scholarly journals CRISPR-Cas9 Potential in Eradicating HIV Latent Reservoir as The Up-to-date Therapy For HIV-1

2021 ◽  
Vol 4 (1) ◽  
pp. 9-16
Author(s):  
Jesica Putri Salim ◽  
Friska Anggraini ◽  
Safa Nabila Putri ◽  
Ziske Maritska
Keyword(s):  
The Body ◽  
Gene Arrangement ◽  
Viral Reservoir ◽  
Latent Reservoir ◽  
Intracellular Replication ◽  
The Past ◽  
Latent Viral Reservoir ◽  
Immunodeficiency Virus ◽  
Short Palindromic Repeat ◽  
Hiv 1

According to the Ministry of Health in Indonesia, in 2018, there are about 640 thousand cases of people with HIV within the death rate of 38 thousand people. This number grows annually, in fact, according to WHO, there are approximately 38 million people who are diagnosed with HIV in the world in 2019.  Thus, HIV-AIDS is a dangerous health problem and needs to be taken care of as soon as possible. HIV (Human Immunodeficiency Virus) is a retrovirus that got its name from the infecting immune cells in the human body. There are two types of HIV, named HIV-1 and HIV-2. Both have the same basic gene arrangement, transmission process, intracellular replication lane, and both cause AIDS. The differences between them are the HIV-1 spreads globally, while HIV-2 locally happens in West Africa. Currently, ART (Antiretroviral Therapy) is the most commonly used method of treatment for HIV-1. Treatment for HIV-1 with ART is effective in controlling HIV-1 virus replication but has not been able to completely eradicate the latent viral reservoir. In the past few years, it is known that there is a CRISPR (Clustered Regularly Interspaced Short Palindromic Repeat) method that can modify genes (DNA) in the body of an organism. However, apart from its potential in handling HIV-1, there are still obstacles in the mechanism.

scholarly journals Syndecans Serve as Attachment Receptors for Human Immunodeficiency Virus Type 1 on Macrophages

2001 ◽  
Vol 75 (19) ◽  
pp. 9187-9200 ◽  
Author(s):  
Andrew C. S. Saphire ◽  
Michael D. Bobardt ◽  
Zhe Zhang ◽  
Guido David ◽  
Philippe A. Gallay
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Early Stage ◽  
The Body ◽  
Viral Reservoir ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Macrophages are thought to represent one of the first cell types in the body to be infected during the early stage of human immunodeficiency virus type 1 (HIV-1) transmission and represent a potential viral reservoir in vivo. Thus, an understanding of HIV-1 attachment to these cells is fundamental to the development of novel anti-HIV-1 therapies. Although one of the major targets of HIV-1 in vivo—CD4+ T lymphocytes—express high CD4 levels, other major targets such as macrophages do not. We asked in this study whether this low CD4 level on macrophages is sufficient to support HIV-1 attachment to these cells or whether cell surface proteins other than CD4 are required for this process. We show that CD4 alone is not sufficient to support the initial adsorption of HIV-1 to macrophages. Importantly, we find that heparan sulfate proteoglycans (HSPGs) serve as the main class of attachment receptors for HIV-1 on macrophages. Most importantly, we demonstrate that a single family of HSPGs, the syndecans, efficiently mediates HIV-1 attachment and represents an abundant class of attachment receptors on macrophages.

scholarly journals 19 Quantification and correlates of the replication competent HIV-1 latent viral reservoir in a virally suppressed Ugandan population

2016 ◽  
Vol 2 ◽  
pp. 15
Author(s):  
J.L. Prodger ◽  
J.D. Siliciano ◽  
J. Lai ◽  
S.J. Reynolds ◽  
J. Kasule ◽  
...  
Keyword(s):  
Viral Reservoir ◽  
Latent Viral Reservoir ◽  
Hiv 1 ◽  
Ugandan Population

scholarly journals Myeloid and CD4 T Cells Comprise the Latent Reservoir in Antiretroviral Therapy-Suppressed SIVmac251-Infected Macaques

