Search

Background Persistence of HIV-1 in reservoirs necessitates life-long antiretroviral therapy (ART). There are conflicting data using genetic analysis on whether persistence includes an actively replicating reservoir with strong evidence arguing against replication. Methods We investigated the possibility of ongoing viral evolution during suppressive therapy by comparing near full-length viral genomic sequences using phylogenetic analysis of viral RNA in plasma before therapy initiation early after infection and from virus induced to grow from the latent reservoir after a period of suppressive ART. We also focused our analysis on evidence of selective pressure by drugs in the treatment regimen and at sites of selective pressure by the adaptive immune response. Results Viral genomes induced to grow from the latent reservoir from 10 participants with up to 9 years on suppressive ART were highly similar to the nearly homogeneous sequences in plasma taken early after infection at ART initiation. This finding was consistent across the entire genome and when the analysis focused on sites targeted by the drug regimen and by host selective pressure of antibody and cytotoxic T cells. The lack of viral evolution away from pretherapy sequences in spite of demonstrated selective pressure is most consistent with a lack of viral replication during reservoir persistence. Conclusions These results do not support ongoing viral replication as a mechanism of HIV-1 persistence during suppressive ART. [ABSTRACT FROM AUTHOR]

Acquired immunodeficiency syndrome (AIDS) is an enormous global health threat stemming from human immunodeficiency virus (HIV-1) infection. Up to now, the tremendous advances in combination antiretroviral therapy (cART) have shifted HIV-1 infection from a fatal illness into a manageable chronic disorder. However, the presence of latent reservoirs, the multifaceted nature of HIV-1, drug resistance, severe off-target effects, poor adherence, and high cost restrict the efficacy of current cART targeting the distinct stages of the virus life cycle. Therefore, there is an unmet need for the discovery of new therapeutics that not only bypass the limitations of the current therapy but also protect the body's health at the same time. The main goal for complete HIV-1 eradication is purging latently infected cells from patients' bodies. A potential strategy called "lock-in and apoptosis" targets the budding phase of the life cycle of the virus and leads to susceptibility to apoptosis of HIV-1 infected cells for the elimination of HIV-1 reservoirs and, ultimately, for complete eradication. The current work intends to present the main advantages and disadvantages of United States Food and Drug Administration (FDA)-approved anti-HIV-1 drugs as well as plausible strategies for the design and development of more anti-HIV-1 compounds with better potency, favorable pharmacokinetic profiles, and improved safety issues. [ABSTRACT FROM AUTHOR]

Acquired immunodeficiency syndrome (AIDS) is an enormous global health threat stemming from human immunodeficiency virus (HIV-1) infection. Up to now, the tremendous advances in combination antiretroviral therapy (cART) have shifted HIV-1 infection from a fatal illness into a manageable chronic disorder. However, the presence of latent reservoirs, the multifaceted nature of HIV-1, drug resistance, severe off-target effects, poor adherence, and high cost restrict the efficacy of current cART targeting the distinct stages of the virus life cycle. Therefore, there is an unmet need for the discovery of new therapeutics that not only bypass the limitations of the current therapy but also protect the body’s health at the same time. The main goal for complete HIV-1 eradication is purging latently infected cells from patients’ bodies. A potential strategy called “lock-in and apoptosis” targets the budding phase of the life cycle of the virus and leads to susceptibility to apoptosis of HIV-1 infected cells for the elimination of HIV-1 reservoirs and, ultimately, for complete eradication. The current work intends to present the main advantages and disadvantages of United States Food and Drug Administration (FDA)-approved anti-HIV-1 drugs as well as plausible strategies for the design and development of more anti-HIV-1 compounds with better potency, favorable pharmacokinetic profiles, and improved safety issues.

Abstract Reducing the pool of HIV-1 reservoirs in patients is a must to achieve functional cure. The most prominent HIV-1 cell reservoirs are resting CD4 + T cells and brain derived microglial cells. Infected microglial cells are believed to be the source of peripheral tissues reseedings and the emergence of drug resistance. Clearing infected cells from the brain is therefore crucial. However, many characteristics of microglial cells and the central nervous system make extremely difficult their eradication from brain reservoirs. Current methods, such as the “shock and kill”, the “block and lock” and gene editing strategies cannot override these difficulties. Therefore, new strategies have to be designed when considering the elimination of brain reservoirs. We set up an original gene suicide strategy using latently infected microglial cells as model cells. In this paper we provide proof of concept of this strategy.

