Time Scales of CD4+ T Cell Depletion in HIV Infection

Rob De Boer discusses a new study that investigated whether a runaway process of T cell activation/infection would be compatible with the slow time scale of memory CD4+ T cell depletion in humans with chronic HIV infection

Impaired immune evasion in HIV through intracellular delays and multiple infection of cells

With its high mutation rate, HIV is capable of escape from recognition, suppression and/or killing by CD8(+) cytotoxic T lymphocytes (CTLs). The rate at which escape variants replace each other can give insights into the selective pressure imposed by single CTL clones. We investigate the effects of specific characteristics of the HIV life cycle on the dynamics of immune escape. First, it has been found that cells in HIV-infected patients can carry multiple copies of proviruses. To investigate how this process affects the emergence of immune escape, we develop a mathematical model of HIV dynamics with multiple infections of cells. Increasing the frequency of multiple-infected cells delays the appearance of immune escape variants, slows down the rate at which they replace the wild-type variant and can even prevent escape variants from taking over the quasi-species. Second, we study the effect of the intracellular eclipse phase on the rate of escape and show that escape rates are expected to be slower than previously anticipated. In summary, slow escape rates do not necessarily imply inefficient CTL-mediated killing of HIV-infected cells, but are at least partly a result of the specific characteristics of the viral life cycle

The Integration Hypothesis: An Evolutionary Pathway to Benign SIV Infection

Untreated human immunodeficiency virus (HIV) infection in humans is typically characterised by persistent high virus load, failure of the immune response to clear the virus, and fatal disease outcome. Natural hosts of closely related simian immunodeficiency viruses (SIVs)—e.g., sooty mangabeys [1,2]—maintain comparably high persistent virus levels and yet remain healthy

The black silicon method: a universal method for determining the parameter setting of a fluorine-based reactive ion etcher in deep silicon trench etching with profile control

Very deep trenches (up to 200 µm) with high aspect ratios (up to 10) in silicon and polymers are etched using a fluorine-based plasma (SF6/O2/CHF3). Isotropic, positively and negatively (i.e. reverse) tapered as well as fully vertical walls with smooth surfaces are achieved by controlling the plasma chemistry. A convenient way to find the processing conditions needed for a vertical wall is described: the black silicon method. This new procedure is checked for three different reactive ion etchers (RIE), two parallel-plate reactors and a hexode. The influence of the RF power, pressure and gas mixture on the profile will be shown. Scanning electron microscope (SEM) photos are included to demonstrate the black silicon method, the influence of the gases on the profile, and the use of this method in fabricating microelectromechanical systems (MEMS)

The Specificity and Polymorphism of the MHC Class I Prevents the Global Adaptation of HIV-1 to the Monomorphic Proteasome and TAP

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

Estimating Costs and Benefits of CTL Escape Mutations in SIV/HIV Infection

Mutations that allow SIV/HIV to avoid the cytotoxic T lymphocyte (CTL) response are well documented. Recently, there have been a few attempts at estimating the costs of CTL escape mutations in terms of the reduction in viral fitness and the killing rate at which the CTL response specific to one viral epitope clears virus-infected cells. Using a mathematical model we show that estimation of both parameters depends critically on the underlying changes in the replication rate of the virus and the changes in the killing rate over time (which in previous studies were assumed to be constant). We provide a theoretical basis for estimation of these parameters using in vivo data. In particular, we show that 1) by assuming unlimited virus growth one can obtain a minimal estimate of the fitness cost of the escape mutation, and 2) by assuming no virus growth during the escape, one can obtain a minimal estimate of the average killing rate. We also discuss the conditions under which better estimates of the average killing rate can be obtained

Modeling Networks of Coupled Enzymatic Reactions Using the Total Quasi-Steady State Approximation

In metabolic networks, metabolites are usually present in great excess over the enzymes that catalyze their interconversion, and describing the rates of these reactions by using the Michaelis–Menten rate law is perfectly valid. This rate law assumes that the concentration of enzyme–substrate complex (C) is much less than the free substrate concentration (S (0)). However, in protein interaction networks, the enzymes and substrates are all proteins in comparable concentrations, and neglecting C with respect to S (0) is not valid. Borghans, DeBoer, and Segel developed an alternative description of enzyme kinetics that is valid when C is comparable to S (0). We extend this description, which Borghans et al. call the total quasi-steady state approximation, to networks of coupled enzymatic reactions. First, we analyze an isolated Goldbeter–Koshland switch when enzymes and substrates are present in comparable concentrations. Then, on the basis of a real example of the molecular network governing cell cycle progression, we couple two and three Goldbeter–Koshland switches together to study the effects of feedback in networks of protein kinases and phosphatases. Our analysis shows that the total quasi-steady state approximation provides an excellent kinetic formalism for protein interaction networks, because (1) it unveils the modular structure of the enzymatic reactions, (2) it suggests a simple algorithm to formulate correct kinetic equations, and (3) contrary to classical Michaelis–Menten kinetics, it succeeds in faithfully reproducing the dynamics of the network both qualitatively and quantitatively

Intracellular transactivation of HIV can account for the decelerating decay of virus load during drug therapy

Linking the intracellular transactivation circuit of HIV into a virus dynamics model can account for activation of infected cells and reversion into latency.We hypothesize that the activation of latently infected cells is governed by the basal transcription rate of the integrated provirus rather than through extracellular stimuli.This systems approach to modelling virus dynamics offers a promising framework to infer the extracellular dynamics of cell populations from their intracellular reaction networks

Understanding the Slow Depletion of Memory CD4+ T Cells in HIV Infection

Using a simple mathematical model, Andrew Yates and colleagues show that a runaway cycle of T cell activation and infection cannot explain the slow rate of CD4 decline during chronic HIV infection

Anisotropic reactive ion etching of silicon using SF₆/O₂/CHF₃ gas mixtures

Reactive ion etching of silicon in an RF parallel plate system, using SF6/O2/CHF3, plasmas has been studied. Etching behavior was found to be a function of loading, the cathode material, and the mask material. Good results with respect to reproducibility and uniformity have been obtained by using silicon as the cathode material and silicon dioxide as the masking material for mask designs where most of the surface is etched. