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Viruses
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Diversity and Evolution of HIV and HCV
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Diversity and Evolution of HIV and HCV

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

Deadline for manuscript submissions: closed (15 November 2020) | Viewed by 31777

Special Issue Editor

Dr. Miguel A. Martínez

E-Mail Website
Guest Editor
IrsiCaixa, Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona (UAB), 08916 Badalona, Spain
Interests: My research interests are focused in understanding the molecular mechanisms implicated in human viruses pathogenesis. In the last two decades, I have being studying how the genetic variability of HIV-1 and HCV has influenced virus pathogenesis, immunogenicity and response to antiviral therapy. Recently, I have explored how synonymous codon mutations impact HIV-1 protein expression and virus replication capacity. Codon or codon pair biases and HIV-1 RNA dinucleotide frequencies (e.g., CpG/UpA) affect host innate response, virus latency and pathogenesis (reviewed in Jordan-Paiz, Franco and Martinez, Frontiers in Microbiology 2021; Martinez et al Nucleic Acids Research 2019; Martinez et al Trends in Microbiology 2016).
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Human immunodeficiency virus (HIV) and hepatitis C virus (HCV) are two highly variable RNA viruses that cause chronic infections in humans. Although HCV likely preceded the AIDS epidemic by some decades, the global spread of both viruses is a relatively recent event. Nevertheless, since their introduction into the human population, both viruses have greatly diversified. Importantly, millions of individuals have been infected or coinfected by these two viruses, with corresponding effects on mortality and morbidity. The diversity and genetic structure of HIV and HCV populations has determined their rapid adaptation and spread. HIV and HCV diversity has not only impacted their spread, but also their pathogenesis and therapeutics. Nowadays, there are good antivirals to combat HIV and HCV. However, in the midterm, no vaccines against these two viruses are likely to be available for clinical use. Moreover, HIV has no curative therapy. This Special Issue will focus on how HIV and HCV diversity has impacted the evolution of these viruses as well as on how virus diversity will shape their further spread, pathogenesis, and therapeutics.

Dr. Miguel A. Martínez
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
  • HCV
  • genetic and phenotypic diversity
  • spread and epidemiology
  • pathogenesis
  • therapeutics
  • antiviral development and resistance
  • vaccine
  • eradication

Published Papers (10 papers)

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Editorial

Jump to: Research, Review

1 pages, 149 KiB  
Editorial
Diversity and Evolution of HIV and HCV
by Miguel Angel Martinez
Viruses 2021, 13(4), 642; https://0-doi-org.brum.beds.ac.uk/10.3390/v13040642 - 09 Apr 2021
Cited by 1 | Viewed by 1741
Abstract
In this Special Issue focused on human immunodeficiency virus (HIV) and hepatitis C virus (HCV) diversity and evolution, we can find good examples of how the genetic variability of these two viruses is impacting their spread, pathogenesis, and therapeutics [...] Full article
(This article belongs to the Special Issue Diversity and Evolution of HIV and HCV)

