scholarly journals Long-term experimental evolution of HIV-1 reveals effects of environment and mutational history

PLoS Biology ◽  
2020 ◽  
Vol 18 (12) ◽  
pp. e3001010
Author(s):  
Eva Bons ◽  
Christine Leemann ◽  
Karin J. Metzner ◽  
Roland R. Regoes
Keyword(s):  
Evolutionary Dynamics ◽  
Fitness Landscape ◽  
Large Population ◽  
Parallel Evolution ◽  
Cell Types ◽  
Drug Pressure ◽  
Evolutionary Paths ◽  
The Impact ◽  
Hiv 1

An often-returning question for not only HIV-1, but also other organisms, is how predictable evolutionary paths are. The environment, mutational history, and random processes can all impact the exact evolutionary paths, but to which extent these factors contribute to the evolutionary dynamics of a particular system is an open question. Especially in a virus like HIV-1, with a large mutation rate and large population sizes, evolution is expected to be highly predictable if the impact of environment and history is low, and evolution is not neutral. We investigated the effect of environment and mutational history by analyzing sequences from a long-term evolution experiment, in which HIV-1 was passaged on 2 different cell types in 8 independent evolutionary lines and 8 derived lines, 4 of which involved a switch of the environment. The experiments lasted for 240–300 passages, corresponding to approximately 400–600 generations or almost 3 years. The sequences show signs of extensive parallel evolution—the majority of mutations that are shared between independent lines appear in both cell types, but we also find that both environment and mutational history significantly impact the evolutionary paths. We conclude that HIV-1 evolution is robust to small changes in the environment, similar to a transmission event in the absence of an immune response or drug pressure. We also find that the fitness landscape of HIV-1 is largely smooth, although we find some evidence for both positive and negative epistatic interactions between mutations.

scholarly journals A Dual Infection/Competition Assay Shows a Correlation between Ex Vivo Human Immunodeficiency Virus Type 1 Fitness and Disease Progression

2000 ◽  
Vol 74 (19) ◽  
pp. 9222-9233 ◽  
Author(s):  
Miguel E. Quiñones-Mateu ◽  
Sarah C. Ball ◽  
Andre J. Marozsan ◽  
Vincent S. Torre ◽  
Jamie L. Albright ◽  
...  
Keyword(s):  
Immune Response ◽  
Human Immunodeficiency Virus ◽  
Disease Progression ◽  
Ex Vivo ◽  
Relative Fitness ◽  
Immunodeficiency Virus ◽  
The Impact ◽  
Hiv 1

ABSTRACT This study was designed to examine the impact of human immunodeficiency virus type 1 (HIV-1) fitness on disease progression through the use of a dual competition/heteroduplex tracking assay (HTA). Despite numerous studies on the impact of HIV-1 diversity and HIV-specific immune response on disease progression, we still do not have a firm understanding of the long-term pathogenesis of this virus. Strong and early CD8-positive cytotoxic T-cell and CD4-positive T-helper cell responses directed toward HIV-infected cells appear to curb HIV pathogenesis. However, the rate at which the virus infects the CD4+ T-cell population and possibly destroys the HIV-specific immune response may also alter the rate of disease progression. For HIV-1 fitness studies, we established conditions for dual HIV-1 infections of peripheral blood mononuclear cells (PBMC) and a sensitive HTA to measure relative virus production. A pairwise comparison was then performed to estimate the relative fitness of various non-syncytium-inducing/CCR5-tropic (NSI/R5) and syncytium-inducing/CXCR4-tropic (SI/X4) HIV-1 isolates. Four HIV-1 strains (two NSI/R5 and two SI/X4) with moderate ex vivo fitness were then selected as controls and competed against primary HIV-1 isolates from an HIV-infected Belgian cohort. HIV-1 isolates from long-term survivors (LTS) were outcompeted by control strains and were significantly less fit than HIV-1 isolates from patients with accelerated progression to AIDS (PRO). In addition, NSI/R5 HIV-1 isolates from PRO overgrew control SI/X4 strains, suggesting that not all SI/X4 HIV-1 isolates replicate more efficiently than all NSI/R5 isolates. Finally, there were strong, independent correlations between viral load and the total relative fitness values of HIV-1 isolates from PRO (r = 0.84, P = 0.033) and LTS (r = 0.86, P = 0.028). Separation of the PRO and LTS plots suggest that HIV-1 fitness together with viral load may be a strong predictor for the rate of disease progression.

