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Viruses
Special Issues
Homage to Mark Wainberg
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Homage to Mark Wainberg

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

Deadline for manuscript submissions: closed (31 January 2018) | Viewed by 151647

Special Issue Editor

Dr. Thibault Mesplède

E-Mail Website
Guest Editor
Lady Davis Institute, Jewish General Hospital, Montreal, QC, Canada
Interests: antiretroviral drug resistance; HIV; integrase inhibitors; in vitro selection

Special Issue Information

Dear Colleagues,

Dr. Mark Wainberg was more than an outstanding researcher; he was a great mentor for many, including myself. He was a tireless advocate for the interests of those affected by HIV, whether they lived in Western or developing countries. Mark’s scientific contributions to the field of HIV research are immeasurable, and include, most notably, his work in HIV drug resistance. Most recently, his research focused on integrase inhibitors, including dolutegravir and other second-generation inhibitors. It is worth noting that, with the imminent introduction of integrase inhibitors as part of the standard-of-care in developing countries (dolutegravir being available to hundreds of thousands of individuals in Brazil, Botswana, and other developing countries in 2017), Mark’s work will become exponentially more relevant in the years to come.

After contracting a Dengue virus infection during one of his travels, Mark also turned his scientific attention to emerging viral infections, particularly those involving Flaviviridae. He was indeed a man of boundless scientific curiosity and goodwill.

In this Special Issue, dedicated to Dr. Mark Wainberg’s work, we explore and discuss aspects of HIV infection, transmission, drug resistance and pathogenesis. We also open this Special Issue to manuscripts studying diseases caused by emerging viral infections, keeping in mind that most of recent viral epidemics are imbedded within the same social tissue that has been allowing HIV to thrive for far too long.

Together with the Editors and Publisher, and in accordance with Mark’s deep social convictions, we hope to convey a message of hope and solidarity to researchers of the global South. Accordingly, five investigators from developing countries will benefit from waived publication fees when the work of at least ten investigators is accepted for publication in this Special Issue.

Thibault Mesplède, Ph.D.
Guest Editor

Manuscript Submission Information

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. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short 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 thoroughly refereed through a single-blind 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 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • HIV
  • Zika
  • Dengue
  • Flaviviridae
  • viral transmission
  • viral pathogenesis
  • drug resistance

Published Papers (22 papers)