Research

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15 pages, 2687 KiB  
Article
Comparative Analysis of Within-Host Mutation Patterns and Diversity of Hepatitis C Virus Subtypes 1a, 1b, and 3a
by Kaho H. Tisthammer, Weiyan Dong, Jeffrey B. Joy and Pleuni S. Pennings
Viruses 2021, 13(3), 511; https://0-doi-org.brum.beds.ac.uk/10.3390/v13030511 - 19 Mar 2021
Cited by 1 | Viewed by 2121
Abstract
Understanding within-host evolution is critical for predicting viral evolutionary outcomes, yet such studies are currently lacking due to difficulty involving human subjects. Hepatitis C virus (HCV) is an RNA virus with high mutation rates. Its complex evolutionary dynamics and extensive genetic diversity are [...] Read more.
Understanding within-host evolution is critical for predicting viral evolutionary outcomes, yet such studies are currently lacking due to difficulty involving human subjects. Hepatitis C virus (HCV) is an RNA virus with high mutation rates. Its complex evolutionary dynamics and extensive genetic diversity are demonstrated in over 67 known subtypes. In this study, we analyzed within-host mutation frequency patterns of three HCV subtypes, using a large number of samples obtained from treatment-naïve participants by next-generation sequencing. We report that overall mutation frequency patterns are similar among subtypes, yet subtype 3a consistently had lower mutation frequencies and nucleotide diversity, while subtype 1a had the highest. We found that about 50% of genomic sites are highly conserved across subtypes, which are likely under strong purifying selection. We also compared within-host and between-host selective pressures, which revealed that Hyper Variable Region 1 within hosts was under positive selection, but was under slightly negative selection between hosts, which indicates that many mutations created within hosts are removed during the transmission bottleneck. Examining the natural prevalence of known resistance-associated variants showed their consistent existence in the treatment-naïve participants. These results provide insights into the differences and similarities among HCV subtypes that may be used to develop and improve HCV therapies. Full article
(This article belongs to the Special Issue Diversity and Evolution of HIV and HCV)
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14 pages, 1713 KiB  
Article
HIV-1 Gag-Pol Sequences from Ugandan Early Infections Reveal Sequence Variants Associated with Elevated Replication Capacity
by Anne Kapaata, Sheila N. Balinda, Rui Xu, Maria G. Salazar, Kimberly Herard, Kelsie Brooks, Kato Laban, Jonathan Hare, Dario Dilernia, Anatoli Kamali, Eugene Ruzagira, Freddie Mukasa, Jill Gilmour, Jesus F. Salazar-Gonzalez, Ling Yue, Matthew Cotten, Eric Hunter and Pontiano Kaleebu
Viruses 2021, 13(2), 171; https://0-doi-org.brum.beds.ac.uk/10.3390/v13020171 - 23 Jan 2021
Cited by 2 | Viewed by 2571
Abstract
The ability to efficiently establish a new infection is a critical property for human immunodeficiency virus type 1 (HIV-1). Although the envelope protein of the virus plays an essential role in receptor binding and internalization of the infecting virus, the structural proteins, the [...] Read more.
The ability to efficiently establish a new infection is a critical property for human immunodeficiency virus type 1 (HIV-1). Although the envelope protein of the virus plays an essential role in receptor binding and internalization of the infecting virus, the structural proteins, the polymerase and the assembly of new virions may also play a role in establishing and spreading viral infection in a new host. We examined Ugandan viruses from newly infected patients and focused on the contribution of the Gag-Pol genes to replication capacity. A panel of Gag-Pol sequences generated using single genome amplification from incident HIV-1 infections were cloned into a common HIV-1 NL4.3 pol/env backbone and the influence of Gag-Pol changes on replication capacity was monitored. Using a novel protein domain approach, we then documented diversity in the functional protein domains across the Gag-Pol region and identified differences in the Gag-p6 domain that were frequently associated with higher in vitro replication. Full article
(This article belongs to the Special Issue Diversity and Evolution of HIV and HCV)
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12 pages, 1125 KiB  
Article
