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Pandemic diseases such as plague have produced a vast amount of literature providing information about the spatiotemporal extent, transmission, or countermeasures. However, the manual extraction of such information from running text is a tedious process, and much of this information remains locked into a narrative format. Natural Language processing (NLP) is a promising tool for the automated extraction of epidemiological data, and can facilitate the establishment of datasets. In this paper, we explore the utility of NLP to assist in the creation of a plague outbreak dataset. We produced a gold standard list of toponyms by manual annotation of a German plague treatise published by Sticker in 1908. We investigated the performance of five pre-trained NLP libraries (Google, Stanford CoreNLP, spaCy, germaNER and Geoparser) for the automated extraction of location data compared to the gold standard. Of all tested algorithms, spaCy performed best (sensitivity 0.92, F1 score 0.83), followed closely by Stanford CoreNLP (sensitivity 0.81, F1 score 0.87). Google NLP had a slightly lower performance (F1 score 0.72, sensitivity 0.78). Geoparser and germaNER had a poor sensitivity (0.41 and 0.61). We then evaluated how well automated geocoding services such as Google geocoding, Geonames and Geoparser located these outbreaks correctly. All geocoding services performed poorly - particularly for historical regions - and returned the correct GIS information only in 60.4%, 52.7% and 33.8% of all cases. Finally, we compared our newly digitized plague dataset to a re-digitized version of the plague treatise by Biraben and provide an update of the spatio-temporal extent of the second pandemic plague outbreaks. We conclude that NLP tools have their limitations, but they are potentially useful to accelerate the collection of data and the generation of a global plague outbreak database., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Pathogens can elicit high selective pressure on hosts, potentially altering genetic diversity over short evolutionary timescales. Intraspecific variation in immune response is observable as variable survivability from specific infections. The great gerbil ( Rhombomys opimus ) is a rodent plague host with a heterogenic but highly resistant phenotype. Here, we investigate the genomic basis for plague-resistant phenotypes by exposing wild-caught great gerbils to plague ( Yersinia pestis ). Whole genome sequencing of 10 survivors and 10 moribund individuals revealed a subset of genomic regions showing elevated differentiation. Gene ontology analysis of candidate genes in these regions demonstrated enrichment of genes directly involved in immune functions, cellular metabolism and the regulation of apoptosis as well as pathways involved in transcription, translation, and gene regulation. Transcriptomic analysis revealed that the early activated great gerbil immune response to plague consisted of classical components of the innate immune system. Our approach combining challenge experiments with transcriptomics and population level sequencing, provides new insight into the genetic background of plague-resistance and confirms its complex nature, most likely involving multiple genes and pathways of both the immune system and regulation of basic cellular functions., (© The Author(s) 2022. Published by Oxford University Press on behalf of National Academy of Sciences.)

After several pandemics over the last two millennia, the wildlife reservoirs of plague (Yersinia pestis) now persist around the world, including in the western United States. Routine surveillance in this region has generated comprehensive records of human cases and animal seroprevalence, creating a unique opportunity to test how plague reservoirs are responding to environmental change. Here, we test whether animal and human data suggest that plague reservoirs and spillover risk have shifted since 1950. To do so, we develop a new method for detecting the impact of climate change on infectious disease distributions, capable of disentangling long-term trends (signal) and interannual variation in both weather and sampling (noise). We find that plague foci are associated with high-elevation rodent communities, and soil biochemistry may play a key role in the geography of long-term persistence. In addition, we find that human cases are concentrated only in a small subset of endemic areas, and that spillover events are driven by higher rodent species richness (the amplification hypothesis) and climatic anomalies (the trophic cascade hypothesis). Using our detection model, we find that due to the changing climate, rodent communities at high elevations have become more conducive to the establishment of plague reservoirs-with suitability increasing up to 40% in some places-and that spillover risk to humans at mid-elevations has increased as well, although more gradually. These results highlight opportunities for deeper investigation of plague ecology, the value of integrative surveillance for infectious disease geography, and the need for further research into ongoing climate change impacts., (© 2021 The Authors. Global Change Biology published by John Wiley & Sons Ltd.)