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Research

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13 pages, 2213 KiB  
Communication
Identification of Novel HIV-1 Latency-Reversing Agents from a Library of Marine Natural Products
by Khumoekae Richard, David E. Williams, E. Dilip De Silva, Mark A. Brockman, Zabrina L. Brumme, Raymond J. Andersen and Ian Tietjen
Viruses 2018, 10(7), 348; https://doi.org/10.3390/v10070348 - 27 Jun 2018
Cited by 29 | Viewed by 4730
Abstract
Natural products originating from marine and plant materials are a rich source of chemical diversity and unique antimicrobials. Using an established in vitro model of HIV-1 latency, we screened 257 pure compounds from a marine natural product library and identified 4 (psammaplin A, [...] Read more.
Natural products originating from marine and plant materials are a rich source of chemical diversity and unique antimicrobials. Using an established in vitro model of HIV-1 latency, we screened 257 pure compounds from a marine natural product library and identified 4 (psammaplin A, aplysiatoxin, debromoaplysiatoxin, and previously-described alotaketal C) that induced expression of latent HIV-1 provirus in both cell line and primary cell models. Notably, aplysiatoxin induced similar levels of HIV-1 expression as prostratin but at up to 900-fold lower concentrations and without substantial effects on cell viability. Psammaplin A enhanced HIV-1 expression synergistically when treated in combination with the protein kinase C (PKC) activator prostratin, but not the histone deacetylase inhibitor (HDACi) panobinostat, suggesting that psammaplin A functions as a latency-reversing agent (LRA) of the HDACi class. Conversely, aplysiatoxin and debromoaplysiatoxin synergized with panobinostat but not prostratin, suggesting that they function as PKC activators. Our study identifies new compounds from previously untested marine natural products and adds to the repertoire of LRAs that can inform therapeutic “shock-and-kill”-based strategies to eliminate latent HIV-infected reservoirs. Full article
(This article belongs to the Special Issue Homage to Mark Wainberg)
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23 pages, 3772 KiB  
Article
DNA Vaccine-Encoded Flagellin Can Be Used as an Adjuvant Scaffold to Augment HIV-1 gp41 Membrane Proximal External Region Immunogenicity
by Lara Ajamian, Luca Melnychuk, Patrick Jean-Pierre and Gerasimos J. Zaharatos
Viruses 2018, 10(3), 100; https://doi.org/10.3390/v10030100 - 27 Feb 2018
Cited by 11 | Viewed by 4546
Abstract
Flagellin’s potential as a vaccine adjuvant has been increasingly explored over the last three decades. Monomeric flagellin proteins are the only known agonists of Toll-like receptor 5 (TLR5). This interaction evokes a pro-inflammatory state that impacts upon both innate and adaptive immunity. While [...] Read more.
Flagellin’s potential as a vaccine adjuvant has been increasingly explored over the last three decades. Monomeric flagellin proteins are the only known agonists of Toll-like receptor 5 (TLR5). This interaction evokes a pro-inflammatory state that impacts upon both innate and adaptive immunity. While pathogen associated molecular patterns (PAMPs) like flagellin have been used as stand-alone adjuvants that are co-delivered with antigen, some investigators have demonstrated a distinct advantage to incorporating antigen epitopes within the structure of flagellin itself. This approach has been particularly effective in enhancing humoral immune responses. We sought to use flagellin as both scaffold and adjuvant for HIV gp41 with the aim of eliciting antibodies to the membrane proximal external region (MPER). Accordingly, we devised a straightforward step-wise approach to select flagellin-antigen fusion proteins for gene-based vaccine development. Using plasmid DNA vector-based expression in mammalian cells, we demonstrate robust expression of codon-optimized full length and hypervariable region-deleted constructs of Salmonella enterica subsp. enterica serovar Typhi flagellin (FliC). An HIV gp41 derived sequence including the MPER (gp41607–683) was incorporated into various positions of these constructs and the expressed fusion proteins were screened for effective secretion, TLR5 agonist activity and adequate MPER antigenicity. We show that incorporation of gp41607–683 into a FliC-based scaffold significantly augments gp41607–683 immunogenicity in a TLR5 dependent manner and elicits modest MPER-specific humoral responses in a mouse model. Full article
(This article belongs to the Special Issue Homage to Mark Wainberg)
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16 pages, 2471 KiB  
Article
Blood Mitochondrial DNA Content in HIV-Exposed Uninfected Children with Autism Spectrum Disorder
by Matthew A. Budd, Kristina Calli, Lindy Samson, Jennifer Bowes, Anthony Y. Y. Hsieh, John C. Forbes, Ari Bitnun, Joel Singer, Fatima Kakkar, Ariane Alimenti, Evelyn J. Maan, M. E. Suzanne Lewis, Carole Gentile, Hélène C.F. Côté and Jason C. Brophy
Viruses 2018, 10(2), 77; https://doi.org/10.3390/v10020077 - 11 Feb 2018
Cited by 16 | Viewed by 4973
Abstract
Long-term outcomes of perinatal exposure to maternal antiretroviral therapy in HIV-exposed uninfected (HEU) children are unknown. However, both HIV antiretroviral therapy and autism spectrum disorder (ASD) have been associated with mitochondrial alterations. Leukocyte mitochondrial DNA (mtDNA) content can serve as a marker for [...] Read more.
Long-term outcomes of perinatal exposure to maternal antiretroviral therapy in HIV-exposed uninfected (HEU) children are unknown. However, both HIV antiretroviral therapy and autism spectrum disorder (ASD) have been associated with mitochondrial alterations. Leukocyte mitochondrial DNA (mtDNA) content can serve as a marker for mitochondrial dysfunction. In this cross-sectional, nested case-control study, HEU children with ASD were matched approximately 1:3 on age, sex, and ethnicity to HEU children without ASD, HIV-unexposed uninfected (HUU) controls, and HUU children with ASD. Leukocyte mtDNA content was measured using quantitative PCR. Among 299 HEU in this study, 14 (4.7%) were diagnosed with ASD, which is higher than the general population prevalence estimates. HEU children without ASD and HUU children with ASD had higher mtDNA content than HUU controls. HEU children with ASD had significantly higher mtDNA content than all other study groups. Our results suggest a clear association between elevated leukocyte mtDNA content and both HEU and ASD status. This may implicate mitochondrial dysfunction as a contributor to the high ASD prevalence observed in our cohort. Full article