Increased HIV Subtype Diversity Reflecting Demographic Changes in the HIV Epidemic in New South Wales, Australia
by Francesca Di Giallonardo, Angie N. Pinto, Phillip Keen, Ansari Shaik, Alex Carrera, Hanan Salem, Christine Selvey, Steven J. Nigro, Neil Fraser, Karen Price, Joanne Holden, Frederick J. Lee, Dominic E. Dwyer, Benjamin R. Bavinton, Andrew E. Grulich, Anthony D. Kelleher and on behalf of the NSW HIV Prevention Partnership Project
Viruses 2020, 12(12), 1402; https://0-doi-org.brum.beds.ac.uk/10.3390/v12121402 - 06 Dec 2020
Cited by 3 | Viewed by 2237
Abstract
Changes over time in HIV-1 subtype diversity within a population reflect changes in factors influencing the development of local epidemics. Here we report on the genetic diversity of 2364 reverse transcriptase sequences from people living with HIV-1 in New South Wales (NSW) notified [...] Read more.
Changes over time in HIV-1 subtype diversity within a population reflect changes in factors influencing the development of local epidemics. Here we report on the genetic diversity of 2364 reverse transcriptase sequences from people living with HIV-1 in New South Wales (NSW) notified between 2004 and 2018. These data represent >70% of all new HIV-1 notifications in the state over this period. Phylogenetic analysis was performed to identify subtype-specific transmission clusters. Subtype B and non-B infections differed across all demographics analysed (p < 0.001). We found a strong positive association for infections among females, individuals not born in Australia or reporting heterosexual transmission being of non-B origin. Further, we found an overall increase in non-B infections among men who have sex with men from 50 to 79% in the last 10 years. However, we also found differences between non-B subtypes; heterosexual transmission was positively associated with subtype C only. In addition, the majority of subtype B infections were associated with clusters, while the majority of non-B infections were singletons. However, we found seven non-B clusters (≥5 sequences) indicative of local ongoing transmission. In conclusion, we present how the HIV-1 epidemic has changed over time in NSW, becoming more heterogeneous with distinct subtype-specific demographic associations. Full article
(This article belongs to the Special Issue Diversity and Evolution of HIV and HCV)
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9 pages, 2338 KiB  
Article
Phylodynamic Analysis and Implication of HCV Genotype 4 Variability on Antiviral Drug Response and T-Cell Recognition
by Giuseppina Maria Elena Colomba, Noemi Urone, Vito di Marco and Donatella Ferraro
Viruses 2020, 12(12), 1363; https://0-doi-org.brum.beds.ac.uk/10.3390/v12121363 - 28 Nov 2020
Cited by 5 | Viewed by 1609
Abstract
Therapies for HCV care could change the prevalence and the geographic distribution of genotypes due to differences in Sustained Virologic Response (SVR). In this scenario, uncommon genotypes/subtypes, such as genotype 4, could spread from high-risk groups, replacing genotypes eradicated by antiviral drugs. Genotype [...] Read more.
Therapies for HCV care could change the prevalence and the geographic distribution of genotypes due to differences in Sustained Virologic Response (SVR). In this scenario, uncommon genotypes/subtypes, such as genotype 4, could spread from high-risk groups, replacing genotypes eradicated by antiviral drugs. Genotype eradication is also strongly influenced by the CD8+ T cell response. In this study, the genetic variability in HCV genotype 4 strains obtained from a cohort of 67 patients naïve to DAA therapy was evaluated. We found that the presence of resistance-associated substitutions (RAS) was able to affect drug responses. Next, using a prediction tool, viral mutations were identified by their ability, or lack thereof, to reduce the binding affinity with HLA, which affects T cell recognition. The Bayesian coalescent analysis suggested two different circulation clusters, one in risk groups (IDUs and MSM) and the other due to migration flows, dated to 1940 and 1915, respectively. Most of the RAS overlapped with HLA and a lack of binding mutations was observed in 96% of strains. This study describes the introduction of HCV genotype 4 in a region of the Mediterranean basin and evaluates how HCV genotype 4’s genetic variability could affect the response of antiviral drugs and CD8+ T cell recognition. Full article
