scholarly journals Clonal interference can cause wavelet-like oscillations of multilocus linkage disequilibrium

2018 ◽  
Vol 15 (140) ◽  
pp. 20170921 ◽  
Author(s):  
Victor Garcia ◽  
Emily C. Glassberg ◽  
Arbel Harpak ◽  
Marcus W. Feldman
Keyword(s):  
Human Immunodeficiency Virus ◽  
Linkage Disequilibrium ◽  
Evolutionary Dynamics ◽  
Host Adaptation ◽  
Clonal Interference ◽  
Beneficial Mutations ◽  
Fitness Effects ◽  
Infection Models ◽  
Immunodeficiency Virus ◽  
Over Time

Within-host adaptation of pathogens such as human immunodeficiency virus (HIV) often occurs at more than two loci. Multiple beneficial mutations may arise simultaneously on different genetic backgrounds and interfere, affecting each other's fixation trajectories. Here, we explore how these evolutionary dynamics are mirrored in multilocus linkage disequilibrium (MLD), a measure of multi-way associations between alleles. In the parameter regime corresponding to HIV, we show that deterministic early infection models induce MLD to oscillate over time in a wavelet-like fashion. We find that the frequency of these oscillations is proportional to the rate of adaptation. This signature is robust to drift, but can be eroded by high variation in fitness effects of beneficial mutations. Our findings suggest that MLD oscillations could be used as a signature of interference among multiple equally advantageous mutations and may aid the interpretation of MLD in data.

scholarly journals Finite-sites multiple mutations interference gives rise to wavelet-like oscillations of multilocus linkage disequilibrium

2016 ◽  
Author(s):  
Victor Garcia ◽  
Emily C. Glassberg ◽  
Arbel Harpak ◽  
Marcus W. Feldman
Keyword(s):  
Human Immunodeficiency Virus ◽  
Linkage Disequilibrium ◽  
Adaptive Dynamics ◽  
Host Adaptation ◽  
Early Infection ◽  
Beneficial Mutations ◽  
Fitness Effects ◽  
Infection Models ◽  
Immunodeficiency Virus ◽  
Over Time

Within-host adaptation of pathogens such as human immunodeficiency virus (HIV) often occurs at more than two loci. Multiple beneficial mutations may arise simultaneously on different genetic backgrounds and interfere, affecting each other's fixation trajectories. Here, we explore how these adaptive dynamics are mirrored in multilocus linkage disequilibrium (MLD), a measure of multi-way associations between alleles. In the parameter regime corresponding to HIV, we show that deterministic early infection models induce MLD to oscillate over time in a wavelet-like fashion. We find that the frequency of these oscillations is proportional to the rate of adaptation. This signature is robust to drift, but can be eroded by high variation in fitness effects of beneficial mutations. Our findings suggest that MLD oscillations could be used as a signature of interference among multiple equally advantageous mutations and may aid the interpretation of MLD in data.

scholarly journals Evolution of Envelope Sequences from the Genital Tract and Peripheral Blood of Women Infected with Clade A Human Immunodeficiency Virus Type 1

1998 ◽  
Vol 72 (10) ◽  
pp. 8240-8251 ◽  
Author(s):  
Mary Poss ◽  
Allen G. Rodrigo ◽  
John J. Gosink ◽  
Gerald H. Learn ◽  
Dana de Vange Panteleeff ◽  
...  
Keyword(s):  
Amino Acids ◽  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Peripheral Blood ◽  
Tissue Compartment ◽  
Immunodeficiency Virus ◽  
Hiv 1 ◽  
Over Time