(This article belongs to the Special Issue Homage to Mark Wainberg)
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21 pages, 3315 KiB  
Article
High Levels of Dual-Class Drug Resistance in HIV-Infected Children Failing First-Line Antiretroviral Therapy in Southern Ethiopia
by Birkneh Tilahun Tadesse, Natalie N. Kinloch, Bemuluyigza Baraki, Hope R. Lapointe, Kyle D. Cobarrubias, Mark A. Brockman, Chanson J. Brumme, Byron A. Foster, Degu Jerene, Eyasu Makonnen, Eleni Aklillu and Zabrina L. Brumme
Viruses 2018, 10(2), 60; https://doi.org/10.3390/v10020060 - 01 Feb 2018
Cited by 11 | Viewed by 5040
Abstract
Clinical monitoring of pediatric HIV treatment remains a major challenge in settings where drug resistance genotyping is not routinely available. As a result, our understanding of drug resistance, and its impact on subsequent therapeutic regimens available in these settings, remains limited. We investigate [...] Read more.
Clinical monitoring of pediatric HIV treatment remains a major challenge in settings where drug resistance genotyping is not routinely available. As a result, our understanding of drug resistance, and its impact on subsequent therapeutic regimens available in these settings, remains limited. We investigate the prevalence and correlates of HIV-1 drug resistance among 94 participants of the Ethiopia Pediatric HIV Cohort failing first-line combination antiretroviral therapy (cART) using dried blood spot-based genotyping. Overall, 81% (73/90) of successfully genotyped participants harbored resistance mutations, including 69% (62/90) who harbored resistance to both Nucleoside Reverse Transcriptase Inhibitors (NRTIs) and Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs). Strikingly, 42% of resistant participants harbored resistance to all four NRTIs recommended for second-line use in this setting, meaning that there are effectively no remaining cART options for these children. Longer cART duration and prior regimen changes were significantly associated with detection of drug resistance mutations. Replicate genotyping increased the breadth of drug resistance detected in 34% of cases, and thus is recommended for consideration when typing from blood spots. Implementation of timely drug resistance testing and access to newer antiretrovirals and drug classes are urgently needed to guide clinical decision-making and improve outcomes for HIV-infected children on first-line cART in Ethiopia. Full article
(This article belongs to the Special Issue Homage to Mark Wainberg)
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15 pages, 1777 KiB  
Article
Higher Cytopathic Effects of a Zika Virus Brazilian Isolate from Bahia Compared to a Canadian-Imported Thai Strain
by Sergio P. Alpuche-Lazcano, Craig R. McCullogh, Olivier Del Corpo, Elodie Rance, Robert J. Scarborough, Andrew J. Mouland, Selena M. Sagan, Mauro M. Teixeira and Anne Gatignol
Viruses 2018, 10(2), 53; https://doi.org/10.3390/v10020053 - 27 Jan 2018
Cited by 18 | Viewed by 5642
Abstract
Zika virus (ZIKV) is an emerging pathogen from the Flaviviridae family. It represents a significant threat to global health due to its neurological and fetal pathogenesis (including microcephaly and congenital malformations), and its rapid dissemination across Latin America in recent years. The virus [...] Read more.
Zika virus (ZIKV) is an emerging pathogen from the Flaviviridae family. It represents a significant threat to global health due to its neurological and fetal pathogenesis (including microcephaly and congenital malformations), and its rapid dissemination across Latin America in recent years. The virus has spread from Africa to Asia, the Pacific islands and the Americas with limited knowledge about the pathogenesis associated with infection in recent years. Herein, we compared the ability of the Canadian-imported Thai strain PLCal_ZV and the Brazilian isolate HS-2015-BA-01 from Bahia to produce infectious ZIKV particles and cytopathic effects in a cell proliferation assay. We also compared the intracellular viral RNA accumulation of the two strains by quantitative RT-PCR (reverse transcription polymerase chain reaction) analyses. Our observations show that HS-2015-BA-01 is more cytopathic than PLCal_ZV in proliferation assays in Vero, Human Embryonic Kidney HEK 293T and neuroblastoma SH-SY5Y cells. Quantitative RT-PCR shows that the level of viral RNA is higher with HS-2015-BA-01 than with PLCal_ZV in two cell lines, but similar in a neuroblastoma cell line. The two strains have 13 amino acids polymorphisms and we analyzed their predicted protein secondary structure. The increased cytopathicity and RNA accumulation of the Brazilian ZIKV isolate compared to the Thai isolate could contribute to the increased pathogenicity observed during the Brazilian epidemic. Full article
(This article belongs to the Special Issue Homage to Mark Wainberg)
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24 pages, 1689 KiB  
Article
Biomarkers of Progression after HIV Acute/Early Infection: Nothing Compares to CD4+ T-cell Count?
by Gabriela Turk, Yanina Ghiglione, Macarena Hormanstorfer, Natalia Laufer, Romina Coloccini, Jimena Salido, César Trifone, María Julia Ruiz, Juliana Falivene, María Pía Holgado, María Paula Caruso, María Inés Figueroa, Horacio Salomón, Luis D. Giavedoni, María De los Ángeles Pando, María Magdalena Gherardi, Roberto Daniel Rabinovich, Pedro A. Pury and Omar Sued
Viruses 2018, 10(1), 34; https://doi.org/10.3390/v10010034 - 13 Jan 2018
Cited by 10 | Viewed by 4939
Abstract
Progression of HIV infection is variable among individuals, and definition disease progression biomarkers is still needed. Here, we aimed to categorize the predictive potential of several variables using feature selection methods and decision trees. A total of seventy-five treatment-naïve subjects were enrolled during [...] Read more.
