Competition and Facilitation between a Disease and a Predator in a Stunted Prey Population.

The role of diseases and parasites has received relatively little attention in modelling ecological dynamics despite mounting evidence of their importance in structuring communities. In contrast to predators, parasites do not necessarily kill their host but instead they may change host life history. Here, we study the impact of a parasite that selectively infects juvenile prey individuals and prevents them from maturing into adults. The model is inspired by the Ligula intestinalis tape worm and its cyprinid fish host Rutilis rutilis. We demonstrate that the parasite can promote as well as demote the so-called stunting in its host population, that is, the accumulation of juvenile prey, which leads to strong exploitation competition and consequently to a bottleneck in maturation. If competition between infected and uninfected individuals is strong, stunting will be enhanced and bistability between a stunted and non-stunted prey population occurs. In this case, the disease competes with the predator of its host species, possibly leading to predator extinction. In contrast, if the competition between infected and uninfected individuals is weak, the stunting is relieved, and epi-zoonotic cycles will occur, with recurrent epidemic outbreaks. Here, the disease facilitates the predator, and predator density will be substantially increased. We discuss the implications of our results for the dynamics and structure of the natural Ligula-Roach system.

Catastrophic collapse can occur without early warning: examples of silent catastrophes in structured ecological models.

Catastrophic and sudden collapses of ecosystems are sometimes preceded by early warning signals that potentially could be used to predict and prevent a forthcoming catastrophe. Universality of these early warning signals has been proposed, but no formal proof has been provided. Here, we show that in relatively simple ecological models the most commonly used early warning signals for a catastrophic collapse can be silent. We underpin the mathematical reason for this phenomenon, which involves the direction of the eigenvectors of the system. Our results demonstrate that claims on the universality of early warning signals are not correct, and that catastrophic collapses can occur without prior warning. In order to correctly predict a collapse and determine whether early warning signals precede the collapse, detailed knowledge of the mathematical structure of the approaching bifurcation is necessary. Unfortunately, such knowledge is often only obtained after the collapse has already occurred.

Spatial pattern switching enables cyclic evolution in spatial epidemics.

Infectious diseases often spread as spatial epidemic outbreak waves. A number of model studies have shown that such spatial pattern formation can have important consequences for the evolution of pathogens. Here, we show that such spatial patterns can cause cyclic evolutionary dynamics in selection for the length of the infectious period. The necessary reversal in the direction of selection is enabled by a qualitative change in the spatial pattern from epidemic waves to irregular local outbreaks. The spatial patterns are an emergent property of the epidemic system, and they are robust against changes in specific model assumptions. Our results indicate that emergent spatial patterns can act as a rich source for complexity in pathogen evolution.

27 years of the HIV epidemic amongst men having sex with men in the Netherlands: an in depth mathematical model-based analysis.

BACKGROUND: There has been increasing concern about a resurgent epidemic of HIV-1 amongst men having sex with men in the Netherlands, which has parallels with similar epidemics now occurring in many other countries. METHODS: A transmission model applicable to HIV-1 epidemics, including the use of antiretroviral therapy, is presented in a set of ordinary differential equations. The model is fitted by maximum likelihood to national HIV-1 and AIDS diagnosis data from 1980 to 2006, estimating parameters on average changes in unsafe sex and time to diagnosis. Robustness is studied with a detailed univariate sensitivity analysis, and a range of hypothetical scenarios are explored for the past and next decade. RESULTS: With a reproduction number around the epidemic threshold one, the HIV-1 epidemic amongst men having sex with men in the Netherlands is still not under control. Scenario analysis showed that in the absence of antiretroviral therapy limiting infectiousness in treated patients, the epidemic could have been more than double its current size. Ninety percent of new HIV transmissions are estimated to take place before diagnosis of the index case. Decreasing time from infection to diagnosis, which was 2.5 years on average in 2006, can prevent many future infections. CONCLUSIONS: Sexual risk behaviour amongst men having sex with men who are not aware of their infection is the most likely factor driving this epidemic.

Transmission networks of HIV-1 among men having sex with men in the Netherlands.