ABSTRACT The development of viral diversity during the course of human immunodeficiency virus type 1 (HIV-1) infection may significantly influence viral pathogenesis. The paradigm for HIV-1 evolution is based primarily on studies of male cohorts in which individuals were presumably infected with a single virus variant of subtype B HIV-1. In this study, we evaluated virus evolution based on sequence information of the V1, V2, and V3 portions of HIV-1 clade A envelope genes obtained from peripheral blood and cervical secretions of three women with genetically heterogeneous viral populations near seroconversion. At the first sample following seroconversion, the number of nonsynonymous substitutions per potential nonsynonymous site (dn) significantly exceeded substitutions at potential synonymous sites (ds) in plasma viral sequences from all individuals. Generally, values of dn remained higher than values of ds as sequences from blood or mucosa evolved. Mutations affected each of the three variable regions of the envelope gene differently; insertions and deletions dominated changes in V1, substitutions involving charged amino acids occurred in V2, and sequential replacement of amino acids over time at a small subset of positions distinguished V3. The relationship among envelope nucleotide sequences obtained from peripheral blood mononuclear cells, plasma, and cervical secretions was evaluated for each individual by both phylogenetic and phenetic analyses. In all subjects, sequences from within each tissue compartment were more closely related to each other than to sequences from other tissues (phylogenetic tissue compartmentalization). At time points after seroconversion in two individuals, there was also greater genetic identity among sequences from the same tissue compartment than among sequences from different tissue compartments (phenetic tissue compartmentalization). Over time, temporal phylogenetic and phenetic structure was detectable in mucosal and plasma viral samples from all three women, suggesting a continual process of migration of one or a few infected cells into each compartment followed by localized expansion and evolution of that population.

scholarly journals Neurocognitive Development in Perinatally Human Immunodeficiency Virus–infected Adolescents on Long-term Treatment, Compared to Healthy Matched Controls: A Longitudinal Study

2019 ◽  
Author(s):  
Malon Van den Hof ◽  
Anne Marleen ter Haar ◽  
Henriette J Scherpbier ◽  
Johanna H van der Lee ◽  
Peter Reiss ◽  
...  
Keyword(s):  
Working Memory ◽  
Human Immunodeficiency Virus ◽  
Executive Functioning ◽  
Processing Speed ◽  
Learning Ability ◽  
Z Score ◽  
Immunodeficiency Virus ◽  
Group Time ◽  
Visual Motor ◽  
Over Time

Abstract Background A cross-sectional analysis of the Neurological, cOgnitive and VIsual performance in hiv-infected Children cohort showed significant cognitive impairment in combination antiretroviral therapy (cART)-treated, perinatally human immunodeficiency virus (HIV)-infected adolescents (PHIV+) compared to age-, sex-, ethnicity- and socioeconomic status (SES)-matched HIV-negative controls (HIV−). In this longitudinal study, we compared cognitive development in the same adolescents over time. Methods We repeated the standardized cognitive test battery after a mean of 4.6 years (standard deviation 0.3). In participants who completed both assessments, we compared cognitive trajectories between groups in the domains of intelligence quotient (IQ), processing speed, working memory, executive functioning, learning ability, and visual-motor function, using linear mixed models. We explored associations with disease- and treatment-related factors and used multivariate normative comparison (MNC) to determine the prevalence of cognitive impairment. Results There were 21 PHIV+ and 23 HIV− participants that completed 2 assessments and were similar concerning age, sex, ethnicity, and SES. Compared to HIV− participants, in PHIV+ participants the IQ score increased significantly more over time (group*time 6.01, 95% confidence interval [CI] 1.5–10.50; P = .012), whereas executive functioning decreased significantly more (group*time −1.43 z score, 95% CI −2.12 to −0.75; P < .001), resulting in the disappearance and appearance of significant differences. Processing speed, working memory, learning ability, and visual-motor function trajectories were not statistically different between groups. Univariately, those who had started cART at an older age deviated more in executive functioning (−0.13 z score, 95% CI −0.24 to −0.02; P = .043). The prevalence of cognitive impairments by MNC was similar in both groups, at both time points. Conclusions The cART-treated PHIV+ adolescents appeared to have similar global cognitive development, compared to their healthy peers. Executive functioning trajectory appears to deviate, potentially explained by earlier brain damage.

scholarly journals Sequential Turnover of Human Immunodeficiency Virus Type 1 env throughout the Course of Infection

2006 ◽  
Vol 80 (21) ◽  
pp. 10591-10599 ◽  
Author(s):  
Tara M. Riddle ◽  
Norah J. Shire ◽  
Marc S. Sherman ◽  
Kelly F. Franco ◽  
Haynes W. Sheppard ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cell ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Cell Loss ◽  
Cd4 Counts ◽  
Immunodeficiency Virus ◽  
Hiv 1 ◽  
Over Time