Plague has been known since ancient times as a re-emerging infectious disease, causing considerable socioeconomic burden in regional hotspots. To better understand the epidemiological cycle of the causative agent of the plague, its potential occurrence, and possible future dispersion, one must carefully consider the taxonomy, distribution, and ecological requirements of reservoir-species in relation either to natural or human-driven changes (e.g. climate change or urbanization). In recent years, the depth of knowledge on species taxonomy and species composition in different landscapes has undergone a dramatic expansion, driven by modern taxonomic methods such as synthetic surveys that take into consideration morphology, genetics, and the ecological setting of captured animals to establish their species identities. Here, we consider the recent taxonomic changes of the rodent species in known plague reservoirs and detail their distribution across the world, with a particular focus on those rodents considered to be keystone host species. A complete checklist of all known plague-infectable vertebrates living in plague foci is provided as a Supporting Information table., (© 2020 International Society of Zoological Sciences, Institute of Zoology/Chinese Academy of Sciences and John Wiley & Sons Australia, Ltd.)

The great gerbil (Rhombomys opimus) is a social rodent living in permanent, complex burrow systems distributed throughout Central Asia, where it serves as the main host of several important vector-borne infectious pathogens including the well-known plague bacterium (Yersinia pestis). Here, we present a continuous annotated genome assembly of the great gerbil, covering over 96% of the estimated 2.47-Gb genome. Taking advantage of the recent genome assemblies of the sand rat (Psammomys obesus) and the Mongolian gerbil (Meriones unguiculatus), comparative immunogenomic analyses reveal shared gene losses within TLR gene families (i.e., TLR8, TLR10, and the entire TLR11-subfamily) for Gerbillinae, accompanied with signs of diversifying selection of TLR7 and TLR9. Most notably, we find a great gerbil-specific duplication of the MHCII DRB locus. In silico analyses suggest that the duplicated gene provides high peptide binding affinity for Yersiniae epitopes as well as Leishmania and Leptospira epitopes, putatively leading to increased capability to withstand infections by these pathogens. Our study demonstrates the power of whole-genome sequencing combined with comparative genomic analyses to gain deeper insight into the immunogenomic landscape of the great gerbil and its close relatives., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.)

Yersinia pestis is transmitted from fleas to rodents when the bacterium develops an extensive biofilm in the foregut of a flea, starving it into a feeding frenzy, or, alternatively, during a brief period directly after feeding on a bacteremic host. These two transmission modes are in a trade-off regulated by the amount of biofilm produced by the bacterium. Here by investigating 446 global isolated Y. pestis genomes, including 78 newly sequenced isolates sampled over 40 years from a plague focus in China, we provide evidence for strong selection pressures on the RNA polymerase ω-subunit encoding gene rpoZ. We demonstrate that rpoZ variants have an increased rate of biofilm production in vitro, and that they evolve in the ecosystem during colder and drier periods. Our results support the notion that the bacterium is constantly adapting-through extended phenotype changes in the fleas-in response to climate-driven changes in the niche.

Plague remains a threat to public health and is considered as a re-emerging infectious disease today. Rodents play an important role as major hosts in plague persistence and driving plague outbreaks in natural foci; however, few studies have tested the association between host diversity in ecosystems and human plague risk. Here we use zero-inflated generalized additive models to examine the association of species richness with human plague presence (where plague outbreaks could occur) and intensity (the average number of annual human cases when they occurred) in China during the Third Pandemic. We also account for transportation network density, annual precipitation levels and human population size. We found rodent species richness, particularly of rodent plague hosts, is positively associated with the presence of human plague. Further investigation shows that species richness of both wild and commensal rodent plague hosts are positively correlated with the presence, but only the latter correlated with the intensity. Our results indicated a positive relationship between rodent diversity and human plague, which may provide suggestions for the plague surveillance system., Competing Interests: We have no competing interests.

Zoonoses, such as plague, are primarily animal diseases that spill over into human populations. While the goal of eradicating such diseases is enticing, historical experience validates abandoning eradication in favor of ecologically based control strategies (which reduce morbidity and mortality to a locally accepted risk level). During the 20th century, one of the most extensive plague-eradication efforts in recorded history was undertaken to enable large-scale changes in land use in the former Soviet Union (including vast areas of central Asia). Despite expending tremendous resources in its attempt to eradicate plague, the Soviet antiplague response gradually abandoned the goal of eradication in favor of plague control linked with developing basic knowledge of plague ecology. Drawing from this experience, we combine new gray-literature sources, historical and recent research, and fieldwork to outline best practices for the control of spillover from zoonoses while minimally disrupting wildlife ecosystems, and we briefly compare the Soviet case with that of endemic plague in the western United States. We argue for the allocation of sufficient resources to maintain ongoing local surveillance, education, and targeted control measures; to incorporate novel technologies selectively; and to use ecological research to inform developing landscape-based models for transmission interruption. We conclude that living with emergent and reemergent zoonotic diseases-switching to control-opens wider possibilities for interrupting spillover while preserving natural ecosystems, encouraging adaptation to local conditions, and using technological tools judiciously and in a cost-effective way., Competing Interests: The authors declare no conflict of interest., (Copyright © 2019 the Author(s). Published by PNAS.)