Progression of HIV infection is variable among individuals, and definition disease progression biomarkers is still needed. Here, we aimed to categorize the predictive potential of several variables using feature selection methods and decision trees. A total of seventy-five treatment-naïve subjects were enrolled during acute/early HIV infection. CD4+ T-cell counts (CD4TC) and viral load (VL) levels were determined at enrollment and for one year. Immune activation, HIV-specific immune response, Human Leukocyte Antigen (HLA) and C-C chemokine receptor type 5 (CCR5) genotypes, and plasma levels of 39 cytokines were determined. Data were analyzed by machine learning and non-parametric methods. Variable hierarchization was performed by Weka correlation-based feature selection and J48 decision tree. Plasma interleukin (IL)-10, interferon gamma-induced protein (IP)-10, soluble IL-2 receptor alpha (sIL-2Rα) and tumor necrosis factor alpha (TNF-α) levels correlated directly with baseline VL, whereas IL-2, TNF-α, fibroblast growth factor (FGF)-2 and macrophage inflammatory protein (MIP)-1β correlated directly with CD4+ T-cell activation (p < 0.05). However, none of these cytokines had good predictive values to distinguish “progressors” from “non-progressors”. Similarly, immune activation, HIV-specific immune responses and HLA/CCR5 genotypes had low discrimination power. Baseline CD4TC was the most potent discerning variable with a cut-off of 438 cells/μL (accuracy = 0.93, κ-Cohen = 0.85). Limited discerning power of the other factors might be related to frequency, variability and/or sampling time. Future studies based on decision trees to identify biomarkers of post-treatment control are warrantied. Full article
(This article belongs to the Special Issue Homage to Mark Wainberg)
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2282 KiB  
Article
Regulation of CD4 Receptor and HIV-1 Entry by MicroRNAs-221 and -222 during Differentiation of THP-1 Cells
by Robert Lodge, Julian C. Gilmore, Jérémy A. Ferreira Barbosa, Félix Lombard-Vadnais and Éric A. Cohen
Viruses 2018, 10(1), 13; https://doi.org/10.3390/v10010013 - 30 Dec 2017
Cited by 11 | Viewed by 6699
Abstract
Human immunodeficiency virus type-1 (HIV-1) infection of monocyte/macrophages is modulated by the levels of entry receptors cluster of differentiation 4 (CD4) and C-C chemokine receptor type 5 (CCR5), as well as by host antiviral restriction factors, which mediate several post-entry blocks. We recently [...] Read more.
Human immunodeficiency virus type-1 (HIV-1) infection of monocyte/macrophages is modulated by the levels of entry receptors cluster of differentiation 4 (CD4) and C-C chemokine receptor type 5 (CCR5), as well as by host antiviral restriction factors, which mediate several post-entry blocks. We recently identified two microRNAs, miR-221 and miR-222, which limit HIV-1 entry during infection of monocyte-derived macrophages (MDMs) by down-regulating CD4 expression. Interestingly, CD4 is also down-regulated during the differentiation of monocytes into macrophages. In this study, we compared microRNA expression profiles in primary monocytes and macrophages by RNAseq and found that miR-221/miR-222 are enhanced in macrophages. We took advantage of the monocytic THP-1 cell line that, once differentiated, is poorly susceptible to HIV-1. Accordingly, we found that CD4 levels are very low in THP-1 differentiated cells and that this down-regulation of the virus receptor is the result of miR-221/miR-222 up-regulation during differentiation. We thus established a THP-1 cell line stably expressing a modified CD4 (THP-1-CD4R) that is not modulated by miR-221/miR-222. We show that in contrast to parental THP-1, this line is productively infected by HIV-1 following differentiation, sustaining efficient HIV-1 CD4-dependent replication and spread. This new THP-1-CD4R cell line represents a useful tool for the study of HIV-1-macrophage interactions particularly in contexts where spreading of viral infection is necessary. Full article
(This article belongs to the Special Issue Homage to Mark Wainberg)
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5954 KiB  
Article
HIV-1 Subtypes and 5’LTR-Leader Sequence Variants Correlate with Seroconversion Status in Pumwani Sex Worker Cohort
by Raghavan Sampathkumar, Joel Scott-Herridge, Binhua Liang, Joshua Kimani, Francis A. Plummer and Ma Luo
Viruses 2018, 10(1), 4; https://doi.org/10.3390/v10010004 - 23 Dec 2017
Cited by 2 | Viewed by 5616
Abstract
Within the Pumwani sex worker cohort, a subgroup remains seronegative, despite frequent exposure to HIV-1; some of them seroconverted several years later. This study attempts to identify viral variations in 5’LTR-leader sequences (5’LTR-LS) that might contribute to the late seroconversion. The 5’LTR-LS contains [...] Read more.
Within the Pumwani sex worker cohort, a subgroup remains seronegative, despite frequent exposure to HIV-1; some of them seroconverted several years later. This study attempts to identify viral variations in 5’LTR-leader sequences (5’LTR-LS) that might contribute to the late seroconversion. The 5’LTR-LS contains sites essential for replication and genome packaging, viz, primer binding site (PBS), major splice donor (SD), and major packaging signal (PS). The 5’LTR-LS of 20 late seroconverters (LSC) and 122 early seroconverters (EC) were amplified, cloned, and sequenced. HelixTree 6.4.3 was employed to classify HIV subtypes and sequence variants based on seroconversion status. We find that HIV-1 subtypes A1.UG and D.UG were overrepresented in the viruses infecting the LSC (P < 0.0001). Specific variants of PBS (Pc < 0.0001), SD1 (Pc < 0.0001), and PS (Pc < 0.0001) were present only in the viral population from EC or LSC. Combinations of PBS [PBS-2 (Pc < 0.0001) and PBS-3 (Pc < 0.0001)] variants with specific SD sequences were only seen in LSC or EC. Combinations of A1.KE or D with specific PBS and SD variants were only present in LSC or EC (Pc < 0.0001). Furthermore, PBS variants only present in LSC co-clustered with PBS references utilizing tRNAArg; whereas, the PBS variants identified only in EC co-clustered with PBS references using tRNALys3 and its variants. This is the first report that specific PBS, SD1, and PS sequence variants within 5’LTR-LS are associated with HIV-1 seroconversion, and it could aid designing effective anti-HIV strategies. Full article
(This article belongs to the Special Issue Homage to Mark Wainberg)
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933 KiB  
Article
Characterization of HIV-1 Near Full-Length Proviral Genome Quasispecies from Patients with Undetectable Viral Load Undergoing First-Line HAART Therapy
by Brunna M. Alves, Juliana D. Siqueira, Marianne M. Garrido, Ornella M. Botelho, Isabel M. Prellwitz, Sayonara R. Ribeiro, Esmeralda A. Soares and Marcelo A. Soares
Viruses 2017, 9(12), 392; https://doi.org/10.3390/v9120392 - 19 Dec 2017
Cited by 18 | Viewed by 5182
Abstract