scholarly journals Constrained mutational sampling of amino acids in HIV-1 protease evolution

2018 ◽  
Author(s):  
Jeffrey I. Boucher ◽  
Troy W. Whitfield ◽  
Ann Dauphin ◽  
Gily Nachum ◽  
Carl Hollins ◽  
...  
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Genetic Code ◽  
Protein Sequence ◽  
Fitness Landscape ◽  
Sequence Evolution ◽  
Single Mutation ◽  
The Impact ◽  
Protein Sequence Evolution ◽  
Hiv 1

AbstractThe evolution of HIV-1 protein sequences should be governed by a combination of factors including nucleotide mutational probabilities, the genetic code, and fitness. The impact of these factors on protein sequence evolution are interdependent, making it challenging to infer the individual contribution of each factor from phylogenetic analyses alone. We investigated the protein sequence evolution of HIV-1 by determining an experimental fitness landscape of all individual amino acid changes in protease. We compared our experimental results to the frequency of protease variants in a publicly available dataset of 32,163 sequenced isolates from drug-naïve individuals. The most common amino acids in sequenced isolates supported robust experimental fitness, indicating that the experimental fitness landscape captured key features of selection acting on protease during viral infections of hosts. Amino acid changes requiring multiple mutations from the likely ancestor were slightly less likely to support robust experimental fitness than single mutations, consistent with the genetic code favoring chemically conservative amino acid changes. Amino acids that were common in sequenced isolates were predominantly accessible by single mutations from the likely protease ancestor. Multiple mutations commonly observed in isolates were accessible by mutational walks with highly fit single mutation intermediates. Our results indicate that the prevalence of multiple base mutations in HIV-1 protease is strongly influenced by mutational sampling.

scholarly journals Parallel evolution of influenza across multiple spatiotemporal scales

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Katherine S Xue ◽  
Terry Stevens-Ayers ◽  
Angela P Campbell ◽  
Janet A Englund ◽  
Steven A Pergam ◽  
...  
Keyword(s):  
Evolutionary Dynamics ◽  
De Novo ◽  
Parallel Evolution ◽  
Global Scale ◽  
De Novo Mutations ◽  
Small Set ◽  
Spatiotemporal Scales ◽  
H3n2 Influenza ◽  
Multiple Patients

Viral variants that arise in the global influenza population begin as de novo mutations in single infected hosts, but the evolutionary dynamics that transform within-host variation to global genetic diversity are poorly understood. Here, we demonstrate that influenza evolution within infected humans recapitulates many evolutionary dynamics observed at the global scale. We deep-sequence longitudinal samples from four immunocompromised patients with long-term H3N2 influenza infections. We find parallel evolution across three scales: within individual patients, in different patients in our study, and in the global influenza population. In hemagglutinin, a small set of mutations arises independently in multiple patients. These same mutations emerge repeatedly within single patients and compete with one another, providing a vivid clinical example of clonal interference. Many of these recurrent within-host mutations also reach a high global frequency in the decade following the patient infections. Our results demonstrate surprising concordance in evolutionary dynamics across multiple spatiotemporal scales.

scholarly journals Sarcoma as Second Cancer in a Childhood Cancer Survivor: Case Report, Large Population Analysis and Literature Review