OBJECTIVE: To obtain insight in the HIV-1 transmission networks among men having sex with men (MSM) in the Netherlands. DESIGN: A phylogenetic tree was constructed from polymerase sequences isolated from 2877 HIV-1 subtype B-infected patients monitored as part of the AIDS Therapy Evaluation in the Netherlands (ATHENA) nationwide observational cohort. METHODS: For MSM with a known date of infection, the most similar sequences were selected as potential transmission pairs when they clustered with bootstrap value of at least 99%. Time from infection to onward transmission was estimated as the median time between dates of infection for each transmission pair. The source of infections with a resistant strain was traced using the entire phylogenetic tree. RESULTS: Of sequences from 403 MSM with a known date of infection between 1987 and 2007, 175 (43%) formed 63 clusters. Median time to onward transmission was 1.4 years (interquartile range 0.6-2.7). Twenty-four (6%) MSM carried a virus with resistance-related mutations, 13 of these were in eight clusters together with sequences from 28 other patients in the entire phylogenetic tree. Six clusters contained sequences obtained from 29 men all presenting the same resistance-related mutations. CONCLUSION: From our selection of likely transmission pairs, we conclude that onward transmission of HIV-1 from infected MSM in the Netherlands happens both during and after primary infection. Transmission of resistant strains from the antiretroviral therapy-treated population is limited, but strains with resistance-related mutations have formed subepidemics.

A resurgent HIV-1 epidemic among men who have sex with men in the era of potent antiretroviral therapy.

OBJECTIVE: Reducing viral load, highly active antiretroviral therapy has the potential to limit onwards transmission of HIV-1 and thus help contain epidemic spread. However, increases in risk behaviour and resurgent epidemics have been widely reported post-highly active antiretroviral therapy. The aim of this study was to quantify the impact that highly active antiretroviral therapy had on the epidemic. DESIGN: We focus on the HIV-1 epidemic among men who have sex with men in the Netherlands, which has been well documented over the past 20 years within several long-standing national surveillance programs. METHODS: We used a mathematical model including highly active antiretroviral therapy use and estimated the changes in risk behaviour and diagnosis rate needed to explain annual data on HIV and AIDS diagnoses. RESULTS: We show that the reproduction number R(t), a measure of the state of the epidemic, declined early on from initial values above two and was maintained below one from 1985 to 2000. Since 1996, when highly active antiretroviral therapy became widely used, the risk behaviour rate has increased 66%, resulting in an increase of R(t) to 1.04 in the latest period 2000-2004 (95% confidence interval 0.98-1.09) near or just above the threshold for a self-sustaining epidemic. Hypothetical scenario analysis shows that the epidemiological benefits of highly active antiretroviral therapy and earlier diagnosis on incidence have been entirely offset by increases in the risk behaviour rate. CONCLUSION: We provide the first detailed quantitative analysis of the HIV epidemic in a well defined population and find a resurgent epidemic in the era of highly active antiretroviral therapy, most likely predominantly caused by increasing sexual risk behaviour.

Adaptation of HIV-1 depends on the host-cell environment.

Many viruses have the ability to rapidly develop resistance against antiviral drugs and escape from the host immune system. To which extent the host environment affects this adaptive potential of viruses is largely unknown. Here we show that for HIV-1, the host-cell environment is key to the adaptive potential of the virus. We performed a large-scale selection experiment with two HIV-1 strains in two different T-cell lines (MT4 and C8166). Over 110 days of culture, both virus strains adapted rapidly to the MT4 T-cell line. In contrast, when cultured on the C8166 T-cell line, the same strains did not show any increase in fitness. By sequence analyses and infections with viruses expressing either yellow or cyan fluorescent protein, we were able to show that the absence of adaptation was linked to a lower recombination rate in the C8166 T-cell line. Our findings suggest that if we can manipulate the host-cellular factors that mediate viral evolution, we may be able to significantly retard viral adaptability.

Effects of random mutations in the human immunodeficiency virus type 1 transcriptional promoter on viral fitness in different host cell environments.

A mutation's effect on fitness or phenotype may in part depend on the interaction of the mutation with the environment. The resulting phenotype or fitness is important, since it determines the adaptive potential of a species. To date, most studies have focused on alterations to protein-coding regions of the genome and their consequential fitness effects. Non-protein-coding regulatory regions have been largely neglected, although they make up a large and important part of an organism's genome. Here, we use human immunodeficiency virus type 1 as a model system to investigate fitness effects of random mutations in noncoding DNA-binding sites of the transcriptional promoter. We determined 242 fitness values for 35 viral promoter mutants with one, two, or three mutations across seven distinct cellular environments and identified that (i) all mutants have an effect in at least one cellular environment; (ii) fitness effects are highly dependent on the cellular environment; (iii) disadvantageous and advantageous mutations occur at high and similar frequencies; and (iv) epistatic effects of multiple mutations are rare. Our results underline the evolutionary potential of regulatory regions and indicate that DNA-binding sites evolve under strong selection, while at the same time, they are very plastic to environmental change.

