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Special Issue "HIV Latency"

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A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Animal Viruses".

Deadline for manuscript submissions: closed (31 July 2014)

Special Issue Editor

Guest Editor
Prof. Dr. Fatah Kashanchi (Website)

Director of Research, National Center for Biodefense and Infectious Diseases, Professor of Microbiology, George Mason University, Discovery Hall, Room 182, 10900 University Blvd. MS 1H8, Manassas, Va 20110
Phone: 301-802-5431
Fax: +703 993 7022

Special Issue Information

Submission

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. Papers will be published continuously (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are refereed through a peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Viruses is an international peer-reviewed Open Access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1500 CHF (Swiss Francs).

Published Papers (7 papers)

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Research

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Open AccessArticle Fitness Impaired Drug Resistant HIV-1 Is Not Compromised in Cell-to-Cell Transmission or Establishment of and Reactivation from Latency
Viruses 2014, 6(9), 3487-3499; doi:10.3390/v6093487
Received: 18 July 2014 / Revised: 1 September 2014 / Accepted: 17 September 2014 / Published: 19 September 2014
Cited by 5 | PDF Full-text (735 KB) | HTML Full-text | XML Full-text
Abstract
Both the presence of latently infected cells and cell-to-cell viral transmission are means whereby HIV can partially evade the inhibitory activities of antiretroviral drugs. The clinical use of a novel integrase inhibitor, dolutegravir (DTG), has established hope that this compound may limit [...] Read more.
Both the presence of latently infected cells and cell-to-cell viral transmission are means whereby HIV can partially evade the inhibitory activities of antiretroviral drugs. The clinical use of a novel integrase inhibitor, dolutegravir (DTG), has established hope that this compound may limit HIV persistence, since no treatment-naïve patient treated with DTG has yet developed resistance against this drug, even though a R263K substitution in integrase confers low-level resistance to this drug in tissue culture. Here, we have studied the impact of R263K on HIV replication capacity and the ability of HIV to establish or be reactivated from latency and/or spread through cell-to-cell transmission. We affirm that DTG-resistant viruses have diminished capacity to replicate and establish infection. However, DTG-resistant viruses were efficiently transmitted via cell-to-cell contacts, and were as likely to establish and be reactivated from latent infection as wildtype viruses. Both cell-to-cell transmission of HIV and the establishment of and reemergence from latency are important for the establishment and maintenance of viral reservoirs. Since the DTG and other drug-resistant viruses studied here do not seem to have been impaired in regard to these activities, studies should be undertaken to characterize HIV reservoirs in patients who have been treated with DTG. Full article
(This article belongs to the Special Issue HIV Latency)
Open AccessArticle Quantifying Susceptibility of CD4+ Stem Memory T-Cells to Infection by Laboratory Adapted and Clinical HIV-1 Strains
Viruses 2014, 6(2), 709-726; doi:10.3390/v6020709
Received: 20 December 2013 / Revised: 5 February 2014 / Accepted: 6 February 2014 / Published: 10 February 2014
Cited by 5 | PDF Full-text (1421 KB) | HTML Full-text | XML Full-text
Abstract
CD4+ T cells are principal targets for human immunodeficiency virus type 1 (HIV-1) infection. CD4+ T cell subsets are heterogeneous cell populations, divided by functional and phenotypic differences into naïve and memory T cells. The memory CD4+ T cells [...] Read more.
