Evolution of HIV virulence in response to disease-modifying vaccines: A modeling study.

Pathogens face a tradeoff with respect to virulence; while more virulent strains often have higher per-contact transmission rates, they are also more likely to kill their hosts earlier. Because virulence is a heritable trait, there is concern that a disease-modifying vaccine, which reduces the disease severity of an infected vaccinee without changing the underlying pathogen genotype, may result in the evolution of higher pathogen virulence. We explored the potential for such virulence evolution with a disease-modifying HIV-1 vaccine in an agent-based stochastic epidemic model of HIV in United States men who have sex with men (MSM).

Risk compensation after HIV-1 vaccination may accelerate viral adaptation and reduce cost-effectiveness: a modeling study.

Pathogen populations can evolve in response to selective pressure from vaccine-induced immune responses. For HIV, models predict that viral adaptation, either via strain replacement or selection on de novo mutation, may rapidly reduce the effectiveness of an HIV vaccine. We hypothesized that behavioral risk compensation after vaccination may accelerate the transmission of vaccine resistant strains, increasing the rate of viral adaptation and leading to a more rapid decline in vaccine effectiveness.

Test-and-treat coverage and HIV virulence evolution among men who have sex with men.

HIV set point viral load (SPVL), the viral load established shortly after initial infection, is a proxy for HIV virulence: higher SPVLs lead to higher risk of transmission and faster disease progression. Three models of test-and-treat scenarios, mainly in heterosexual populations, found that increasing treatment coverage selected for more virulent viruses. We modeled virulence evolution in a population of men who have sex with men (MSM) with increasing test-and-treat coverage.

Models to predict the public health impact of vaccine resistance: A systematic review.

Pathogen evolution is a potential threat to the long-term benefits provided by public health vaccination campaigns. Mathematical modeling can be a powerful tool to examine the forces responsible for the development of vaccine resistance and to predict its public health implications. We conducted a systematic review of existing literature to understand the construction and application of vaccine resistance models.

HIV population-level adaptation can rapidly diminish the impact of a partially effective vaccine.

Background: Development of an HIV vaccine might be essential to ending the HIV/AIDS pandemic. However, vaccines can result in the emergence and spread of vaccine-resistant strains. Indeed, analyses of breakthrough infections in the HIV phase 3 vaccine trial RV144 identified HIV genotypes with differential rates of transmission in vaccine and placebo recipients.

Evolution of HIV virulence in response to widespread scale up of antiretroviral therapy: a modeling study.

There are global increases in the use of HIV antiretroviral therapy (ART), guided by clinical benefits of early ART initiation and the efficacy of treatment as prevention of transmission. Separately, it has been shown theoretically and empirically that HIV virulence can evolve over time; observed virulence levels may reflect an adaptive balance between infected lifespan and per-contact transmission rate. However, the potential effects of widespread ART usage on HIV virulence are unknown.

Mycobacterium tuberculosis strains lacking surface lipid phthiocerol dimycocerosate are susceptible to killing by an early innate host response.

The innate immune response plays an important but unknown role in host defense against Mycobacterium tuberculosis. To define the function of innate immunity during tuberculosis, we evaluated M. tuberculosis replication dynamics during murine infection.

Acyl-homoserine lactone-dependent eavesdropping promotes competition in a laboratory co-culture model.

Many Proteobacteria use acyl-homoserine lactone (AHL)-mediated quorum sensing to activate the production of antibiotics at high cell density. Extracellular factors like antibiotics can be considered public goods shared by individuals within a group. Quorum-sensing control of antibiotic production may be important for protecting a niche or competing for limited resources in mixed bacterial communities.

Construction of regulatory networks using expression time-series data of a genotyped population.

The inference of regulatory and biochemical networks from large-scale genomics data is a basic problem in molecular biology. The goal is to generate testable hypotheses of gene-to-gene influences and subsequently to design bench experiments to confirm these network predictions. Coexpression of genes in large-scale gene-expression data implies coregulation and potential gene-gene interactions, but provide little information about the direction of influences.

Competition favours reduced cost of plasmids to host bacteria.

Conjugative plasmids of Gram-negative bacteria have both vertical and horizontal modes of transmission: they are segregated to daughter cells during division, and transferred between hosts by plasmid-encoded conjugative machinery. Despite maintaining horizontal mobility, many plasmids carry fertility inhibition (fin) systems that repress their own conjugative transfer. To assess the ecological basis of self-transfer repression, we compared the invasion of bacterial populations by fin(+) and fin(-) variants of the plasmid R1 using a computational model and co-culture competitions.

Selection dramatically reduces effective population size in HIV-1 infection.

Background: In HIV-1 evolution, a 100-100,000 fold discrepancy between census size and effective population size (Ne) has been noted. Although it is well known that selection can reduce Ne, high in vivo mutation and recombination rates complicate attempts to quantify the effects of selection on HIV-1 effective size.

Results: We use the inbreeding coefficient and the variance in allele frequency at a linked neutral locus to estimate the reduction in Ne due to selection in the presence of mutation and recombination.

Optimal timing and duration of induction therapy for HIV-1 infection.

The tradeoff between the need to suppress drug-resistant viruses and the problem of treatment toxicity has led to the development of various drug-sparing HIV-1 treatment strategies. Here we use a stochastic simulation model for viral dynamics to investigate how the timing and duration of the induction phase of induction-maintenance therapies might be optimized. Our model suggests that under a variety of biologically plausible conditions, 6-10 mo of induction therapy are needed to achieve durable suppression and maximize the probability of eradicating viruses resistant to the maintenance regimen.

Granulocyte-monocyte colony-stimulating factor upregulates HIV-1 replication in monocyte-derived macrophages cultured at low density.

The effects that granulocyte-monocyte colony-stimulating factor (GM-CSF) has on HIV-1 replication in monocyte-derived macrophage are controversial. We noted that groups reporting that GM-CSF inhibits HIV-1 replication performed their experiments at relatively high cell densities. To address this issue, we performed experiments at different macrophage densities.

Cachers, scavengers, and thieves: a novel mechanism for desert rodent coexistence.

A biologically explicit simulation model of resource competition between two species of seed-eating heteromyid rodent indicates that stable coexistence is possible on a homogeneous resource if harvested food is stored and consumers steal each other's caches. Here we explore the coexistence mechanisms involved by analyzing how consumer phenotypes and presence of a noncaching consumer affect the competitive outcome. Without cache exchange, the winning consumer is better at harvesting seeds and produces more offspring per gram of stored food.