On 3 August 1900, bubonic plague ( Yersinia pestis ) broke out in Glasgow for the first time during the Third Pandemic. The local sanitary authorities rigorously tracked the spread of the disease and they found that nearly all of the 35 cases could be linked by contact with a previous case. Despite trapping hundreds of rats in the area, there was no evidence of a rat epizootic and the investigators speculated that the outbreak could be due to human-to-human transmission of bubonic plague. Here we use a likelihood-based method to reconstruct transmission trees for the outbreak. From the description of the outbreak and the reconstructed trees, we infer several epidemiological parameters. We found that the estimated mean serial interval was 7.4-9.2 days and the mean effective reproduction number dropped below 1 after implementation of control measures. We also found a high rate of secondary transmissions within households and observations of transmissions from individuals who were not terminally septicaemic. Our results provide important insights into the epidemiology of a bubonic plague outbreak during the Third Pandemic in Europe., Competing Interests: The authors declare no competing interests.

Over the last few years, genomic studies on Yersinia pestis , the causative agent of all known plague epidemics, have considerably increased in numbers, spanning a period of about 5,000 y. Nonetheless, questions concerning historical reservoirs and routes of transmission remain open. Here, we present and describe five genomes from the second half of the 14th century and reconstruct the evolutionary history of Y. pestis by reanalyzing previously published genomes and by building a comprehensive phylogeny focused on strains attributed to the Second Plague Pandemic (14th to 18th century). Corroborated by historical and ecological evidence, the presented phylogeny, which includes our Y. pestis genomes, could support the hypothesis of an entry of plague into Western European ports through distinct waves of introduction during the Medieval Period, possibly by means of fur trade routes, as well as the recirculation of plague within the human population via trade routes and human movement., Competing Interests: The authors declare no conflict of interest., (Copyright © 2018 the Author(s). Published by PNAS.)

Plague, caused by the bacterium Yersinia pestis , can spread through human populations by multiple transmission pathways. Today, most human plague cases are bubonic, caused by spillover of infected fleas from rodent epizootics, or pneumonic, caused by inhalation of infectious droplets. However, little is known about the historical spread of plague in Europe during the Second Pandemic (14-19th centuries), including the Black Death, which led to high mortality and recurrent epidemics for hundreds of years. Several studies have suggested that human ectoparasite vectors, such as human fleas ( Pulex irritans ) or body lice ( Pediculus humanus humanus ), caused the rapidly spreading epidemics. Here, we describe a compartmental model for plague transmission by a human ectoparasite vector. Using Bayesian inference, we found that this model fits mortality curves from nine outbreaks in Europe better than models for pneumonic or rodent transmission. Our results support that human ectoparasites were primary vectors for plague during the Second Pandemic, including the Black Death (1346-1353), ultimately challenging the assumption that plague in Europe was predominantly spread by rats., Competing Interests: The authors declare no conflict of interest., (Copyright © 2018 the Author(s). Published by PNAS.)

Objective: In three pilot regions of The Netherlands, all 16-29 year olds were invited to participate in three annual rounds of Chlamydia screening. The aim of the present study is to evaluate the cost-effectiveness of repeated Chlamydia screening, based on empirical data., Methods: A mathematical model was employed to estimate the influence of repeated screening on prevalence and incidence of Chlamydial infection. A model simulating the natural history of Chlamydia was combined with cost and utility data to estimate the number of major outcomes and quality-adjusted life-years (QALYs) associated with Chlamydia. Six screening scenarios (16-29 years annually; 16-24 years annually; women only; biennial screening; biennial screening women only; screening every five years) were compared with no screening in two sexual networks, representing both lower ('national network') and higher ('urban network') baseline prevalence. Incremental cost-effectiveness ratios (ICERs) for the different screening scenarios were estimated. Uncertainty and sensitivity analyses were performed., Results: In all scenarios and networks, cost per major outcome averted are above €5000. Cost per QALY are at least €50,000. The default scenario as piloted in the Netherlands was least cost-effective, with ICERs of €232,000 in the national and €145,000 in the urban sexual network. Results were robust in sensitivity analyses., Conclusions: It is unlikely that repeated rounds of Chlamydia screening will be cost-effective. Only at high levels of willingness to pay for a QALY (>€50,000) screening may be more cost-effective than no screening., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