CD4+ T cells are principal targets for human immunodeficiency virus type 1 (HIV-1) infection. CD4+ T cell subsets are heterogeneous cell populations, divided by functional and phenotypic differences into naïve and memory T cells. The memory CD4+ T cells are further segregated into central, effector and transitional memory cell subsets by functional, phenotypic and homeostatic characteristics. Defining the distribution of HIV-1 infection in different T cell subsets is important, as this can play a role in determining the size and composition of the viral reservoir. Both central memory and transitional memory CD4+ T cells have been described as long-lived viral reservoirs for HIV. Recently, the newly described stem memory T cell subset has also been implicated as a long-lived HIV reservoir. Using green fluorescent protein (GFP) reporter strains of HIV-1 and multi parameter flow cytometry, we developed an assay to simultaneously quantify the susceptibility of stem memory (TSCM), central memory, effector memory, transitional memory and naïve CD4+ T cell subsets, to HIV-1 infection in vitro. We show that TSCM are susceptible to infection with laboratory adapted and clinical HIV-1 strains. Our system facilitates the quantitation of HIV-1 infection in alternative T cell subsets by CCR5- and CXCR4-using viruses across different HIV-1 subtypes, and will be useful for studies of HIV-1 pathogenesis and viral reservoirs. Full article
(This article belongs to the Special Issue HIV Latency)
Open AccessArticle Induced Degradation of Tat by Nucleocapsid (NC) via the Proteasome Pathway and Its Effect on HIV Transcription
Viruses 2013, 5(4), 1143-1152; doi:10.3390/v5041143
Received: 18 March 2013 / Revised: 16 April 2013 / Accepted: 16 April 2013 / Published: 23 April 2013
Cited by 2 | PDF Full-text (467 KB) | HTML Full-text | XML Full-text
Abstract
Human Immunodeficiency Virus type 1 (HIV-1) is a retrovirus that causes acquired immunodeficiency syndrome (AIDS). HIV-1 Tat protein upregulates transcriptional transactivation. The nucleocapsid protein NC of HIV-1 is a component of virion and plays a key role in genome packaging. Herein, we [...] Read more.
Human Immunodeficiency Virus type 1 (HIV-1) is a retrovirus that causes acquired immunodeficiency syndrome (AIDS). HIV-1 Tat protein upregulates transcriptional transactivation. The nucleocapsid protein NC of HIV-1 is a component of virion and plays a key role in genome packaging. Herein, we have demonstrated the interaction between NC and Tat by means of a yeast two-hybrid assay, GST pull-down analysis, co-immunoprecipitation and subcellular colocalization analysis. We observed that the level of Tat was significantly reduced in the presence of NC. But NC did not affect mRNA expression level of Tat. The level of Tat in the presence of NC was increased by treating cells with a proteasome inhibitor, MG132. The ubiquitination state of Tat was not seen to increase in the presence of NC, suggesting the proteasomal degradation was independent of ubiquitination. Lowered level of Tat in the presence of NC led to a decrease in Tat-mediated transcriptional transactivation. Full article
(This article belongs to the Special Issue HIV Latency)
Open AccessArticle Lost in Transcription: Molecular Mechanisms that Control HIV Latency
Viruses 2013, 5(3), 902-927; doi:10.3390/v5030902
Received: 27 February 2013 / Revised: 15 March 2013 / Accepted: 18 March 2013 / Published: 21 March 2013
Cited by 22 | PDF Full-text (899 KB) | HTML Full-text | XML Full-text
Abstract
Highly active antiretroviral therapy (HAART) has limited the replication and spread of the human immunodeficiency virus (HIV). However, despite treatment, HIV infection persists in latently infected reservoirs, and once therapy is interrupted, viral replication rebounds quickly. Extensive efforts are being directed at [...] Read more.
Highly active antiretroviral therapy (HAART) has limited the replication and spread of the human immunodeficiency virus (HIV). However, despite treatment, HIV infection persists in latently infected reservoirs, and once therapy is interrupted, viral replication rebounds quickly. Extensive efforts are being directed at eliminating these cell reservoirs. This feat can be achieved by reactivating latent HIV while administering drugs that prevent new rounds of infection and allow the immune system to clear the virus. However, current approaches to HIV eradication have not been effective. Moreover, as HIV latency is multifactorial, the significance of each of its molecular mechanisms is still under debate. Among these, transcriptional repression as a result of reduced levels and activity of the positive transcription elongation factor b (P-TEFb: CDK9/cyclin T) plays a significant role. Therefore, increasing levels of P-TEFb expression and activity is an excellent strategy to stimulate viral gene expression. This review summarizes the multiple steps that cause HIV to enter into latency. It positions the interplay between transcriptionally active and inactive host transcriptional activators and their viral partner Tat as valid targets for the development of new strategies to reactivate latent viral gene expression and eradicate HIV. Full article
(This article belongs to the Special Issue HIV Latency)