Medicina ◽  
2020 ◽  
Vol 56 (5) ◽  
pp. 224 ◽  
Author(s):  
Thinh H. Nguyen ◽  
Monish Ram Makena ◽  
Siddhartha Yavvari ◽  
Maninder Kaur ◽  
Teresia Pham ◽  
...  
Keyword(s):  
Literature Review ◽  
Cancer Survivors ◽  
Pediatric Cancer ◽  
Population Analysis ◽  
Large Population ◽  
Primary Cancer ◽  
Second Cancer ◽  
Pediatric Cancer Survivors ◽  
The Impact

The majority of pediatric patients are cured of their primary cancer with current advanced developments in pediatric cancer therapy. However, survivors often experience long-term complications from therapies for primary cancer. The delayed mortality rate has been decreasing with the effort to reduce the therapeutic exposure of patients with pediatric cancers. Our study investigates the incidence of sarcoma as second cancer in pediatric cancer survivors. We present a 9-year-old male who survived embryonal hepatoblastoma diagnosed at 22 months of age. At 4.5 years of age, he presented with a non-metastatic primitive neuroectodermal tumor (PNET) of the left submandibular area. He has no evidence of recurrence of either cancer for 51 months after finishing all chemotherapy and radiotherapy. We used the Surveillance, Epidemiology, and End Results (SEER) database to identify the current rate of second sarcomas in pediatric cancer survivors. Our literature review and large population analysis emphasize the impact of sarcoma as a second malignancy and provide help to physicians caring for pediatric cancer survivors.

Effect of L-Carnitine on Human Immunodeficiency Virus-1 Infection-Associated Apoptosis: A Pilot Study

Blood ◽  
1998 ◽  
Vol 91 (10) ◽  
pp. 3817-3824 ◽  
Author(s):  
Sonia Moretti ◽  
Edoardo Alesse ◽  
Luisa Di Marzio ◽  
Francesca Zazzeroni ◽  
Barbara Ruggeri ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Fas Ligand ◽  
Cd4 Counts ◽  
Immunodeficiency Virus ◽  
The Impact ◽  
Ceramide Production ◽  
Hiv 1

Abstract The Fas/Fas ligand system is involved in uncontrolled apoptosis, which ultimately leads to the loss of T lymphocytes in human immunodeficiency virus (HIV)-infected individuals. The signal transduced by Fas receptor involves the activation of an acidic sphingomyelinase, sphingomyelin breakdown, and ceramide production. Our recent reports have shown that L-carnitine inhibits Fas-induced apoptosis and ceramide production both in vitro and in vivo. The aim of this study was to study, in a preliminary fashion, the impact of long-term L-carnitine administration on CD4 and CD8 absolute counts, rate, and apoptosis in HIV-1–infected subjects. The generation of cell-associated ceramide and HIV-1 viremia was also investigated. Eleven, asymptomatic, HIV-1–infected subjects, who refused any antiretroviral treatment despite experiencing a progressive decline of CD4 counts, were treated with daily infusions of L-carnitine (6 g) for 4 months. Immunologic and virologic measures and safety were monitored at the start of the treatment and then on days 15, 30, 90, and 150. L-carnitine therapy resulted in an increase of absolute CD4 counts, which was statistically significant on day 90 and 150 (P = .010 and P = .019, respectively). A positive, not significant trend was also observed even in the change in absolute counts of CD8 lymphocytes. L-carnitine therapy also led to a drop in the frequency of apoptotic CD4 and CD8 lymphocytes. This reduction occurred gradually, but changes in actual values between each time point and baseline were strongly significant (P = .001 at the end of the study compared with the baseline). A strong reduction (P = .001) in cell-associated ceramide levels was found at the end of the study. In general, HIV-1 viremia increased slightly. No toxicity related to L-carnitine therapy was observed and dose reductions were not necessary. In HIV-1–infected subjects, long-term infusions of L-carnitine produced substantial increases in the rate and absolute counts of CD4 and, to a lesser degree, of CD8 lymphocytes. This was paralleled by a reduced frequency of apoptotic cells of both subgroups and a decline in the levels of ceramide. No clinically relevant change of HIV-1 viremia was observed.