The Black Death, originating in Asia, arrived in the Mediterranean harbors of Europe in 1347 CE, via the land and sea trade routes of the ancient Silk Road system. This epidemic marked the start of the second plague pandemic, which lasted in Europe until the early 19th century. This pandemic is generally understood as the consequence of a singular introduction of Yersinia pestis, after which the disease established itself in European rodents over four centuries. To locate these putative plague reservoirs, we studied the climate fluctuations that preceded regional plague epidemics, based on a dataset of 7,711 georeferenced historical plague outbreaks and 15 annually resolved tree-ring records from Europe and Asia. We provide evidence for repeated climate-driven reintroductions of the bacterium into European harbors from reservoirs in Asia, with a delay of 15 ± 1 y. Our analysis finds no support for the existence of permanent plague reservoirs in medieval Europe.

Plague, the causative agent of three devastating pandemics in history, is currently a re-emerging disease, probably due to climate change and other anthropogenic changes. Without understanding the response of plague systems to anthropogenic or climate changes in their trophic web, it is unfeasible to effectively predict years with high risks of plague outbreak, hampering our ability for effective prevention and control of the disease. Here, by using surveillance data, we apply structural equation modelling to reveal the drivers of plague prevalence in two very different rodent systems: those of the solitary Daurian ground squirrel and the social Mongolian gerbil. We show that plague prevalence in the Daurian ground squirrel is not detectably related to its trophic web, and that therefore surveillance efforts should focus on detecting plague directly in this ecosystem. On the other hand, plague in the Mongolian gerbil is strongly embedded in a complex, yet understandable trophic web of climate, vegetation, and rodent and flea densities, making the ecosystem suitable for more sophisticated low-cost surveillance practices, such as remote sensing. As for the trophic webs of the two rodent species, we find that increased vegetation is positively associated with higher temperatures and precipitation for both ecosystems. We furthermore find a positive association between vegetation and ground squirrel density, yet a negative association between vegetation and gerbil density. Our study thus shows how past surveillance records can be used to design and improve existing plague prevention and control measures, by tailoring them to individual plague foci. Such measures are indeed highly needed under present conditions with prevailing climate change., (© 2014 The Author(s) Published by the Royal Society. All rights reserved.)

Currently, large-scale transmissions of infectious diseases are becoming more closely associated with accelerated globalization and climate change, but quantitative analyses are still rare. By using an extensive dataset consisting of date and location of cases for the third plague pandemic from 1772 to 1964 in China and a novel method (nearest neighbour approach) which deals with both short- and long-distance transmissions, we found the presence of major roads, rivers and coastline accelerated the spread of plague and shaped the transmission patterns. We found that plague spread velocity was positively associated with wet conditions (measured by an index of drought and flood events) in China, probably due to flood-driven transmission by people or rodents. Our study provides new insights on transmission patterns and possible mechanisms behind variability in transmission speed, with implications for prevention and control measures. The methodology may also be applicable to studies of disease dynamics or species movement in other systems.

Background: A large trial to investigate the effectiveness of population based screening for chlamydia infections was conducted in the Netherlands in 2008-2012. The trial was register based and consisted of four rounds of screening of women and men in the age groups 16-29 years in three regions in the Netherlands. Data were collected on participation rates and positivity rates per round. A modeling study was conducted to project screening effects for various screening strategies into the future., Methods and Findings: We used a stochastic network simulation model incorporating partnership formation and dissolution, aging and a sexual life course perspective. Trends in baseline rates of chlamydia testing and treatment were used to describe the epidemiological situation before the start of the screening program. Data on participation rates was used to describe screening uptake in rural and urban areas. Simulations were used to project the effectiveness of screening on chlamydia prevalence for a time period of 10 years. In addition, we tested alternative screening strategies, such as including only women, targeting different age groups, and biennial screening. Screening reduced prevalence by about 1% in the first two screening rounds and leveled off after that. Extrapolating observed participation rates into the future indicated very low participation in the long run. Alternative strategies only marginally changed the effectiveness of screening. Higher participation rates as originally foreseen in the program would have succeeded in reducing chlamydia prevalence to very low levels in the long run., Conclusions: Decreasing participation rates over time profoundly impact the effectiveness of population based screening for chlamydia infections. Using data from several consecutive rounds of screening in a simulation model enabled us to assess the future effectiveness of screening on prevalence. If participation rates cannot be kept at a sufficient level, the effectiveness of screening on prevalence will remain limited.