Copyright of Klinická Mikrobiologie a Infekční Lékařství is the property of TRIOS, spol. sr.o. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Reducing the pool of HIV-1 reservoirs in patients is a must to achieve functional cure. The most prominent HIV-1 cell reservoirs are resting CD4 + T cells and brain derived microglial cells. Infected microglial cells are believed to be the source of peripheral tissues reseedings and the emergence of drug resistance. Clearing infected cells from the brain is therefore crucial. However, many characteristics of microglial cells and the central nervous system make extremely difficult their eradication from brain reservoirs. Current methods, such as the "shock and kill", the "block and lock" and gene editing strategies cannot override these difficulties. Therefore, new strategies have to be designed when considering the elimination of brain reservoirs. We set up an original gene suicide strategy using latently infected microglial cells as model cells. In this paper we provide proof of concept of this strategy. [ABSTRACT FROM AUTHOR]

Abstract This paper studies the global stability of two discrete-time HIV infection models. The models integrate (i) latently infected cells, (ii) long-lived chronically infected cells and (iii) short-lived infected cells. The second model generalizes the first one by assuming that the incidence rate of infection as well as the production and removal rates of the HIV particles and cells are modeled by general nonlinear functions. We discretize the continuous-time models by using a nonstandard finite difference scheme. The positivity and boundedness of solutions are established. The basic reproduction number is derived. By using the Lyapunov method, we prove the global stability of the models. Numerical simulations are presented to illustrate our theoretical results.

[Display omitted] Nowadays, combination antiretroviral therapy (cART) is the standard treatment for all people with human immunodeficiency virus (HIV-1). Although cART is effective in treating productive infection, it does not eliminate latent reservoirs of the virus. This leads to lifelong treatment associated with the occurrence of side effects and the development of drug-resistant HIV-1. Suppression of viral latency is therefore the major hurdle to HIV-1 eradication. Multiple mechanisms exist to regulate viral gene expression and drive the transcriptional and post-transcriptional establishment of latency. Epigenetic processes are amongst the most studied mechanisms influencing both productive and latent infection states. The central nervous system (CNS) represents a key anatomical sanctuary for HIV and is the focal point of considerable research efforts. However, limited and difficult access to CNS compartments makes understanding the HIV-1 infection state in latent brain cells such as microglial cells, astrocytes, and perivascular macrophages challenging. This review examines the latest advances on epigenetic transformations involved in CNS viral latency and targeting of brain reservoirs. Evidence from clinical studies as well as in vivo and in vitro models of HIV-1 persistence in the CNS will be discussed, with a special focus on recent 3D in vitro models such as human brain organoids. Finally, the review will address therapeutic considerations for targeting latent CNS reservoirs. [ABSTRACT FROM AUTHOR]

In adherent individuals, antiretroviral therapy (ART) suppresses HIV replication, restores immune function, and prevents the development of AIDS. However, ART is not curative and has to be followed lifelong. Persistence of viral reservoirs forms the major obstacle to an HIV cure. HIV latent reservoirs persist primarily by cell longevity and proliferation, but replenishment by residual virus replication despite ART has been proposed as another potential mechanism of HIV persistence. It is a matter of debate whether different ART regimens are equally potent in suppressing HIV replication. Here, we summarized the current knowledge on the role of ART regimens in HIV persistence, focusing on differences in residual plasma viremia and other virological markers of the HIV reservoir between infected individuals treated with combination ART composed of different antiretroviral drug classes.

In this paper, we construct an Human immunodeficiency virus (HIV) dynamics model with impairment of B-cell functions and the general incidence rate. We incorporate three types of infected cells, (i) latently-infected cells, which contain the virus, but do not generate HIV particles, (ii) short-lived productively-infected cells, which live for a short time and generate large numbers of HIV particles, and (iii) long-lived productively-infected cells, which live for a long time and generate small numbers of HIV particles. The model considers five distributed time delays to characterize the time between the HIV contact of an uninfected CD4 + T-cell and the creation of mature HIV. The nonnegativity and boundedness of the solutions are proven. The model admits two equilibria, infection-free equilibrium E P 0 and endemic equilibrium E P 1 . We derive the basic reproduction number R 0 , which determines the existence and stability of the two equilibria. The global stability of each equilibrium is proven by utilizing the Lyapunov function and LaSalle’s invariance principle. We prove that if R 0 < 1 , then E P 0 is globally asymptotically stable, and if R 0 > 1 , then E P 1 is globally asymptotically stable. These theoretical results are illustrated by numerical simulations. The effect of impairment of B-cell functions, time delays, and antiviral treatment on the HIV dynamics are studied. We show that if the functions of B-cells are impaired, then the concentration of HIV is increased in the plasma. Moreover, we observe that the time delay has a similar effect to drug efficacy. This gives some impression for developing a new class of treatments to increase the delay period and then suppress the HIV replication.

Globally, 240,000 infants are newly infected with HIV-1 each year and 3.2 million children are living with the infection. Combination antiretroviral therapy (cART) has reduced HIV-1-related disease and mortality in children but is not curative owing to the early generation of a latent reservoir of long-lived memory CD4+ T cells bearing replication-competent HIV-1 provirus integrated into cellular DNA. This review focuses on recent advances in our understanding of the establishment of HIV-1 persistence in children and how early initiation of cART in the setting of the developing infant immune system limits the formation of the long-lived latent CD4+ cell reservoir that remains a barrier to remission or cure. [ABSTRACT FROM AUTHOR]