scholarly journals Heritability of the HIV-1 reservoir size and decay under long-term suppressive ART

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Chenjie Wan ◽  
◽  
Nadine Bachmann ◽  
Venelin Mitov ◽  
François Blanquart ◽  
...  
Keyword(s):  
Viral Genome ◽  
Genetic Factors ◽  
Significant Fraction ◽  
Genome Sequences ◽  
Subtype B ◽  
Tentative Evidence ◽  
Full Length Genome ◽  
The Impact ◽  
Hiv 1

Abstract The HIV-1 reservoir is the major hurdle to curing HIV-1. However, the impact of the viral genome on the HIV-1 reservoir, i.e. its heritability, remains unknown. We investigate the heritability of the HIV-1 reservoir size and its long-term decay by analyzing the distribution of those traits on viral phylogenies from both partial-pol and viral near full-length genome sequences. We use a unique nationwide cohort of 610 well-characterized HIV-1 subtype-B infected individuals on suppressive ART for a median of 5.4 years. We find that a moderate but significant fraction of the HIV-1 reservoir size 1.5 years after the initiation of ART is explained by genetic factors. At the same time, we find more tentative evidence for the heritability of the long-term HIV-1 reservoir decay. Our findings indicate that viral genetic factors contribute to the HIV-1 reservoir size and hence the infecting HIV-1 strain may affect individual patients’ hurdle towards a cure.

scholarly journals The impact of antiretroviral therapy on population-level virulence evolution of HIV-1

2015 ◽  
Vol 12 (113) ◽  
pp. 20150888 ◽  
Author(s):  
Hannah E. Roberts ◽  
Philip J. R. Goulder ◽  
Angela R. McLean
Keyword(s):  
Antiretroviral Therapy ◽  
Deterministic Model ◽  
Population Level ◽  
Threshold Condition ◽  
Virulence Evolution ◽  
Downward Pressure ◽  
The Individual ◽  
The Impact ◽  
Hiv 1

In HIV-infected patients, an individual's set point viral load (SPVL) strongly predicts disease progression. Some think that SPVL is evolving, indicating that the virulence of the virus may be changing, but the data are not consistent. In addition, the widespread use of antiretroviral therapy (ART) has the potential to drive virulence evolution. We develop a simple deterministic model designed to answer the following questions: what are the expected patterns of virulence change in the initial decades of an epidemic? Could administration of ART drive changes in virulence evolution and, what is the potential size and direction of this effect? We find that even without ART we would not expect monotonic changes in average virulence. Transient decreases in virulence following the peak of an epidemic are not necessarily indicative of eventual evolution to avirulence. In the short term, we would expect widespread ART to cause limited downward pressure on virulence. In the long term, the direction of the effect is determined by a threshold condition, which we define. We conclude that, given the surpassing benefits of ART to the individual and in reducing onward transmission, virulence evolution considerations need have little bearing on how we treat.

scholarly journals Optimized Culture Conditions for Improved Growth and Functional Differentiation of Mouse and Human Colon Organoids

2021 ◽  
Vol 11 ◽  
Author(s):  
Sarah S. Wilson ◽  
Martha Mayo ◽  
Terry Melim ◽  
Heather Knight ◽  
Lori Patnaude ◽  
...  
Keyword(s):  
Epithelial Cell ◽  
Current Knowledge ◽  
Human Colon ◽  
Cell Types ◽  
Functional Differentiation ◽  
Culture Conditions ◽  
Conditioned Media ◽  
Term Survival ◽  
The Impact