mBio ◽  
2019 ◽  
Vol 10 (4) ◽  
Author(s):  
Celina M. Abreu ◽  
Rebecca T. Veenhuis ◽  
Claudia R. Avalos ◽  
Shelby Graham ◽  
Daymond R. Parrilla ◽  
...  
Keyword(s):  
T Cells ◽  
Antiretroviral Therapy ◽  
Life Span ◽  
Latent Reservoir ◽  
Viral Rebound ◽  
Hiv Cure ◽  
Short Life ◽  
Short Life Span ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Human immunodeficiency virus (HIV) eradication or long-term suppression in the absence of antiretroviral therapy (ART) requires an understanding of all viral reservoirs that could contribute to viral rebound after ART interruption. CD4 T cells (CD4s) are recognized as the predominant reservoir in HIV type 1 (HIV-1)-infected individuals. However, macrophages are also infected by HIV-1 and simian immunodeficiency virus (SIV) during acute infection and may persist throughout ART, contributing to the size of the latent reservoir. We sought to determine whether tissue macrophages contribute to the SIVmac251 reservoir in suppressed macaques. Using cell-specific quantitative viral outgrowth assays (CD4-QVOA and MΦ-QVOA), we measured functional latent reservoirs in CD4s and macrophages in ART-suppressed SIVmac251-infected macaques. Spleen, lung, and brain in all suppressed animals contained latently infected macrophages, undetectable or low-level SIV RNA, and detectable SIV DNA. Silent viral genomes with potential for reactivation and viral spread were also identified in blood monocytes, although these cells might not be considered reservoirs due to their short life span. Additionally, virus produced in the MΦ-QVOA was capable of infecting healthy activated CD4s. Our results strongly suggest that functional latent reservoirs in CD4s and macrophages can contribute to viral rebound and reestablishment of productive infection after ART interruption. These findings should be considered in the design and implementation of future HIV cure strategies. IMPORTANCE This study provides further evidence that the latent reservoir is comprised of both CD4+ T cells and myeloid cells. The data presented here suggest that CD4+ T cells and macrophages found throughout tissues in the body can contain replication-competent SIV and contribute to rebound of the virus after treatment interruption. Additionally, we have shown that monocytes in blood contain latent virus and, though not considered a reservoir themselves due to their short life span, could contribute to the size of the latent reservoir upon entering the tissue and differentiating into long-lived macrophages. These new insights into the size and location of the SIV reservoir using a model that is heavily studied in the HIV field could have great implications for HIV-infected individuals and should be taken into consideration with the development of future HIV cure strategies.

scholarly journals HIV-1/Mycobacterium tuberculosisCoinfection Immunology: How Does HIV-1 Exacerbate Tuberculosis?

2011 ◽  
Vol 79 (4) ◽  
pp. 1407-1417 ◽  
Author(s):  
Collin R. Diedrich ◽  
JoAnne L. Flynn
Keyword(s):  
Human Immunodeficiency Virus ◽  
Immune Cells ◽  
Clinical Studies ◽  
Treatment Options ◽  
The Past ◽  
Multiple Hypotheses ◽  
Immunodeficiency Virus ◽  
Basic Understanding ◽  
Hiv 1

ABSTRACTHuman immunodeficiency virus type 1 (HIV) andMycobacterium tuberculosishave become intertwined over the past few decades in a “syndemic” that exacerbates the morbidity and mortality associated with each pathogen alone. The severity of the coinfection has been extensively examined in clinical studies. The extrapolation of peripheral evidence from clinical studies has increased our basic understanding of how HIV increases susceptibility to TB. These studies have resulted in multiple hypotheses of how HIV exacerbates TB pathology through the manipulation of granulomas. Granulomas can be located in many tissues, most prominently the lungs and associated lymph nodes, and are made up of multiple immune cells that can actively containM. tuberculosis. Granuloma-based research involving both animal models and clinical studies is needed to confirm these hypotheses, which will further our understanding of this coinfection and may lead to better treatment options. This review examines the data that support each hypothesis of how HIV manipulates TB pathology while emphasizing a need for more tissue-based experiments.

scholarly journals Designing and Interpreting Limiting Dilution Assays: General Principles and Applications to the Latent Reservoir for Human Immunodeficiency Virus-1

2015 ◽  
Vol 2 (4) ◽  
Author(s):  
Daniel I. S. Rosenbloom ◽  
Oliver Elliott ◽  
Alison L. Hill ◽  
Timothy J. Henrich ◽  
Janet M. Siliciano ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Latent Infection ◽  
Latent Reservoir ◽  
Online Tool ◽  
Infectious Disease Research ◽  
Immunodeficiency Virus ◽  
Standard Assay ◽  
Assay Design ◽  
Hiv 1 ◽  
Limiting Dilution