Review

Jump to: Research

Open AccessReview HIV Eradication: Combinatorial Approaches to Activate Latent Viruses
Viruses 2014, 6(11), 4581-4608; doi:10.3390/v6114581
Received: 16 September 2014 / Revised: 1 November 2014 / Accepted: 13 November 2014 / Published: 21 November 2014
Cited by 5 | PDF Full-text (731 KB) | HTML Full-text | XML Full-text
Abstract
The concept of eradication of the Human Immune Deficiency Virus (HIV) from infected patients has gained much attention in the last few years. While combination Anti-Retroviral Therapy (c-ART) has been extremely effective in suppressing viral replication, it is not curative. This is [...] Read more.
The concept of eradication of the Human Immune Deficiency Virus (HIV) from infected patients has gained much attention in the last few years. While combination Anti-Retroviral Therapy (c-ART) has been extremely effective in suppressing viral replication, it is not curative. This is due to the presence of a reservoir of latent HIV infected cells, which persist in the presence of c-ART. Recently, pharmaceutical approaches have focused on the development of molecules able to induce HIV-1 replication from latently infected cells in order to render them susceptible to viral cytopathic effects and host immune responses. Alternative pathways and transcription complexes function to regulate the activity of the HIV promoter and might serve as molecular targets for compounds to activate latent HIV. A combined therapy coupling various depressors and activators will likely be the most effective in promoting HIV replication while avoiding pleiotropic effects at the cellular level. Moreover, in light of differences among HIV subtypes and variability in integration sites, the combination of multiple agents targeting multiple pathways will increase likelihood of therapeutic effectiveness and prevent mutational escape. This review provides an overview of the mechanisms that can be targeted to induce HIV activation focusing on potential combinatorial approaches. Full article
(This article belongs to the Special Issue HIV Latency)
Open AccessReview HIV-1 Latency in Monocytes/Macrophages
Viruses 2014, 6(4), 1837-1860; doi:10.3390/v6041837
Received: 2 January 2014 / Revised: 11 March 2014 / Accepted: 28 March 2014 / Published: 22 April 2014
Cited by 35 | PDF Full-text (971 KB) | HTML Full-text | XML Full-text
Abstract
Human immunodeficiency virus type 1 (HIV-1) targets CD4+ T cells and cells of the monocyte/macrophage lineage. HIV pathogenesis is characterized by the depletion of T lymphocytes and by the presence of a population of cells in which latency has been established [...] Read more.
Human immunodeficiency virus type 1 (HIV-1) targets CD4+ T cells and cells of the monocyte/macrophage lineage. HIV pathogenesis is characterized by the depletion of T lymphocytes and by the presence of a population of cells in which latency has been established called the HIV-1 reservoir. Highly active antiretroviral therapy (HAART) has significantly improved the life of HIV-1 infected patients. However, complete eradication of HIV-1 from infected individuals is not possible without targeting latent sources of infection. HIV-1 establishes latent infection in resting CD4+ T cells and findings indicate that latency can also be established in the cells of monocyte/macrophage lineage. Monocyte/macrophage lineage includes among others, monocytes, macrophages and brain resident macrophages. These cells are relatively more resistant to apoptosis induced by HIV-1, thus are important stable hideouts of the virus. Much effort has been made in the direction of eliminating HIV-1 resting CD4+ T-cell reservoirs. However, it is impossible to achieve a cure for HIV-1 without considering these neglected latent reservoirs, the cells of monocyte/macrophage lineage. In this review we will describe our current understanding of the mechanism of latency in monocyte/macrophage lineage and how such cells can be specifically eliminated from the infected host. Full article
(This article belongs to the Special Issue HIV Latency)
Open AccessReview HIV-1 Latency: An Update of Molecular Mechanisms and Therapeutic Strategies
Viruses 2014, 6(4), 1715-1758; doi:10.3390/v6041715
Received: 2 January 2014 / Revised: 18 March 2014 / Accepted: 20 March 2014 / Published: 14 April 2014
Cited by 18 | PDF Full-text (2110 KB) | HTML Full-text | XML Full-text
Abstract
The major obstacle towards HIV-1 eradication is the life-long persistence of the virus in reservoirs of latently infected cells. In these cells the proviral DNA is integrated in the host’s genome but it does not actively replicate, becoming invisible to the host [...] Read more.
The major obstacle towards HIV-1 eradication is the life-long persistence of the virus in reservoirs of latently infected cells. In these cells the proviral DNA is integrated in the host’s genome but it does not actively replicate, becoming invisible to the host immune system and unaffected by existing antiviral drugs. Rebound of viremia and recovery of systemic infection that follows interruption of therapy, necessitates life-long treatments with problems of compliance, toxicity, and untenable costs, especially in developing countries where the infection hits worst. Extensive research efforts have led to the proposal and preliminary testing of several anti-latency compounds, however, overall, eradication strategies have had, so far, limited clinical success while posing several risks for patients. This review will briefly summarize the more recent advances in the elucidation of mechanisms that regulates the establishment/maintenance of latency and therapeutic strategies currently under evaluation in order to eradicate HIV persistence. Full article
(This article belongs to the Special Issue HIV Latency)

Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Type of Paper: Review

Title: HIV eradication: multiple approaches to activate viral replication
Author:
Tokameh Mahmoudi
Affiliation:
Associate Professor of Biochemistry, Erasmus University Medical Centre Ee634, Dr. Molewaterplein 50, 3015GE Rotterdam, The Netherlands
Abstract:
The concept of eradication of the Human Immune Deficiency Virus (HIV) from infected patients has gained much attention in the last few years. While combination Anti-Retroviral Therapy (c-ART) has been extremely effective in suppressing viral replication, it is not curative. This is due to the presence  of a reservoir of latent HIV infected cells, which are replication competent, and which persist in the presence of c-ART. Recently, pharmaceutical approaches have focused on the development, characterization and testing of molecules able to induce HIV-1 replication from latently infected cells in order to render them susceptible to viral cytopathic effects and host immune responses. Whereas HIV treatment has been one of the birthplaces of the concept of combinational therapy, now also spreading to cancer treatment, clinical studies on the activation of latent HIV has remained the domain of single drug treatments. Studies on the regulation of HIV gene expression indicate that alternative pathways and transcription complexes function to regulate the activity of the HIV promoter and might serve as molecular targets for compounds to activate latent HIV. A combined therapy coupling LTR depressors and activators will likely be the most effective in promoting HIV replication while at the same time conferring high specificity for the HIV-1 promoter and avoiding pleiotropic effects at the cellular level. Moreover, the combination of multiple agents will increase likelihood of effectiveness in light of differences in LTR organization among HIV subtypes, and variability in integration sites and at the same time will prevent mutational escape.  This review provides an overview of the mechanism that can be targeted to induce HIV activation focusing on potential combinatorial approaches.

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