Background & AimsDiligent side-by-side comparisons of how different methodologies affect growth efficiency and quality of intestinal colonoids have not been performed leaving a gap in our current knowledge. Here, we summarize our efforts to optimize culture conditions for improved growth and functional differentiation of mouse and human colon organoids.MethodsMouse and human colon organoids were grown in four different media. Media-dependent long-term growth was measured by quantifying surviving organoids via imaging and a cell viability readout over five passages. The impact of diverse media on differentiation was assessed by quantifying the number of epithelial cell types using markers for enterocytes, stem cells, Goblet cells, and enteroendocrine cells by qPCR and histology upon removal of growth factors.ResultsIn contrast to Wnt3a-conditioned media, media supplemented with recombinant Wnt3a alone did not support long-term survival of human or mouse colon organoids. Mechanistically, this observation can be attributed to the fact that recombinant Wnt3a did not support stem cell survival or proliferation as demonstrated by decreased LGR5 and Ki67 expression. When monitoring expression of markers for epithelial cell types, the highest level of organoid differentiation was observed after combined removal of Wnt3a, Noggin, and R-spondin from Wnta3a-conditioned media cultures.ConclusionOur study defined Wnt3a-containing conditioned media as optimal for growth and survival of human and mouse organoids. Furthermore, we established that the combined removal of Wnt3a, Noggin, and R-spondin results in optimal differentiation. This study provides a step forward in optimizing conditions for intestinal organoid growth to improve standardization and reproducibility of this model platform.

scholarly journals Subunit-Selective Mutational Analysis and Tissue Culture Evaluations of the Interactions of the E138K and M184I Mutations in HIV-1 Reverse Transcriptase

2012 ◽  
Vol 86 (16) ◽  
pp. 8422-8431 ◽  
Author(s):  
Hong-Tao Xu ◽  
Maureen Oliveira ◽  
Peter K. Quashie ◽  
Matthew McCallum ◽  
Yingshan Han ◽  
...  
Keyword(s):  
Tissue Culture ◽  
Reverse Transcriptase ◽  
Evolutionary Dynamics ◽  
Mutational Analysis ◽  
Transcriptase Inhibitor ◽  
Rnase H ◽  
Viral Fitness ◽  
Nonnucleoside Reverse Transcriptase Inhibitor ◽  
The Impact ◽  
Hiv 1

The emergence of HIV-1 drug resistance remains a major obstacle in antiviral therapy. M184I/V and E138K are signature mutations of clinical relevance in HIV-1 reverse transcriptase (RT) for the nucleoside reverse transcriptase inhibitors (NRTIs) lamivudine (3TC) and emtricitabine (FTC) and the second-generation (new) nonnucleoside reverse transcriptase inhibitor (NNRTI) rilpivirine (RPV), respectively, and the E138K mutation has also been shown to be selected by etravirine in cell culture. The E138K mutation was recently shown to compensate for the low enzyme processivity and viral fitness associated with the M184I/V mutations through enhanced deoxynucleoside triphosphate (dNTP) usage, while the M184I/V mutations compensated for defects in polymerization rates associated with the E138K mutations under conditions of high dNTP concentrations. The M184I mutation was also shown to enhance resistance to RPV and ETR when present together with the E138K mutation. These mutual compensatory effects might also enhance transmission rates of viruses containing these two mutations. Therefore, we performed tissue culture studies to investigate the evolutionary dynamics of these viruses. Through experiments in which E138K-containing viruses were selected with 3TC-FTC and in which M184I/V viruses were selected with ETR, we demonstrated that ETR was able to select for the E138K mutation in viruses containing the M184I/V mutations and that the M184I/V mutations consistently emerged when E138K viruses were selected with 3TC-FTC. We also performed biochemical subunit-selective mutational analyses to investigate the impact of the E138K mutation on RT function and interactions with the M184I mutation. We now show that the E138K mutation decreased rates of polymerization, impaired RNase H activity, and conferred ETR resistance through the p51 subunit of RT, while an enhancement of dNTP usage as a result of the simultaneous presence of both mutations E138K and M184I occurred via both subunits.

scholarly journals The Impact of Macroscopic Epistasis on Long-Term Evolutionary Dynamics

Genetics ◽  
2014 ◽  
Vol 199 (1) ◽  
pp. 177-190 ◽  
Author(s):  
Benjamin H. Good ◽  
Michael M. Desai
Keyword(s):  
Evolutionary Dynamics ◽  
The Impact
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