scholarly journals Why the HIV Reservoir Never Runs Dry: Clonal Expansion and the Characteristics of HIV-Infected Cells Challenge Strategies to Cure and Control HIV Infection

Viruses ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2512
Author(s):  
Chuen-Yen Lau ◽  
Matthew A. Adan ◽  
Frank Maldarelli
Keyword(s):  
Hiv Infection ◽  
Clonal Expansion ◽  
Marrow Transplant ◽  
Clinical Events ◽  
Immunodeficiency Virus ◽  
Latently Infected ◽  
Hiv Eradication ◽  
Infected Cells ◽  
And Control ◽  
Number Of Individuals

Antiretroviral therapy (ART) effectively reduces cycles of viral replication but does not target proviral populations in cells that persist for prolonged periods and that can undergo clonal expansion. Consequently, chronic human immunodeficiency virus (HIV) infection is sustained during ART by a reservoir of long-lived latently infected cells and their progeny. This proviral landscape undergoes change over time on ART. One of the forces driving change in the landscape is the clonal expansion of infected CD4 T cells, which presents a key obstacle to HIV eradication. Potential mechanisms of clonal expansion include general immune activation, antigenic stimulation, homeostatic proliferation, and provirus-driven clonal expansion, each of which likely contributes in varying, and largely unmeasured, amounts to maintaining the reservoir. The role of clinical events, such as infections or neoplasms, in driving these mechanisms remains uncertain, but characterizing these forces may shed light on approaches to effectively eradicate HIV. A limited number of individuals have been cured of HIV infection in the setting of bone marrow transplant; information from these and other studies may identify the means to eradicate or control the virus without ART. In this review, we describe the mechanisms of HIV-1 persistence and clonal expansion, along with the attempts to modify these factors as part of reservoir reduction and cure strategies.

scholarly journals Effects of Prostratin on T-Cell Activation and Human Immunodeficiency Virus Latency

2002 ◽  
Vol 76 (16) ◽  
pp. 8118-8123 ◽  
Author(s):  
Yael D. Korin ◽  
David G. Brooks ◽  
Stephen Brown ◽  
Andrew Korotzer ◽  
Jerome A. Zack
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cell ◽  
Hiv Infection ◽  
Cell Activation ◽  
Cellular Proliferation ◽  
Latent Virus ◽  
Immunodeficiency Virus ◽  
Latently Infected ◽  
Infected Cells ◽  
Latent Hiv

ABSTRACT Human immunodeficiency virus (HIV) replication is linked to cellular gene transcription and requires target cell activation. The latent reservoir of HIV-1 in quiescent T cells is thought to be a major obstacle to clearance of infection by highly active antiretroviral therapy (HAART). Thus, identification of agents that can induce expression of latent virus may, in the presence of HAART, allow elimination of the infected cells by the immune response. We previously used the SCID-hu (Thy/Liv) mouse model to establish that activation-inducible HIV can be generated at high frequency during thymopoiesis. Latently infected mature thymocytes can be exported into the periphery, providing an efficient primary cell model to determine cellular activation signals that induce renewed expression of latent virus. Here we characterized the effects of prostratin, a non-tumor-promoting phorbol ester, on primary human peripheral blood lymphocytes (PBLs) and assessed its ability to reactivate latent HIV infection from thymocytes and PBLs in the SCID-hu (Thy/Liv) model. Prostratin stimulation alone did not induce proliferation of quiescent PBLs; however, it could provide a secondary signal in the context of T-cell receptor stimulation or a primary activation signal in the presence of CD28 stimulation to induce T-cell proliferation. While prostratin alone was not sufficient to allow de novo HIV infection, it efficiently reactivated HIV expression from latently infected cells generated in the SCID-hu mouse. Our data indicate that prostratin alone is able to specifically reactivate latent virus in the absence of cellular proliferation, making it an attractive candidate for further study as an adjunctive therapy for the elimination of the latent HIV reservoir.

scholarly journals Efficacy of the Post-Exposure Prophylaxis and of the HIV Latent Reservoir in HIV Infection

Mathematics ◽  
2019 ◽  
Vol 7 (6) ◽  
pp. 515 ◽  
Author(s):  
Carla M. A. Pinto ◽  
Ana R. M. Carvalho ◽  
Dumitru Baleanu ◽  
Hari M. Srivastava
Keyword(s):  
Hiv Infection ◽  
Antiretroviral Drugs ◽  
Latent Reservoir ◽  
Post Exposure Prophylaxis ◽  
Post Exposure ◽  
Immunodeficiency Virus ◽  
Latently Infected ◽  
Infected Cells ◽  
Exposure Prophylaxis

We propose a fractional order model to study the efficacy of the Post-Exposure Prophylaxis (PEP) in human immunodeficiency virus (HIV) within-host dynamics, in the presence of the HIV latent reservoir. Latent reservoirs harbor infected cells that contain a transcriptionally silent but reactivatable provirus. The latter constitutes a major difficulty to the eradication of HIV in infected patients. PEP is used as a way to prevent HIV infection after a recent possible exposure to HIV. It consists of the in-take of antiretroviral drugs for, usually, 28 days. In this study, we focus on the dosage and dosage intervals of antiretroviral therapy (ART) during PEP and in the role of the latent reservoir in HIV infected patients. We thus simulate the model for immunologically important parameters concerning the drugs and the fraction of latently infected cells. The results may add important information to clinical practice of HIV infected patients.