Increased access to highly active antiretroviral therapy (HAART) by human immunodeficiency virus postive (HIV+) individuals has become a reality worldwide. In Brazil, HAART currently reaches over half of HIV-infected subjects. In the context of a remarkable HIV-1 genetic variability, highly related [...] Read more.
Increased access to highly active antiretroviral therapy (HAART) by human immunodeficiency virus postive (HIV+) individuals has become a reality worldwide. In Brazil, HAART currently reaches over half of HIV-infected subjects. In the context of a remarkable HIV-1 genetic variability, highly related variants, called quasispecies, are generated. HIV quasispecies generated during infection can influence virus persistence and pathogenicity, representing a challenge to treatment. However, the clinical relevance of minority quasispecies is still uncertain. In this study, we have determined the archived proviral sequences, viral subtype and drug resistance mutations from a cohort of HIV+ patients with undetectable viral load undergoing HAART as first-line therapy using next-generation sequencing for near full-length virus genome (NFLG) assembly. HIV-1 consensus sequences representing NFLG were obtained for eleven patients, while for another twelve varying genome coverage rates were obtained. Phylogenetic analysis showed the predominance of subtype B (83%; 19/23). Considering the minority variants, 18 patients carried archived virus harboring at least one mutation conferring antiretroviral resistance; for six patients, the mutations correlated with the current ARVs used. These data highlight the importance of monitoring HIV minority drug resistant variants and their clinical impact, to guide future regimen switches and improve HIV treatment success. Full article
(This article belongs to the Special Issue Homage to Mark Wainberg)
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4604 KiB  
Article
A Bioinformatic Pipeline for Monitoring of the Mutational Stability of Viral Drug Targets with Deep-Sequencing Technology
by Yuri Kravatsky, Vladimir Chechetkin, Daria Fedoseeva, Maria Gorbacheva, Galina Kravatskaya, Olga Kretova and Nickolai Tchurikov
Viruses 2017, 9(12), 357; https://doi.org/10.3390/v9120357 - 23 Nov 2017
Cited by 3 | Viewed by 3992
Abstract
The efficient development of antiviral drugs, including efficient antiviral small interfering RNAs (siRNAs), requires continuous monitoring of the strict correspondence between a drug and the related highly variable viral DNA/RNA target(s). Deep sequencing is able to provide an assessment of both the general [...] Read more.
The efficient development of antiviral drugs, including efficient antiviral small interfering RNAs (siRNAs), requires continuous monitoring of the strict correspondence between a drug and the related highly variable viral DNA/RNA target(s). Deep sequencing is able to provide an assessment of both the general target conservation and the frequency of particular mutations in the different target sites. The aim of this study was to develop a reliable bioinformatic pipeline for the analysis of millions of short, deep sequencing reads corresponding to selected highly variable viral sequences that are drug target(s). The suggested bioinformatic pipeline combines the available programs and the ad hoc scripts based on an original algorithm of the search for the conserved targets in the deep sequencing data. We also present the statistical criteria for the threshold of reliable mutation detection and for the assessment of variations between corresponding data sets. These criteria are robust against the possible sequencing errors in the reads. As an example, the bioinformatic pipeline is applied to the study of the conservation of RNA interference (RNAi) targets in human immunodeficiency virus 1 (HIV-1) subtype A. The developed pipeline is freely available to download at the website http://virmut.eimb.ru/. Brief comments and comparisons between VirMut and other pipelines are also presented. Full article
(This article belongs to the Special Issue Homage to Mark Wainberg)
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1901 KiB  
Article
Expression Profiles of Ligands for Activating Natural Killer Cell Receptors on HIV Infected and Uninfected CD4+ T Cells
by Alexandra Tremblay-McLean, Julie Bruneau, Bertrand Lebouché, Irene Lisovsky, Rujun Song and Nicole F. Bernard
Viruses 2017, 9(10), 295; https://doi.org/10.3390/v9100295 - 12 Oct 2017
Cited by 15 | Viewed by 5789
Abstract
Natural Killer (NK) cell responses to HIV-infected CD4 T cells (iCD4) depend on the integration of signals received through inhibitory (iNKR) and activating NK receptors (aNKR). iCD4 activate NK cells to inhibit HIV replication. HIV infection-dependent changes in the human leukocyte antigen (HLA) [...] Read more.
Natural Killer (NK) cell responses to HIV-infected CD4 T cells (iCD4) depend on the integration of signals received through inhibitory (iNKR) and activating NK receptors (aNKR). iCD4 activate NK cells to inhibit HIV replication. HIV infection-dependent changes in the human leukocyte antigen (HLA) ligands for iNKR on iCD4 are well documented. By contrast, less is known regarding the HIV infection related changes in ligands for aNKR on iCD4. We examined the aNKR ligand profiles HIV p24+ HIV iCD4s that maintained cell surface CD4 (iCD4+), did not maintain CD4 (iCD4−) and uninfected CD4 (unCD4) T cells for expression of unique long (UL)-16 binding proteins-1 (ULBP-1), ULBP-2/5/6, ULBP-3, major histocompatibility complex (MHC) class 1-related (MIC)-A, MIC-B, CD48, CD80, CD86, CD112, CD155, Intercellular adhesion molecule (ICAM)-1, ICAM-2, HLA-E, HLA-F, HLA-A2, HLA-C, and the ligands to NKp30, NKp44, NKp46, and killer immunoglobulin-like receptor 3DS1 (KIR3DS1) by flow cytometry on CD4 T cells from 17 HIV-1 seronegative donors activated and infected with HIV. iCD4+ cells had higher expression of aNKR ligands than did unCD4. However, the expression of aNKR ligands on iCD4 where CD4 was downregulated (iCD4−) was similar to (ULBP-1, ULBP-2/5/6, ULBP-3, MIC-A, CD48, CD80, CD86 and CD155) or significantly lower than (MIC-B, CD112 and ICAM-2) what was observed on unCD4. Thus, HIV infection can be associated with increased expression of aNKR ligands or either baseline or lower than baseline levels of aNKR ligands, concomitantly with the HIV-mediated downregulation of cell surface CD4 on infected cells. Full article
(This article belongs to the Special Issue Homage to Mark Wainberg)
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Review

