SIV DNA was detected in thymocytes, suggesting that thymocytes are not a major reservoir for virus in pig-tailed macaques. The results provide the first evidence for a latent viral reservoir for SIV in macaques and the most extensive survey of the distribution of latently infected cells in the host.

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Editing out HIV: application of gene editing technology to achieve functional cure

Retrovirology ◽

10.1186/s12977-021-00581-1 ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

Jingna Xun ◽

Xinyu Zhang ◽

Shuyan Guo ◽

Hongzhou Lu ◽

Jun Chen

Keyword(s):

Highly Active Antiretroviral Therapy ◽

Gene Editing ◽

Functional Cure ◽

Hiv Replication ◽

Highly Active ◽

Immunodeficiency Virus ◽

Latently Infected ◽

Infected Cells ◽

Living With Hiv

AbstractHighly active antiretroviral therapy (HAART) successfully suppresses human immunodeficiency virus (HIV) replication and improves the quality of life of patients living with HIV. However, current HAART does not eradicate HIV infection because an HIV reservoir is established in latently infected cells and is not recognized by the immune system. The successful curative treatment of the Berlin and London patients following bone marrow transplantation inspired researchers to identify an approach for the functional cure of HIV. As a promising technology, gene editing-based strategies have attracted considerable attention and sparked much debate. Herein, we discuss the development of different gene editing strategies in the functional cure of HIV and highlight the potential for clinical applications prospects. Graphical Abstract

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Effect of Latent Human Immunodeficiency Virus Infection on Cell Surface Phenotype

Journal of Virology ◽

10.1128/jvi.76.4.1673-1681.2002 ◽

2002 ◽

Vol 76 (4) ◽

pp. 1673-1681 ◽

Cited By ~ 21

Author(s):

David G. Brooks ◽

Jerome A. Zack

Keyword(s):

Human Immunodeficiency Virus ◽

Highly Active Antiretroviral Therapy ◽

Virus Production ◽

Cellular Interactions ◽

Cellular Activation ◽

Highly Active ◽

Immunodeficiency Virus ◽

Latently Infected ◽

Infected Cells

ABSTRACT Highly active antiretroviral therapy has succeeded in many cases in suppressing virus production in patients infected with human immunodeficiency virus (HIV); however, once treatment is discontinued, virus replication is rekindled. One reservoir capable of harboring HIV in a latent state and igniting renewed infection once therapy is terminated is a resting T cell. Due to the sparsity of T cells latently infected with HIV in vivo, it has been difficult to study viral and cellular interactions during latency. The SCID-hu (Thy/Liv) mouse model of HIV latency, however, provides high percentages of latently infected cells, allowing a detailed analysis of phenotype. Herein we show that latently infected cells appear phenotypically normal. Following cellular stimulation, the virus completes its life cycle and induces phenotypic changes, such as CD4 and major histocompatibility complex class I down-regulation, in the infected cell. In addition, HIV expression following activation did not correlate with expression of the cellular activation marker CD25. The apparently normal phenotype and lack of HIV expression in latently infected cells could prevent recognition by the immune response and contribute to the long-lived nature of this reservoir.

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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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Management of HIV-1 Infection in Adults and Adolescents

Journal of Pharmacy Practice ◽

10.1106/0v98-29pd-m1aj-2dbx ◽

2000 ◽

Vol 13 (6) ◽

pp. 426-441 ◽

Cited By ~ 1

Author(s):

Kenneth R. Eugenio ◽

Caroline S. Zeind

Keyword(s):

Highly Active Antiretroviral Therapy ◽

Patient Adherence ◽

Social Barriers ◽

Highly Active ◽

Immunodeficiency Virus ◽

Improve Patient Adherence ◽

Substantial Decline ◽

Improve Patient ◽

Hiv 1 ◽

New Strategies

The management of Human Immunodeficiency Virus-1 (HIV-1) infection has undergone dramatic change since its initial identification. Advances have occurred in drug development, viral pathology understanding, laboratory monitoring and genetic analysis. With the advent of highly active antiretroviral therapy (HAART), there has been a substantial decline in HIV-1-related morbidity and mortality. Today, HIV-1 infection is treated as a chronic disease that requires strict patient adherence to HAART. Pharmacists provide pharmaceutical care to patients with HIV disease in a variety of ways, and they can improve patient adherence rates. Current therapeutic strategies have not resulted in eradication of HIV-1 infection. Present and future therapeutic challenges include viral resistance, reservoirs of virus and drug toxicities. Globally, the spread of HIV-1 infection continues at an alarming rate, and economic and social barriers may limit access and success of HAART. New strategies and novel approaches in managing HIV-1 infection continue to be developed in an effort to cure and eradicate this disease.

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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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