scholarly journals Reduce and Control: A Combinatorial Strategy for Achieving Sustained HIV Remissions in the Absence of Antiretroviral Therapy

Viruses ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 188 ◽  
Author(s):  
Roland Schwarzer ◽  
Andrea Gramatica ◽  
Warner C. Greene
Keyword(s):  
Immune Response ◽  
Antiretroviral Therapy ◽  
Effective Means ◽  
Global Scale ◽  
Post Treatment ◽  
Viral Rebound ◽  
Latently Infected ◽  
Hiv Eradication ◽  
Infected Cells ◽  
And Control

Human immunodeficiency virus (HIV-1) indefinitely persists, despite effective antiretroviral therapy (ART), within a small pool of latently infected cells. These cells often display markers of immunologic memory and harbor both replication-competent and -incompetent proviruses at approximately a 1:100 ratio. Although complete HIV eradication is a highly desirable goal, this likely represents a bridge too far for our current and foreseeable technologies. A more tractable goal involves engineering a sustained viral remission in the absence of ART––a “functional cure.” In this setting, HIV remains detectable during remission, but the size of the reservoir is small and the residual virus is effectively controlled by an engineered immune response or other intervention. Biological precedence for such an approach is found in the post-treatment controllers (PTCs), a rare group of HIV-infected individuals who, following ART withdrawal, do not experience viral rebound. PTCs are characterized by a small reservoir, greatly reduced inflammation, and the presence of a poorly understood immune response that limits viral rebound. Our goal is to devise a safe and effective means for replicating durable post-treatment control on a global scale. This requires devising methods to reduce the size of the reservoir and to control replication of this residual virus. In the following sections, we will review many of the approaches and tools that likely will be important for implementing such a “reduce and control” strategy and for achieving a PTC-like sustained HIV remission in the absence of ART.

scholarly journals Refractory pharyngeal ulceration due to cytomegalovirus in a patient with HIV infection: a case report and literature review

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Morichika Osa ◽  
Akihiro Sato ◽  
Maki Sakagami ◽  
Masaki Machida ◽  
Takao Sato ◽  
...  
Keyword(s):  
Hiv Infection ◽  
Pathological Examination ◽  
Cmv Infection ◽  
Case Presentation ◽  
Immunodeficiency Virus ◽  
Before And After ◽  
Infected Cells ◽  
Immunocompromised Hosts ◽  
Inflammatory Syndrome ◽  
Nonspecific Inflammation

Abstract Background Cytomegalovirus (CMV) is an important pathogen among immunocompromised hosts. Typically, CMV in human immunodeficiency virus (HIV) infection causes diseases of the retina, digestive tract, lungs and liver, but there are few cases of CMV infection of the pharynx and larynx. Case presentation A 57-year-old man with HIV infection was admitted because of pharyngeal pain. Before and after admission, pharyngeal biopsies guided by laryngeal endoscopy were performed four times, but pathological examination showed nonspecific inflammation, and the cause of pharyngeal ulceration was unclear. Additionally, the ulceration deteriorated after initiation of retroviral therapy. Laryngomicrosurgery was conducted under general anesthesia to remove tissue, and pathological diagnosis confirmed CMV infection. Pathological features included enlargement of the cytoplasm and nucleus in infected cells, and intranuclear bodies called owl’s eye inclusions. Ganciclovir dramatically improved the symptoms and laryngoscopic findings. Conclusions This case was diagnosed as pharyngitis and pharyngeal ulceration caused by CMV infection, related to immune reconstitution inflammatory syndrome. In previous reports of CMV-induced pharyngeal or laryngeal ulceration in HIV infection, we found six cases similar to our present case. All cases were diagnosed by biopsy. The present case indicates the importance of biopsy for definitive diagnosis. CMV infection should be considered as a differential diagnosis of pharyngeal ulceration in patients with HIV infection.

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 No evidence of ongoing HIV replication or compartmentalization in tissues during combination antiretroviral therapy: Implications for HIV eradication

2019 ◽  
Vol 5 (9) ◽  
pp. eaav2045 ◽  
Author(s):  
G. Bozzi ◽  
F. R. Simonetti ◽  
S. A. Watters ◽  
E. M. Anderson ◽  
M. Gouzoulis ◽  
...  
Keyword(s):  
Antiretroviral Therapy ◽  
Clonal Expansion ◽  
Combination Antiretroviral Therapy ◽  
Hiv Replication ◽  
Hiv Persistence ◽  
Hiv Eradication ◽  
Infected Cells ◽  
Anatomic Locations