Speculation on how the bacterium Yersinia pestis re-emerges after years of absence in the Prebalkhash region in Kazakhstan has been ongoing for half a century, but the mechanism is still unclear. One of the theories is that plague persists in its reservoir host (the great gerbil) in so-called hotspots, i.e. small regions in which the conditions remain favourable for plague to persist during times where the conditions in the Prebalkhash region as a whole have become unfavourable for plague persistence. In this paper we use a metapopulation model that describes the dynamics of the great gerbil. With this model we study the minimum size of an individual hotspot and the combined size of multiple hotspots in the Prebalkhash region that would be required for Y. pestis to persist through an inter-epizootic period. We show that the combined area of hotspots required for plague persistence is so large that it would be unlikely to have been missed by existing plague surveillance. This suggests that persistence of plague in that region cannot solely be explained by the existence of hotspots, and therefore other hypotheses, such as survival in multiple host species, and persistence in fleas or in the soil should be considered as well., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Objective: To evaluate the effectiveness of register based, yearly chlamydia screening., Design: Controlled trial with randomised stepped wedge implementation in three blocks., Setting: Three regions of the Netherlands: Amsterdam, Rotterdam, and South Limburg., Participants: 317 304 women and men aged 16-29 years listed on municipal registers at start of trial., Intervention: From March 2008 to February 2011, the Chlamydia Screening Implementation programme offered yearly chlamydia screening tests. Postal invitations asked people to use an internet site to request a kit for self collection of samples, which would then be sent to regional laboratories for testing. Treatment and partner notification were done by the general practitioner or at a sexually transmitted infection clinic., Main Outcome Measures: Primary outcomes were the percentage of chlamydia tests positive (positivity), percentage of invitees returning a specimen (uptake), and estimated chlamydia prevalence. Secondary outcomes were positivity according to sex, age, region, and sociodemographic factors; adherence to screening invitations; and incidence of self reported pelvic inflammatory disease., Results: The participation rate was 16.1% (43 358/269 273) after the first invitation, 10.8% after the second, and 9.5% after the third, compared with 13.0% (6223/48 031) in the control block invited at the end of round two of the intervention. Chlamydia positivity in the intervention blocks at the first invitation was the same as in the control block (4.3%) and 0.2% lower at the third invitation (odds ratio 0.96 (95% confidence interval 0.83 to 1.10)). No substantial decreases in positivity were seen after three screening rounds in any region or sociodemographic group. Among the people who participated three times (2.8% of all invitees), positivity fell from 5.9% to 2.9% (odds ratio 0.49 (0.47 to 0.50))., Conclusions: There was no statistical evidence of an impact on chlamydia positivity rates or estimated population prevalence from the Chlamydia Screening Implementation programme after three years at the participation levels obtained. The current evidence does not support a national roll out of this register based chlamydia screening programme., Trial Registration: NTR 3071 (Netherlands Trial Register, www.trialregister.nl).

Chlamydia trachomatis is the most common bacterial sexually transmitted infection (STI) in many developed countries. The highest prevalence rates are found among young adults who have frequent partner change rates. Three published individual-based models have incorporated a detailed description of age-specific sexual behaviour in order to quantify the transmission of C. trachomatis in the population and to assess the impact of screening interventions. Owing to varying assumptions about sexual partnership formation and dissolution and the great uncertainty about critical parameters, such models show conflicting results about the impact of preventive interventions. Here, we perform a detailed evaluation of these models by comparing the partnership formation and dissolution dynamics with data from Natsal 2000, a population-based probability sample survey of sexual attitudes and lifestyles in Britain. The data also allow us to describe the dispersion of C. trachomatis infections as a function of sexual behaviour, using the Gini coefficient. We suggest that the Gini coefficient is a useful measure for calibrating infectious disease models that include risk structure and highlight the need to estimate this measure for other STIs.