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22 pages, 1576 KiB  
Review
AIDS Clinical Research in Spain—Large HIV Population, Geniality of Doctors, and Missing Opportunities
by Vicente Soriano, José M. Ramos, Pablo Barreiro and Jose V. Fernandez-Montero
Viruses 2018, 10(6), 293; https://doi.org/10.3390/v10060293 - 30 May 2018
Cited by 11 | Viewed by 5438
Abstract
The first cases of AIDS in Spain were reported in 1982. Since then over 85,000 persons with AIDS have been cumulated, with 60,000 deaths. Current estimates for people living with HIV are of 145,000, of whom 20% are unaware of it. This explains [...] Read more.
The first cases of AIDS in Spain were reported in 1982. Since then over 85,000 persons with AIDS have been cumulated, with 60,000 deaths. Current estimates for people living with HIV are of 145,000, of whom 20% are unaware of it. This explains the still high rate of late HIV presenters. Although the HIV epidemic in Spain was originally driven mostly by injection drug users, since the year 2000 men having sex with men (MSM) account for most new incident HIV cases. Currently, MSM represent over 80% of new yearly HIV diagnoses. In the 80s, a subset of young doctors and nurses working at Internal Medicine hospital wards became deeply engaged in attending HIV-infected persons. Before the introduction of antiretrovirals in the earlier 1990s, diagnosis and treatment of opportunistic infections was their major task. A new wave of infectious diseases specialists was born. Following the wide introduction of triple combination therapy in the late 1990s, drug side effects and antiretroviral resistance led to built a core of highly devoted HIV specialists across the country. Since then, HIV medicine has improved and currently is largely conducted by multidisciplinary teams of health care providers working at hospital-based outclinics, where HIV-positive persons are generally seen every six months. Antiretroviral therapy is currently prescribed to roughly 75,000 persons, almost all attended at clinics belonging to the government health public system. Overall, the impact of HIV/AIDS publications by Spanish teams is the third most important in Europe. HIV research in Spain has classically been funded mostly by national and European public agencies along with pharma companies. Chronologically, some of the major contributions of Spanish HIV research are being in the field of tuberculosis, toxoplasmosis, leishmaniasis, HIV variants including HIV-2, drug resistance, pharmacology, antiretroviral drug-related toxicities, coinfection with viral hepatitis, design and participation in clinical trials with antiretrovirals, immunopathogenesis, ageing, and vaccine development. Full article
(This article belongs to the Special Issue Homage to Mark Wainberg)
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31 pages, 1198 KiB  
Review
The Biology of Monocytes and Dendritic Cells: Contribution to HIV Pathogenesis
by Vanessa Sue Wacleche, Cécile L. Tremblay, Jean-Pierre Routy and Petronela Ancuta
Viruses 2018, 10(2), 65; https://doi.org/10.3390/v10020065 - 06 Feb 2018
Cited by 45 | Viewed by 16383
Abstract
Myeloid cells such as monocytes, dendritic cells (DC) and macrophages (MΦ) are key components of the innate immune system contributing to the maintenance of tissue homeostasis and the development/resolution of immune responses to pathogens. Monocytes and DC, circulating in the blood or infiltrating [...] Read more.
Myeloid cells such as monocytes, dendritic cells (DC) and macrophages (MΦ) are key components of the innate immune system contributing to the maintenance of tissue homeostasis and the development/resolution of immune responses to pathogens. Monocytes and DC, circulating in the blood or infiltrating various lymphoid and non-lymphoid tissues, are derived from distinct bone marrow precursors and are typically short lived. Conversely, recent studies revealed that subsets of tissue resident MΦ are long-lived as they originate from embryonic/fetal precursors that have the ability to self-renew during the life of an individual. Pathogens such as the human immunodeficiency virus type 1 (HIV-1) highjack the functions of myeloid cells for viral replication (e.g., MΦ) or distal dissemination and cell-to-cell transmission (e.g., DC). Although the long-term persistence of HIV reservoirs in CD4+ T-cells during viral suppressive antiretroviral therapy (ART) is well documented, the ability of myeloid cells to harbor replication competent viral reservoirs is still a matter of debate. This review summarizes the current knowledge on the biology of monocytes and DC during homeostasis and in the context of HIV-1 infection and highlights the importance of future studies on long-lived resident MΦ to HIV persistence in ART-treated patients. Full article
(This article belongs to the Special Issue Homage to Mark Wainberg)
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8 pages, 633 KiB  
Review
Resistance to HIV Integrase Inhibitors: About R263K and E157Q Mutations
by Charlotte Charpentier and Diane Descamps
Viruses 2018, 10(1), 41; https://doi.org/10.3390/v10010041 - 18 Jan 2018
Cited by 28 | Viewed by 5700
Abstract
The use of integrase inhibitors (INI) is increasing in antiretroviral therapies (ART) and INI are not all equal regarding genetic barrier to resistance. The aim of this manuscript was to review main in vivo and in vitro knowledge about two particular integrase resistance-associated [...] Read more.
The use of integrase inhibitors (INI) is increasing in antiretroviral therapies (ART) and INI are not all equal regarding genetic barrier to resistance. The aim of this manuscript was to review main in vivo and in vitro knowledge about two particular integrase resistance-associated mutations: R263K and E157Q. The R263K mutation was the first mutation rarely found selected at time of virological failure in patients failing a first-line dolutegravir-based treatment. Further in vitro studies on R263K mutants showed a moderate increase in phenotypic resistance level and a drastic reduction in viral replicative capacity. No compensatory mutations were evidenced. The E157Q mutation is polymorphic, found between 1.7% and 5.6% of viral sequences issued from ART-naïve patients depending on the viral subtype; as well as acquired resistance emerging at failure of a raltegravir-based regimen in two case reports. We reported data on phenotypic resistance level of E157Q mutants and virological response of patients harboring a E157Q virus initiating an INI-based regimen, showing that dolutegravir might be the most recommended INI in such patients. These findings show that there is still a need for a better understanding of resistance mechanisms to INI and emphasized the importance of genotypic background in viral evolution under drug pressure. Full article
(This article belongs to the Special Issue Homage to Mark Wainberg)
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21 pages, 1235 KiB  
Review
Interferons: Reprogramming the Metabolic Network against Viral Infection
by Kavita Raniga and Chen Liang
Viruses 2018, 10(1), 36; https://doi.org/10.3390/v10010036 - 13 Jan 2018
Cited by 45 | Viewed by 11328
Abstract