[Display omitted] Suicide Gene Therapy (SGT) aims to introduce a gene encoding either a toxin or an enzyme making the targeted cell more sensitive to chemotherapy. SGT represents an alternative approach to combat pathologies where conventional treatments fail such as pancreatic cancer or the high-grade glioblastoma which are still desperately lethal. We review the possibility to use SGT to treat these cancers which have shown promising results in vitro and in preclinical trials. However, SGT has so far failed in phase III clinical trials thus further improvements are awaited. We can now take advantages of the many advances made in SGT for treating cancer to combat other pathologies such as HIV-1 infection. In the review we also discuss the feasibility to add SGT to the therapeutic arsenal used to cure HIV-1-infected patients. Indeed, preliminary results suggest that both productive and latently infected cells are targeted by the SGT. In the last section, we address the limitations of this approach and how we might improve it. [ABSTRACT FROM AUTHOR]

In adherent individuals, antiretroviral therapy (ART) suppresses HIV replication, restores immune function, and prevents the development of AIDS. However, ART is not curative and has to be followed lifelong. Persistence of viral reservoirs forms the major obstacle to an HIV cure. HIV latent reservoirs persist primarily by cell longevity and proliferation, but replenishment by residual virus replication despite ART has been proposed as another potential mechanism of HIV persistence. It is a matter of debate whether different ART regimens are equally potent in suppressing HIV replication. Here, we summarized the current knowledge on the role of ART regimens in HIV persistence, focusing on differences in residual plasma viremia and other virological markers of the HIV reservoir between infected individuals treated with combination ART composed of different antiretroviral drug classes. [ABSTRACT FROM AUTHOR]

The human immunodeficiency virus (HIV), responsible for acquired immunodeficiency syndrome or AIDS, is a major public health problem. In Belgium, 2 to 3 new cases are diagnosed every day. Since the advent of combined antiretroviral treatments in 1996, the life expectancy and quality of life of infected patients have greatly improved. However, to date there is no cure for HIV. Individuals infected with HIV must remain on antiretroviral treatment for life. One of the reasons for the difficulty in finding a cure for HIV is that the virus can remain in a latent form, i.e. dormant, in some of the cells it infects. These latent reservoirs are not recognized by the immune system and can reactivate and thus restart the infection if the patient stops the treatment. These latent reservoirs are therefore a major obstacle to cure HIV and a great deal of research is being conducted by the scientific community to find an eradication strategy. In this article, we will present the different characteristics of these latent reservoirs and the different strategies put in place to identify and eliminate them.

This paper studies the global stability of two discrete-time HIV infection models. The models integrate (i) latently infected cells, (ii) long-lived chronically infected cells and (iii) short-lived infected cells. The second model generalizes the first one by assuming that the incidence rate of infection as well as the production and removal rates of the HIV particles and cells are modeled by general nonlinear functions. We discretize the continuous-time models by using a nonstandard finite difference scheme. The positivity and boundedness of solutions are established. The basic reproduction number is derived. By using the Lyapunov method, we prove the global stability of the models. Numerical simulations are presented to illustrate our theoretical results. [ABSTRACT FROM AUTHOR]

In this paper, we construct an Human immunodeficiency virus (HIV) dynamics model with impairment of B-cell functions and the general incidence rate. We incorporate three types of infected cells, (i) latently-infected cells, which contain the virus, but do not generate HIV particles, (ii) short-lived productively-infected cells, which live for a short time and generate large numbers of HIV particles, and (iii) long-lived productively-infected cells, which live for a long time and generate small numbers of HIV particles. The model considers five distributed time delays to characterize the time between the HIV contact of an uninfected CD4 + T-cell and the creation of mature HIV. The nonnegativity and boundedness of the solutions are proven. The model admits two equilibria, infection-free equilibrium E P 0 and endemic equilibrium E P 1 . We derive the basic reproduction number R 0 , which determines the existence and stability of the two equilibria. The global stability of each equilibrium is proven by utilizing the Lyapunov function and LaSalle's invariance principle. We prove that if R 0 < 1 , then E P 0 is globally asymptotically stable, and if R 0 > 1 , then E P 1 is globally asymptotically stable. These theoretical results are illustrated by numerical simulations. The effect of impairment of B-cell functions, time delays, and antiviral treatment on the HIV dynamics are studied. We show that if the functions of B-cells are impaired, then the concentration of HIV is increased in the plasma. Moreover, we observe that the time delay has a similar effect to drug efficacy. This gives some impression for developing a new class of treatments to increase the delay period and then suppress the HIV replication. [ABSTRACT FROM AUTHOR]

More than 30 years after its discovery, human immunodeficiency virus (HIV) continues to be a major global public health issue. Antiretroviral therapy increases survival and quality of life of HIV-infected patients but is not curative. Indeed, interruption of therapy invariably leads to the re-emergence of detectable viral replication, since HIV persists in extremely long-lived viral latent reservoirs. Those viral latent reservoirs constitute the major source of viral recovery following antiretroviral treatment interruption and are considered as the most important hurdle to HIV eradication. Multiple strategies aimed at targeting the HIV latent reservoirs are intensively being explored. We discuss here the most recent innovative works that will hopefully contribute to find a cure for HIV.