ABSTRACT We examined the rates of variant population turnover of the V1-V2 and V4-V5 hypervariable domains of the human immunodeficiency virus type 1 (HIV-1) gp120 molecule in longitudinal plasma samples from 14 men with chronic HIV-1 infection using heteroduplex tracking assays (HTA). Six men had high rates of CD4+ T-cell loss, and eight men had low rates of CD4+ T-cell loss over 2.5 to 8 years of infection. We found that V1-V2 and V4-V5 env populations changed dramatically over time in all 14 subjects; the changes in these regions were significantly correlated with each another over time. The subjects with rapid CD4 loss had significantly less change in their env populations than the subjects with slow CD4 loss. The two subjects with rapid CD4 loss and sustained low CD4 counts (<150/μl for at least 2 years) showed stabilization of their V1-V2 and V4-V5 populations as reflected by low levels of total change in HTA pattern and low HTA indices (a novel measure of the emergence of new bands and band distribution); this stabilization was not observed in other subjects. The stabilization of env variant populations at low CD4 counts following periods of rapid viral evolution suggests that selective pressure on env, likely from new immune responses, is minimal when CD4 counts drop dramatically and remain low for extended periods of time.

scholarly journals “Resistance” to PSC-RANTES Revisited: Two Mutations in Human Immunodeficiency Virus Type 1 HIV-1SF162 or Simian-Human Immunodeficiency Virus SHIVSF162-p3 Do Not Confer Resistance

2010 ◽  
Vol 84 (11) ◽  
pp. 5842-5845 ◽  
Author(s):  
Rebecca Nedellec ◽  
Mia Coetzer ◽  
Michael M. Lederman ◽  
Robin E. Offord ◽  
Oliver Hartley ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Small Molecule ◽  
Receptor Blockade ◽  
Fitness Effects ◽  
Allosteric Inhibitor ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Resistance of human immunodeficiency virus type 1 (HIV-1) to small-molecule CCR5 inhibitors is well demonstrated, but resistance to macromolecular CCR5 inhibitors (e.g., PSC-RANTES) that act by both CCR5 internalization and receptor blockade had not been reported until recently (3). The report of a single simian-human immunodeficiency virus SHIVSF162-p3 variant with one V3 and one gp41 sequence change in gp160 that conferred both altered replicative fitness and resistance to PSC-RANTES was therefore surprising. We introduced the same two mutations into both the parental HIV-1SF162 and the macaque-adapted SHIVSF162-p3 and found minor differences in entry fitness but no changes in sensitivity to inhibition by either PSC-RANTES or the small-molecule allosteric inhibitor TAK-779. We attribute the earlier finding to confounding fitness effects with inhibitor sensitivity.

scholarly journals Adaptation, Clonal Interference, and Frequency-Dependent Interactions in a Long-Term Evolution Experiment with Escherichia coli

2015 ◽  
Author(s):  
Rohan Maddamsetti ◽  
Richard E. Lenski ◽  
Jeffrey E. Barrick
Keyword(s):  
Escherichia Coli ◽  
Frequency Dependence ◽  
Evolutionary Dynamics ◽  
Selective Sweeps ◽  
Clonal Interference ◽  
Beneficial Mutations ◽  
Frequency Dependent ◽  
Evolution Experiment ◽  
History Of

Twelve replicate populations of Escherichia coli have been evolving in the laboratory for more than 25 years and 60,000 generations. We analyzed bacteria from whole-population samples frozen every 500 generations through 20,000 generations for one well-studied population, called Ara???1. By tracking 42 known mutations in these samples, we reconstructed the history of this population???s genotypic evolution over this period. The evolutionary dynamics of Ara???1 show strong evidence of selective sweeps as well as clonal interference between competing lineages bearing different beneficial mutations. In some cases, sets of several mutations approached fixation simultaneously, often conveying no information about their order of origination; we present several possible explanations for the existence of these mutational cohorts. Against a backdrop of rapid selective sweeps both earlier and later, we found that two clades coexisted for over 6000 generations before one drove the other extinct. In that time, at least nine mutations arose in the clade that prevailed. We found evidence that the clades evolved a frequency-dependent interaction, which prevented the competitive exclusion of either clade, but which eventually collapsed as beneficial mutations accumulated in the clade that prevailed. Clonal interference and frequency dependence can occur even in the simplest microbial populations. Furthermore, frequency dependence may generate dynamics that extend the period of coexistence that would otherwise be sustained by clonal interference alone.