Viruses exploit the host and induce drastic metabolic changes to ensure an optimal environment for replication and the production of viral progenies. In response, the host has developed diverse countermeasures to sense and limit these alterations to combat viral infection. One such host [...] Read more.
Viruses exploit the host and induce drastic metabolic changes to ensure an optimal environment for replication and the production of viral progenies. In response, the host has developed diverse countermeasures to sense and limit these alterations to combat viral infection. One such host mechanism is through interferon signaling. Interferons are cytokines that enhances the transcription of hundreds of interferon-stimulated genes (ISGs) whose products are key players in the innate immune response to viral infection. In addition to their direct targeting of viral components, interferons and ISGs exert profound effects on cellular metabolism. Recent studies have started to illuminate on the specific role of interferon in rewiring cellular metabolism to activate immune cells and limit viral infection. This review reflects on our current understanding of the complex networking that occurs between the virus and host at the interface of cellular metabolism, with a focus on the ISGs in particular, cholesterol-25-hydroxylase (CH25H), spermidine/spermine acetyltransferase 1 (SAT1), indoleamine-2,3-dioxygenase (IDO1) and sterile alpha motif and histidine/aspartic acid domain-containing protein 1 (SAMHD1), which were recently discovered to modulate specific metabolic events and consequently deter viral infection. Full article
(This article belongs to the Special Issue Homage to Mark Wainberg)
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4604 KiB  
Review
Sustained IFN-I Expression during Established Persistent Viral Infection: A “Bad Seed” for Protective Immunity
by Xavier Dagenais-Lussier, Hamza Loucif, Armstrong Murira, Xavier Laulhé, Simona Stäger, Alain Lamarre and Julien Van Grevenynghe
Viruses 2018, 10(1), 12; https://doi.org/10.3390/v10010012 - 30 Dec 2017
Cited by 28 | Viewed by 7171
Abstract
Type I interferons (IFN-I) are one of the primary immune defenses against viruses. Similar to all other molecular mechanisms that are central to eliciting protective immune responses, IFN-I expression is subject to homeostatic controls that regulate cytokine levels upon clearing the infection. However, [...] Read more.
Type I interferons (IFN-I) are one of the primary immune defenses against viruses. Similar to all other molecular mechanisms that are central to eliciting protective immune responses, IFN-I expression is subject to homeostatic controls that regulate cytokine levels upon clearing the infection. However, in the case of established persistent viral infection, sustained elevation of IFN-I expression bears deleterious effects to the host and is today considered as the major driver of inflammation and immunosuppression. In fact, numerous emerging studies place sustained IFN-I expression as a common nexus in the pathogenesis of multiple chronic diseases including persistent infections with the human immunodeficiency virus type 1 (HIV-1), simian immunodeficiency virus (SIV), as well as the rodent-borne lymphocytic choriomeningitis virus clone 13 (LCMV clone 13). In this review, we highlight recent studies illustrating the molecular dysregulation and resultant cellular dysfunction in both innate and adaptive immune responses driven by sustained IFN-I expression. Here, we place particular emphasis on the efficacy of IFN-I receptor (IFNR) blockade towards improving immune responses against viral infections given the emerging therapeutic approach of blocking IFNR using neutralizing antibodies (Abs) in chronically infected patients. Full article
(This article belongs to the Special Issue Homage to Mark Wainberg)
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1518 KiB  
Review
Genotypic and Phylogenetic Insights on Prevention of the Spread of HIV-1 and Drug Resistance in “Real-World” Settings
by Bluma G. Brenner, Ruxandra-Ilinca Ibanescu, Isabelle Hardy and Michel Roger
Viruses 2018, 10(1), 10; https://doi.org/10.3390/v10010010 - 28 Dec 2017
Cited by 17 | Viewed by 6346
Abstract
HIV continues to spread among vulnerable heterosexual (HET), Men-having-Sex with Men (MSM) and intravenous drug user (IDU) populations, influenced by a complex array of biological, behavioral and societal factors. Phylogenetics analyses of large sequence datasets from national drug resistance testing programs reveal the [...] Read more.
HIV continues to spread among vulnerable heterosexual (HET), Men-having-Sex with Men (MSM) and intravenous drug user (IDU) populations, influenced by a complex array of biological, behavioral and societal factors. Phylogenetics analyses of large sequence datasets from national drug resistance testing programs reveal the evolutionary interrelationships of viral strains implicated in the dynamic spread of HIV in different regional settings. Viral phylogenetics can be combined with demographic and behavioral information to gain insights on epidemiological processes shaping transmission networks at the population-level. Drug resistance testing programs also reveal emergent mutational pathways leading to resistance to the 23 antiretroviral drugs used in HIV-1 management in low-, middle- and high-income settings. This article describes how genotypic and phylogenetic information from Quebec and elsewhere provide critical information on HIV transmission and resistance, Cumulative findings can be used to optimize public health strategies to tackle the challenges of HIV in “real-world” settings. Full article
(This article belongs to the Special Issue Homage to Mark Wainberg)
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2317 KiB  
Review
RNA Interference Therapies for an HIV-1 Functional Cure
by Robert J. Scarborough and Anne Gatignol
Viruses 2018, 10(1), 8; https://doi.org/10.3390/v10010008 - 27 Dec 2017
Cited by 36 | Viewed by 8784
Abstract
HIV-1 drug therapies can prevent disease progression but cannot eliminate HIV-1 viruses from an infected individual. While there is hope that elimination of HIV-1 can be achieved, several approaches to reach a functional cure (control of HIV-1 replication in the absence of drug [...] Read more.
HIV-1 drug therapies can prevent disease progression but cannot eliminate HIV-1 viruses from an infected individual. While there is hope that elimination of HIV-1 can be achieved, several approaches to reach a functional cure (control of HIV-1 replication in the absence of drug therapy) are also under investigation. One of these approaches is the transplant of HIV-1 resistant cells expressing anti-HIV-1 RNAs, proteins or peptides. Small RNAs that use RNA interference pathways to target HIV-1 replication have emerged as competitive candidates for cell transplant therapy and have been included in all gene combinations that have so far entered clinical trials. Here, we review RNA interference pathways in mammalian cells and the design of therapeutic small RNAs that use these pathways to target pathogenic RNA sequences. Studies that have been performed to identify anti-HIV-1 RNA interference therapeutics are also reviewed and perspectives on their use in combination gene therapy to functionally cure HIV-1 infection are provided. Full article
(This article belongs to the Special Issue Homage to Mark Wainberg)
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909 KiB  