(This article belongs to the Special Issue Diversity and Evolution of HIV and HCV)
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11 pages, 3002 KiB  
Article
Site-Specific Evolutionary Rate Shifts in HIV-1 and SIV
by Maoz Gelbart and Adi Stern
Viruses 2020, 12(11), 1312; https://0-doi-org.brum.beds.ac.uk/10.3390/v12111312 - 16 Nov 2020
Cited by 4 | Viewed by 2836
Abstract
Site-specific evolutionary rate shifts are defined as protein sites, where the rate of substitution has changed dramatically across the phylogeny. With respect to a given clade, sites may either undergo a rate acceleration or a rate deceleration, reflecting a site that was conserved [...] Read more.
Site-specific evolutionary rate shifts are defined as protein sites, where the rate of substitution has changed dramatically across the phylogeny. With respect to a given clade, sites may either undergo a rate acceleration or a rate deceleration, reflecting a site that was conserved and became variable, or vice-versa, respectively. Sites displaying such a dramatic evolutionary change may point to a loss or gain of function at the protein site, reflecting adaptation, or they may indicate epistatic interactions among sites. Here, we analyzed full genomes of HIV and SIV-1 and identified 271 rate-shifting sites along the HIV-1/SIV phylogeny. The majority of rate shifts occurred at long branches, often corresponding to cross-species transmission branches. We noted that in most proteins, the number of rate accelerations and decelerations was equal, and we suggest that this reflects epistatic interactions among sites. However, several accessory proteins were enriched for either accelerations or decelerations, and we suggest that this may be a signature of adaptation to new hosts. Interestingly, the non-pandemic HIV-1 group O clade exhibited a substantially higher number of rate-shift events than the pandemic group M clade. We propose that this may be a reflection of the height of the species barrier between gorillas and humans versus chimpanzees and humans. Our results provide a genome-wide view of the constraints operating on proteins of HIV-1 and SIV. Full article
(This article belongs to the Special Issue Diversity and Evolution of HIV and HCV)
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15 pages, 2768 KiB  
Article
Darunavir-Resistant HIV-1 Protease Constructs Uphold a Conformational Selection Hypothesis for Drug Resistance
by Zhanglong Liu, Trang T. Tran, Linh Pham, Lingna Hu, Kyle Bentz, Daniel A. Savin and Gail E. Fanucci
Viruses 2020, 12(11), 1275; https://0-doi-org.brum.beds.ac.uk/10.3390/v12111275 - 08 Nov 2020
Cited by 8 | Viewed by 2492
Abstract
Multidrug resistance continues to be a barrier to the effectiveness of highly active antiretroviral therapy in the treatment of human immunodeficiency virus 1 (HIV-1) infection. Darunavir (DRV) is a highly potent protease inhibitor (PI) that is oftentimes effective when drug resistance has emerged [...] Read more.
Multidrug resistance continues to be a barrier to the effectiveness of highly active antiretroviral therapy in the treatment of human immunodeficiency virus 1 (HIV-1) infection. Darunavir (DRV) is a highly potent protease inhibitor (PI) that is oftentimes effective when drug resistance has emerged against first-generation inhibitors. Resistance to darunavir does evolve and requires 10–20 amino acid substitutions. The conformational landscapes of six highly characterized HIV-1 protease (PR) constructs that harbor up to 19 DRV-associated mutations were characterized by distance measurements with pulsed electron double resonance (PELDOR) paramagnetic resonance spectroscopy, namely double electron–electron resonance (DEER). The results show that the accumulated substitutions alter the conformational landscape compared to PI-naïve protease where the semi-open conformation is destabilized as the dominant population with open-like states becoming prevalent in many cases. A linear correlation is found between values of the DRV inhibition parameter Ki and the open-like to closed-state population ratio determined from DEER. The nearly 50% decrease in occupancy of the semi-open conformation is associated with reduced enzymatic activity, characterized previously in the literature. Full article
(This article belongs to the Special Issue Diversity and Evolution of HIV and HCV)
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Review