Abstract Limiting dilution assays are widely used in infectious disease research. These assays are crucial for current human immunodeficiency virus (HIV)-1 cure research in particular. In this study, we offer new tools to help investigators design and analyze dilution assays based on their specific research needs. Limiting dilution assays are commonly used to measure the extent of infection, and in the context of HIV they represent an essential tool for studying latency and potential curative strategies. Yet standard assay designs may not discern whether an intervention reduces an already miniscule latent infection. This review addresses challenges arising in this setting and in the general use of dilution assays. We illustrate the major statistical method for estimating frequency of infectious units from assay results, and we offer an online tool for computing this estimate. We recommend a procedure for customizing assay design to achieve desired sensitivity and precision goals, subject to experimental constraints. We consider experiments in which no viral outgrowth is observed and explain how using alternatives to viral outgrowth may make measurement of HIV latency more efficient. Finally, we discuss how biological complications, such as probabilistic growth of small infections, alter interpretations of experimental results.

scholarly journals Rational Design of Drugs That Induce Human Immunodeficiency Virus Replication

2003 ◽  
Vol 77 (19) ◽  
pp. 10227-10236 ◽  
Author(s):  
Dean H. Hamer ◽  
Sven Bocklandt ◽  
Louise McHugh ◽  
Tae-Wook Chun ◽  
Peter M. Blumberg ◽  
...  
Keyword(s):  
Gene Expression ◽  
Human Immunodeficiency Virus ◽  
T Cell Activation ◽  
Rational Design ◽  
Latent Reservoir ◽  
Viral Gene ◽  
Human Immunodeficiency Virus Replication ◽  
Immunodeficiency Virus ◽  
Latently Infected ◽  
Hiv 1

ABSTRACT Drugs that induce human immunodeficiency virus type 1 (HIV-1) replication could be used in combination with highly active antiretroviral therapy (HAART) to reduce the size of the latent reservoir that is in part responsible for viral persistence. Protein kinase C (PKC) is a logical target for such drugs because it activates HIV-1 transcription through multiple mechanisms. Here we show that HIV-1 gene expression can be induced by potent synthetic analogues of the lipid second messenger diacylglycerol (DAG) synthesized on a five-member ring platform that reduces the entropy of binding relative to that of the more flexible DAG template. By varying the alkyl side chains of these synthetic DAG lactones, it was possible to maximize their potency and ability to render latently infected T cells sensitive to killing by an anti-HIV-1 immunotoxin while minimizing the side effects of CD4 and CXCR4 downregulation and tumor necrosis factor alpha upregulation. The two lead compounds, LMC03 and LMC07, regulated a series of PKC-sensitive genes involved in T-cell activation and induced viral gene expression in peripheral blood mononuclear cells from HIV-1-infected individuals. These studies demonstrate the potential for the rational design of agents that, in conjunction with HAART and HIV-specific toxins, can be used to decrease or eliminate the pool of latently infected reservoirs by forcing viral expression.

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.

scholarly journals Characterization of Chemokine Receptor Utilization of Viruses in the Latent Reservoir for Human Immunodeficiency Virus Type 1

2000 ◽  
Vol 74 (17) ◽  
pp. 7824-7833 ◽  
Author(s):  
Theodore Pierson ◽  
Trevor L. Hoffman ◽  
Joel Blankson ◽  
Diana Finzi ◽  
Karen Chadwick ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Chemokine Receptor ◽  
Latent Reservoir ◽  
Immunodeficiency Virus ◽  
Latently Infected ◽  
Hiv 1

ABSTRACT Latently infected resting CD4+ T cells provide a long-term reservoir for human immunodeficiency virus type 1 (HIV-1) and are likely to represent the major barrier to virus eradication in patients on combination antiretroviral therapy. The mechanisms by which viruses enter the latent reservoir and the nature of the chemokine receptors involved have not been determined. To evaluate the phenotype of the virus in this compartment with respect to chemokine receptor utilization, full-length HIV-1 env genes were cloned from latently infected cells and assayed functionally. We demonstrate that the majority of the viruses in the latent reservoir utilize CCR5 during entry, although utilization of several other receptors, including CXCR4, was observed. No alternative coreceptors were shown to be involved in a systematic fashion. Although R5 viruses are present in the latent reservoir, CCR5 was not expressed at high levels on resting CD4+ T cells. To understand the mechanism by which R5 viruses enter latent reservoir, the ability of an R5 virus, HIV-1 Ba-L, to infect highly purified resting CD4+ T lymphocytes from uninfected donors was evaluated. Entry of Ba-L could be observed when virus was applied at a multiplicity approaching 1. However, infection was limited to a subset of cells expressing low levels of CCR5 and markers of immunologic memory. Naive cells could not be infected by an R5 virus even when challenged with a large inoculum. Direct cell fractionation studies showed that latent virus is present predominantly in resting memory cells but also at lower levels in resting naive cells. Taken together, these findings provide support for the hypothesis that the direct infection of naive T cells is not the major mechanism by which the latent infection of resting T cells is established.

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