Review
HTLV-1, the Other Pathogenic Yet Neglected Human Retrovirus: From Transmission to Therapeutic Treatment
by Nicolas Futsch, Renaud Mahieux and Hélène Dutartre
Viruses 2018, 10(1), 1; https://doi.org/10.3390/v10010001 - 21 Dec 2017
Cited by 63 | Viewed by 11298
Abstract
Going back to their discovery in the early 1980s, both the Human T-cell Leukemia virus type-1 (HTLV-1) and the Human Immunodeficiency Virus type-1 (HIV-1) greatly fascinated the virology scene, not only because they were the first human retroviruses discovered, but also because they [...] Read more.
Going back to their discovery in the early 1980s, both the Human T-cell Leukemia virus type-1 (HTLV-1) and the Human Immunodeficiency Virus type-1 (HIV-1) greatly fascinated the virology scene, not only because they were the first human retroviruses discovered, but also because they were associated with fatal diseases in the human population. In almost four decades of scientific research, both viruses have had different fates, HTLV-1 being often upstaged by HIV-1. However, although being very close in terms of genome organization, cellular tropism, and viral replication, HIV-1 and HTLV-1 are not completely commutable in terms of treatment, especially because of the opposite fate of the cells they infect: death versus immortalization, respectively. Nowadays, the antiretroviral therapies developed to treat HIV-1 infected individuals and to limit HIV-1 spread among the human population have a poor or no effect on HTLV-1 infected individuals, and thus, do not prevent the development of HTLV-1-associated diseases, which still lack highly efficient treatments. The present review mainly focuses on the course of HTLV-1 infection, from the initial infection of the host to diseases development and associated treatments, but also investigates HIV-1/HTLV-1 co-infection events and their impact on diseases development. Full article
(This article belongs to the Special Issue Homage to Mark Wainberg)
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677 KiB  
Review
The Th17 Lineage: From Barrier Surfaces Homeostasis to Autoimmunity, Cancer, and HIV-1 Pathogenesis
by Vanessa Sue Wacleche, Alan Landay, Jean-Pierre Routy and Petronela Ancuta
Viruses 2017, 9(10), 303; https://doi.org/10.3390/v9100303 - 19 Oct 2017
Cited by 72 | Viewed by 9454
Abstract
The T helper 17 (Th17) cells represent a subset of CD4+ T-cells with unique effector functions, developmental plasticity, and stem-cell features. Th17 cells bridge innate and adaptive immunity against fungal and bacterial infections at skin and mucosal barrier surfaces. Although Th17 cells have [...] Read more.
The T helper 17 (Th17) cells represent a subset of CD4+ T-cells with unique effector functions, developmental plasticity, and stem-cell features. Th17 cells bridge innate and adaptive immunity against fungal and bacterial infections at skin and mucosal barrier surfaces. Although Th17 cells have been extensively studied in the context of autoimmunity, their role in various other pathologies is underexplored and remains an area of open investigation. This review summarizes the history of Th17 cell discovery and the current knowledge relative to the beneficial role of Th17 cells in maintaining mucosal immunity homeostasis. We further discuss the concept of Th17 pathogenicity in the context of autoimmunity, cancer, and HIV infection, and we review the most recent discoveries on molecular mechanisms regulating HIV replication/persistence in pathogenic Th17 cells. Finally, we stress the need for novel fundamental research discovery-based Th17-specific therapeutic interventions to treat pathogenic conditions associated with Th17 abnormalities, including HIV infection. Full article
(This article belongs to the Special Issue Homage to Mark Wainberg)
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636 KiB  
Review
Current Peptide and Protein Candidates Challenging HIV Therapy beyond the Vaccine Era
by Koollawat Chupradit, Sutpirat Moonmuang, Sawitree Nangola, Kuntida Kitidee, Umpa Yasamut, Marylène Mougel and Chatchai Tayapiwatana
Viruses 2017, 9(10), 281; https://doi.org/10.3390/v9100281 - 29 Sep 2017
Cited by 19 | Viewed by 6182
Abstract
Human immunodeficiency virus (HIV) is a causative agent of acquired immune deficiency syndrome (AIDS). Highly active antiretroviral therapy (HAART) can slow down the replication of HIV-1, leading to an improvement in the survival of HIV-1-infected patients. However, drug toxicities and poor drug administration [...] Read more.
Human immunodeficiency virus (HIV) is a causative agent of acquired immune deficiency syndrome (AIDS). Highly active antiretroviral therapy (HAART) can slow down the replication of HIV-1, leading to an improvement in the survival of HIV-1-infected patients. However, drug toxicities and poor drug administration has led to the emergence of a drug-resistant strain. HIV-1 immunotherapy has been continuously developed, but antibody therapy and HIV vaccines take time to improve its efficiency and have limitations. HIV-1-specific chimeric antigen receptor (CAR)-based immunotherapy founded on neutralizing antibodies is now being developed. In HIV-1 therapy, anti-HIV chimeric antigen receptors showed promising data in the suppression of HIV-1 replication; however, autologous transfusion is still a problem. This has led to the development of effective peptides and proteins for an alternative HIV-1 treatment. In this paper, we provide a comprehensive review of potent anti-HIV-1 peptides and proteins that reveal promising therapeutic activities. The inhibitory mechanisms of each therapeutic molecule in the different stages of the HIV-1 life cycle will be discussed herein. Full article
(This article belongs to the Special Issue Homage to Mark Wainberg)
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1047 KiB  
Brief Report
Sophoraflavenone G Restricts Dengue and Zika Virus Infection via RNA Polymerase Interference
by Alexandre Sze, David Olagnier, Samar Bel Hadj, Xiaoying Han, Xiao Hong Tian, Hong-Tao Xu, Long Yang, Qingwen Shi, Penghua Wang, Mark A. Wainberg, Jian Hui Wu and Rongtuan Lin
Viruses 2017, 9(10), 287; https://doi.org/10.3390/v9100287 - 03 Oct 2017
Cited by 11 | Viewed by 4673
Abstract
Flaviviruses including Zika, Dengue and Hepatitis C virus cause debilitating diseases in humans, and the former are emerging as global health concerns with no antiviral treatments. We investigated Sophora Flavecens, used in Chinese medicine, as a source for antiviral compounds. We isolated [...] Read more.
Flaviviruses including Zika, Dengue and Hepatitis C virus cause debilitating diseases in humans, and the former are emerging as global health concerns with no antiviral treatments. We investigated Sophora Flavecens, used in Chinese medicine, as a source for antiviral compounds. We isolated Sophoraflavenone G and found that it inhibited Hepatitis C replication, but not Sendai or Vesicular Stomatitis Virus. Pre- and post-infection treatments demonstrated anti-flaviviral activity against Dengue and Zika virus, via viral RNA polymerase inhibition. These data suggest that Sophoraflavenone G represents a promising candidate regarding anti-Flaviviridae research. Full article
(This article belongs to the Special Issue Homage to Mark Wainberg)
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