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20 pages, 4410 KiB  
Review
Population Disequilibrium as Promoter of Adaptive Explorations in Hepatitis C Virus
by Carlos García-Crespo, Isabel Gallego, María Eugenia Soria, Ana Isabel de Ávila, Brenda Martínez-González, Lucía Vázquez-Sirvent, Rebeca Lobo-Vega, Elena Moreno, Jordi Gómez, Carlos Briones, Josep Gregori, Josep Quer, Esteban Domingo and Celia Perales
Viruses 2021, 13(4), 616; https://0-doi-org.brum.beds.ac.uk/10.3390/v13040616 - 03 Apr 2021
Cited by 5 | Viewed by 2678
Abstract
Replication of RNA viruses is characterized by exploration of sequence space which facilitates their adaptation to changing environments. It is generally accepted that such exploration takes place mainly in response to positive selection, and that further diversification is boosted by modifications of virus [...] Read more.
Replication of RNA viruses is characterized by exploration of sequence space which facilitates their adaptation to changing environments. It is generally accepted that such exploration takes place mainly in response to positive selection, and that further diversification is boosted by modifications of virus population size, particularly bottleneck events. Our recent results with hepatitis C virus (HCV) have shown that the expansion in sequence space of a viral clone continues despite prolonged replication in a stable cell culture environment. Diagnosis of the expansion was based on the quantification of diversity indices, the occurrence of intra-population mutational waves (variations in mutant frequencies), and greater individual residue variations in mutant spectra than those anticipated from sequence alignments in data banks. In the present report, we review our previous results, and show additionally that mutational waves in amplicons from the NS5A-NS5B-coding region are equally prominent during HCV passage in the absence or presence of the mutagenic nucleotide analogues favipiravir or ribavirin. In addition, by extending our previous analysis to amplicons of the NS3- and NS5A-coding region, we provide further evidence of the incongruence between amino acid conservation scores in mutant spectra from infected patients and in the Los Alamos National Laboratory HCV data banks. We hypothesize that these observations have as a common origin a permanent state of HCV population disequilibrium even upon extensive viral replication in the absence of external selective constraints or changes in population size. Such a persistent disequilibrium—revealed by the changing composition of the mutant spectrum—may facilitate finding alternative mutational pathways for HCV antiviral resistance. The possible significance of our model for other genetically variable viruses is discussed. Full article
(This article belongs to the Special Issue Diversity and Evolution of HIV and HCV)
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17 pages, 1298 KiB  
Review
Therapy Implications of Hepatitis C Virus Genetic Diversity
by Miguel Angel Martinez and Sandra Franco
Viruses 2021, 13(1), 41; https://0-doi-org.brum.beds.ac.uk/10.3390/v13010041 - 29 Dec 2020
Cited by 24 | Viewed by 6700
Abstract
Hepatitis C virus (HCV) is an important human pathogen with a high chronicity rate. An estimated 71 million people worldwide are living with chronic hepatitis C (CHC) infection, which carries the risk of progression to hepatic fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Similar [...] Read more.
Hepatitis C virus (HCV) is an important human pathogen with a high chronicity rate. An estimated 71 million people worldwide are living with chronic hepatitis C (CHC) infection, which carries the risk of progression to hepatic fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Similar to other RNA viruses, HCV has a high rate of genetic variability generated by its high mutation rate and the actions of evolutionary forces over time. There are two levels of HCV genetic variability: intra-host variability, characterized by the distribution of HCV mutant genomes present in an infected individual, and inter-host variability, represented by the globally circulating viruses that give rise to different HCV genotypes and subtypes. HCV genetic diversity has important implications for virus persistence, pathogenesis, immune responses, transmission, and the development of successful vaccines and antiviral strategies. Here we will discuss how HCV genetic heterogeneity impacts viral spread and therapeutic control. Full article
(This article belongs to the Special Issue Diversity and Evolution of HIV and HCV)
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22 pages, 3534 KiB  
Review
The Determination of HIV-1 RT Mutation Rate, Its Possible Allosteric Effects, and Its Implications on Drug Resistance
by Joshua Yi Yeo, Ghin-Ray Goh, Chinh Tran-To Su and Samuel Ken-En Gan
Viruses 2020, 12(3), 297; https://0-doi-org.brum.beds.ac.uk/10.3390/v12030297 - 09 Mar 2020
Cited by 20 | Viewed by 5544
Abstract
The high mutation rate of the human immunodeficiency virus type 1 (HIV-1) plays a major role in treatment resistance, from the development of vaccines to therapeutic drugs. In addressing the crux of the issue, various attempts to estimate the mutation rate of HIV-1 [...] Read more.
The high mutation rate of the human immunodeficiency virus type 1 (HIV-1) plays a major role in treatment resistance, from the development of vaccines to therapeutic drugs. In addressing the crux of the issue, various attempts to estimate the mutation rate of HIV-1 resulted in a large range of 10−5–10−3 errors/bp/cycle due to the use of different types of investigation methods. In this review, we discuss the different assay methods, their findings on the mutation rates of HIV-1 and how the locations of mutations can be further analyzed for their allosteric effects to allow for new inhibitor designs. Given that HIV is one of the fastest mutating viruses, it serves as a good model for the comprehensive study of viral mutations that can give rise to a more horizontal understanding towards overall viral drug resistance as well as emerging viral diseases. Full article
(This article belongs to the Special Issue Diversity and Evolution of HIV and HCV)
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