Role of avidity and breadth of the CD4 T cell response in progression to AIDS.

The great variability in the time between infection with HIV and the onset of AIDS has been the object of intense study. In the current work, we examine a mathematical model that focuses on the role of immune response variability between patients. We study the effect of variation in both the avidity and the breadth of the immune response on within-patient disease dynamics, viral setpoint and time to AIDS. We conclude that immune response variability can explain the observed variability in disease progression to a large extent. It turns out that the avidity, more than the breadth of the immune response, determines disease progression, and that the average avidity of the five best clones is a much better correlate for disease progression than the total number of clones responding. For the design of vaccines, this would suggest that, if given the choice between stimulating a broader, but average avidity response or a narrower high-avidity response, the latter option would yield better control of virus load and consequently slow down disease progression.

Emergent trade-offs and selection for outbreak frequency in spatial epidemics.

Nonspatial theory on pathogen evolution generally predicts selection for maximal number of secondary infections, constrained only by supposed physiological trade-offs between pathogen infectiousness and virulence. Spread of diseases in human populations can, however, exhibit large scale patterns, underlining the need for spatially explicit approaches to pathogen evolution. Here, we show, in a spatial model where all pathogen traits are allowed to evolve independently, that evolutionary trajectories follow a single relationship between transmission and clearance. This trade-off relation is an emergent system property, as opposed to being a property of pathogen physiology, and maximizes outbreak frequency instead of the number of secondary infections. We conclude that spatial pattern formation in contact networks can act to link infectiousness and clearance during pathogen evolution in the absence of any physiological trade-off. Selection for outbreak frequency offers an explanation for the evolution of pathogens that cause mild but frequent infections.

Human immunodeficiency virus type 1 subtypes have a distinct long terminal repeat that determines the replication rate in a host-cell-specific manner.

The long terminal repeat (LTR) transcriptional promoters of different human immunodeficiency virus (HIV) type 1 subtypes were inserted into the LAI molecular clone of subtype B. The viral genotypes represent seven subtypes (A, B, C, D, E, F, and G) and one circulating recombinant form (AG). We performed replication studies with this isogenic set of viruses across six cellular environments. This approach revealed strong cellular environment effects, but the method was not sensitive enough to detect small differences in the replication rate between the subtypes. By conducting pairwise competition experiments between the virus variants in six cellular environments, we could demonstrate significant differences in the replication rates of the subtypes and that LTR-determined viral fitness depends both on the host cell type and the activation state of the cell. In addition, we determined the degree of conservation of the transcription factor-binding sites (TFBS) in the different-subtype LTRs by analyzing sequences from the HIV sequence database. The sequence analyses revealed subtype-specific conservation of certain TFBS. The results indicate that one should consider the possibility of subtype-specific viral replication rates in vivo, which are strongly influenced by the host environment. We argue that the multidimensional host environment may have shaped the genetic structures of the subtype LTRs.

AIDS vaccines that allow HIV-1 to infect and escape immunologic control: a mathematic analysis of mass vaccination.

Cytotoxic T lymphocyte (CTL)-based HIV vaccine concepts shown to reduce viremia and postpone disease but not to prevent infection in monkeys are currently in human phase 1 trials. To evaluate the potential efficacy of vaccines that cannot prevent HIV-1 to infect and escape immunologic control, we designed a mathematic model that correlates the level of viremia to both infectiousness and disease progression. We speculate that vaccinees will have a virologic set point and disease progression rates comparable to untreated HIV-1-infected individuals with the best prognosis. Our model (illustrated with R0 = 3) shows that a sexually active population can ultimately be reduced to 26% of its initial size as a result of AIDS-related mortality in the absence of treatment or vaccination. Start of vaccination when HIV-1 prevalence is still low might postpone the peak incidence of infection and the dramatic decline in population size by up to 22 years. In conclusion, CTL-based vaccines that do not prevent HIV-1 infection but do postpone the time to onset of AIDS have considerable potential to curb the spread of HIV-1 and to postpone high AIDS-related mortality on a population level. The number of long-term survivors is substantially increased only when vaccination is initiated early in an AIDS epidemic, however.