There are four major quantities that are measured in sexual behavior surveys that are thought to be especially relevant for the performance of sexual network models in terms of disease transmission. These are (i) the cumulative distribution of lifetime number of partners, (ii) the distribution of partnership durations, (iii) the distribution of gap lengths between partnerships, and (iv) the number of recent partners. Fitting a network model to these quantities as measured in sexual behavior surveys is expected to result in a good description of Chlamydia trachomatis transmission in terms of the heterogeneity of the distribution of infection in the population. Here we present a simulation model of a sexual contact network, in which we explored the role of behavioral heterogeneity of simulated individuals on the ability of the model to reproduce population-level sexual survey data from the Netherlands and UK. We find that a high level of heterogeneity in the ability of individuals to acquire and maintain (additional) partners strongly facilitates the ability of the model to accurately simulate the powerlaw-like distribution of the lifetime number of partners, and the age at which these partnerships were accumulated, as surveyed in actual sexual contact networks. Other sexual network features, such as the gap length between partnerships and the partnership duration, could-at the current level of detail of sexual survey data against which they were compared-be accurately modeled by a constant value (for transitional concurrency) and by exponential distributions (for partnership duration). Furthermore, we observe that epidemiological measures on disease prevalence in survey data can be used as a powerful tool for building accurate sexual contact networks, as these measures provide information on the level of mixing between individuals of different levels of sexual activity in the population, a parameter that is hard to acquire through surveying individuals.

The classical antigen presentation pathway consists of two monomorphic (proteasome and TAP) and one polymorphic components (MHC Class I). Viruses can escape CTL responses by mutating an epitope so that it is no longer correctly processed by the pathway. Whereas escape mutations that affect MHC binding are typically no longer under selection pressure in the next host of the virus (as hosts differ in their MHC alleles), escape mutations that affect the antigen processing of epitope precursors prevent the use of those epitope precursors by any of the MHC alleles in a host population. Viruses might therefore be under selection pressure to adapt to the monomorphic proteasome and TAP. We designed an agent-based model of a host population, in which an HIV-1 like virus adapts to the antigen presentation pathway of individual hosts, as the virus spreads through the population. We studied how the polymorphism of the MHC and the monomorphism of the proteasome and TAP affected the level of adaptation to the host population that the virus could reach. We found that due to the polymorphism and high specificity of the MHC class I molecules, the CTL epitopes that are targeted by the CTL responses of different hosts do not share many epitope precursors. Therefore, escape mutations in epitope precursors are frequently released from immune selection pressure, and can revert back to the virus wildtype sequence. As a result, the selection pressure on the virus to adapt to the proteasome and TAP is relatively small, which explains the low level of adaptation of the virus to the monomorphic steps in the antigen presentation pathway., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Background: HIV-1 viruses are highly capable of mutating their proteins to escape the presentation of CTL epitopes in their current host. Upon transmission to another host, some escape mutations revert, but other remain stable in the virus sequence for at least several years. Depending on the rate of accumulation and reversion of escape mutations, HIV-1 could reach a high level of adaptation to the human population. Yusim et. al. hypothesized that the apparent clustering of CTL epitopes in the conserved regions of HIV-1 proteins could be an evolutionary signature left by large-scale adaptation of HIV-1 to its human/simian host., Results: In this paper we quantified the distribution of CTL epitopes in HIV-1 and found that that in 99% of the HIV-1 protein sequences, the epitope distribution was indistinguishable from random. Similar percentages were found for HCV, Influenza and for three eukaryote proteomes (Human, Drosophila, Yeast)., Conclusion: We conclude that CTL epitopes in HIV-1 are randomly distributed, and that this distribution is similar to the distribution of CTL epitopes in proteins from other proteomes. Therefore, the visually apparent clustering of CTL epitopes in epitope maps should not be interpreted as a signature of a past large-scale adaptation of HIV-1 to the human cellular immune response.

The large diversity in MHC class I molecules in a population lowers the chance that a virus infects a host to which it is pre-adapted to escape the MHC binding of CTL epitopes. However, viruses can also lose CTL epitopes by escaping the monomorphic antigen processing components of the pathway (proteasome and TAP) that create the epitope precursors. If viruses were to accumulate escape mutations affecting these monomorphic components, they would become pre-adapted to all hosts regardless of the MHC polymorphism. To assess whether viruses exploit this apparent vulnerability, we study the evolution of HIV-1 with bioinformatic tools that allow us to predict CTL epitopes, and quantify the frequency and accumulation of antigen processing escapes. We found that within hosts, proteasome and TAP escape mutations occur frequently. However, on the population level these escapes do not accumulate: the total number of predicted epitopes and epitope precursors in HIV-1 clade B has remained relatively constant over the last 30 years. We argue that this lack of adaptation can be explained by the combined effect of the MHC polymorphism and the high specificity of individual MHC molecules. Because of these two properties, only a subset of the epitope precursors in a host are potential epitopes, and that subset differs between hosts. We estimate that upon transmission of a virus to a new host 39%-66% of the mutations that caused epitope precursor escapes are released from immune selection pressure.