HIV persistence during combination antiretroviral therapy (cART) is the principal obstacle to cure. Mechanisms responsible for persistence remain uncertain; infections may be maintained by persistence and clonal expansion of infected cells or by ongoing replication in anatomic locations with poor antiretroviral penetration. These mechanisms require different strategies for eradication, and determining their contributions to HIV persistence is essential. We used phylogenetic approaches to investigate, at the DNA level, HIV populations in blood, lymphoid, and other infected tissues obtained at colonoscopy or autopsy in individuals who were on cART for 8 to 16 years. We found no evidence of ongoing replication or compartmentalization of HIV; we did detect clonal expansion of infected cells that were present before cART. Long-term persistence, and not ongoing replication, is primarily responsible for maintaining HIV. HIV-infected cells present when cART is initiated represent the only identifiable source of persistence and is the appropriate focus for eradication.

scholarly journals eCD4-Ig Variants That More Potently Neutralize HIV-1

2018 ◽  
Vol 92 (12) ◽  
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.

scholarly journals Establishment of a Novel Humanized Mouse Model To Investigate In Vivo Activation and Depletion of Patient-Derived HIV Latent Reservoirs

2019 ◽  
Vol 93 (6) ◽  
Author(s):  
Nina C. Flerin ◽  
Ariola Bardhi ◽  
Jian Hua Zheng ◽  
Maria Korom ◽  
Joy Folkvord ◽  
...  
Keyword(s):  
Mouse Model ◽  
Hiv Infection ◽  
Mononuclear Cells ◽  
Systemic Infection ◽  
Humanized Mouse Model ◽  
Peripheral Blood Mononuclear ◽  
Immunodeficient Mice ◽  
Latently Infected ◽  
Infected Cells

ABSTRACT Curing HIV infection has been thwarted by the persistent reservoir of latently infected CD4+ T cells, which reinitiate systemic infection after antiretroviral therapy (ART) interruption. To evaluate reservoir depletion strategies, we developed a novel preclinical in vivo model consisting of immunodeficient mice intrasplenically injected with peripheral blood mononuclear cells (PBMC) from long-term ART-suppressed HIV-infected donors. In the absence of ART, these mice developed rebound viremia which, 2 weeks after PBMC injection, was 1,000-fold higher (mean = 9,229,281 HIV copies/ml) in mice injected intrasplenically than in mice injected intraperitoneally (mean = 6,838 HIV copies/ml) or intravenously (mean = 591 HIV copies/ml). One week after intrasplenic PBMC injection, in situ hybridization of the spleen demonstrated extensive disseminated HIV infection, likely initiated from in vivo-reactivated primary latently infected cells. The time to viremia was delayed significantly by treatment with a broadly neutralizing antibody, 10-1074, compared to treatment with 10-1074-FcRnull, suggesting that 10-1074 mobilized Fc-mediated effector mechanisms to deplete the replication-competent reservoir. This was supported by phylogenetic analysis of Env sequences from viral-outgrowth cultures and untreated, 10-1074-treated, or 10-1074-FcRnull-treated mice. The predominant sequence cluster detected in viral-outgrowth cultures and untreated mouse plasma was significantly reduced in the plasma of 10-1074-treated mice, whereas two new clusters emerged that were not detected in viral-outgrowth cultures or plasma from untreated mice. These new clusters lacked mutations associated with 10-1074 resistance. Taken together, these data indicated that 10-1074 treatment depletes the reservoir of latently infected cells harboring replication competent HIV. Furthermore, this mouse model represents a new in vivo approach for the preclinical evaluation of new HIV cure strategies. IMPORTANCE Sustained remission of HIV infection is prevented by a persistent reservoir of latently infected cells capable of reinitiating systemic infection and viremia. To evaluate strategies to reactivate and deplete this reservoir, we developed and characterized a new humanized mouse model consisting of highly immunodeficient mice intrasplenically injected with peripheral blood mononuclear cells from long-term ART-suppressed HIV-infected donors. Reactivation and dissemination of HIV infection was visualized in the mouse spleens in parallel with the onset of viremia. The applicability of this model for evaluating reservoir depletion treatments was demonstrated by establishing, through delayed time to viremia and phylogenetic analysis of plasma virus, that treatment of these humanized mice with a broadly neutralizing antibody, 10-1074, depleted the patient-derived population of latently infected cells. This mouse model represents a new in vivo approach for the preclinical evaluation of new HIV cure strategies.

scholarly journals Decelerating Decay of Latently Infected Cells during Prolonged Therapy for Human Immunodeficiency Virus Type 1 Infection

2002 ◽  
Vol 76 (17) ◽  
pp. 8963-8965 ◽  
Author(s):  
Viktor Müller ◽  
Javier Flavio Vigueras-Gómez ◽  
Sebastian Bonhoeffer
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Virus Production ◽  
Immunodeficiency Virus ◽  
Latently Infected ◽  
Infected Cells ◽  
Activation Rates ◽  
Rapid Drop

ABSTRACT Antiviral therapy induces a rapid drop in human immunodeficiency virus type 1 viremia, but the decline of virus levels decelerates over time. Mathematical modeling demonstrates that the source of residual virus production might be a single compartment of latently infected cells with an extended distribution of activation rates.

scholarly journals 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

2003 ◽  
Vol 77 (8) ◽  
pp. 4938-4949 ◽  
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.

Sign in / Sign up

Export Citation Format

Share Document