Aberrant and Unstable Expression of Immunoglobulin Genes in Persons Infected With Human Immunodeficiency Virus

Blood ◽  
1998 ◽  
Vol 92 (4) ◽  
pp. 1317-1323 ◽  
Author(s):  
Alberto Bessudo ◽  
Laura Rassenti ◽  
Diane Havlir ◽  
Douglas Richman ◽  
Ellen Feigal ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Hiv Infection ◽  
Healthy Adults ◽  
Immunoglobulin Genes ◽  
Expression Levels ◽  
Humoral Immune ◽  
Immunodeficiency Virus ◽  
Vh Gene ◽  
American Society ◽  
Over Time

We examined the IgM VH gene subgroup use-distribution in serial blood samples of 37 human immunodeficiency virus (HIV)-infected patients and a group of HIV-seronegative healthy adults. The IgM VH gene repertoires of healthy adults were relatively similar to one another and were stable over time. In contrast, individuals infected with HIV had IgM VH gene repertoires that were significantly more heterogeneous and unstable. Persons at early stages of HIV infection generally had abnormal expression levels of Ig VH3 genes and frequently displayed marked fluctuations in the relative expression levels of this VHgene subgroup over time. In contrast, persons with established acquired immunodeficiency syndrome (AIDS) had a significantly lower incidence of abnormalities in Ig VH3 expression levels, although continued to display abnormalities and instability in the expression levels of the smaller Ig VH gene subgroups. Moreover, the skewing and/or fluctuations in the expressed-IgM VHgene repertoire appeared greatest for persons at earlier stages of HIV infection. These studies show that persons infected with HIV have aberrant and unstable expression of immunoglobulin genes suggestive of a high degree humoral immune dysregulation and ongoing humoral immune responses to HIV-associated antigens and superantigens. © 1998 by The American Society of Hematology.

scholarly journals Intrapatient Diversity and Its Correlation with Viral Setpoint in Human Immunodeficiency Virus Type 1 CRF02_A/G-IbNG Infection

2002 ◽  
Vol 76 (21) ◽  
pp. 10745-10755 ◽  
Author(s):  
Indu Mani ◽  
Peter Gilbert ◽  
Jean-Louis Sankalé ◽  
Geoffrey Eisen ◽  
Souleymane Mboup ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Viral Load ◽  
Human Immunodeficiency Virus Type ◽  
Disease Free Interval ◽  
Free Interval ◽  
Immunodeficiency Virus ◽  
Disease Free ◽  
Hiv 1 ◽  
Over Time

ABSTRACT The human immunodeficiency virus type 1 (HIV-1) viral setpoint during the disease-free interval has been strongly associated with future risk of disease progression. An awareness of the correlation between viral setpoint and HIV-1 genetic evolution over time is important in the understanding of viral dynamics and infection. We examined genetic diversity in HIV-1 CRF02_A/G-IbNG-infected seroincident women in Dakar, Senegal; determined whether a viral setpoint kinetic pattern existed for CRF02_A/G-IbNG during the disease-free interval; and correlated viral load level and diversity. Samples were drawn during the disease-free interval from consenting CRF02_A/G-IbNG-infected, antiretroviral therapy-naïve female commercial sex workers in Dakar, Senegal. Based on sequential plasma RNA values, low and high viral setpoint groups were established. Intrapatient diversity and divergence over time was determined from earlier and later time point DNA samples from each person. Most individuals followed the viral setpoint paradigm. For each 1|−|log10 copy/ml of plasma increase in viral load, intrapatient diversity increased by 1.4% (P = 0.028). A greater diversification rate was observed in the high viral setpoint group than in the low viral setpoint group (P = 0.01). Greater nucleotide (P = 0.015) and amino acid (P = 0.048) divergences and a greater nucleotide divergence rate (P = 0.03) were found in the high viral setpoint group. There was no difference between the groups in the ratio of the number of nonsynonymous substitutions per nonsynonymous site to the number of synonymous substitutions per synonymous site. The greater intrapatient diversity, divergence, and diversification rates observed in the high viral setpoint group supports the notion that diversity is driven by cycles of viral replication resulting in accumulated mutations. Recognizing diversity potential based on viral load levels in individuals may inform the design of vaccines and therapies.

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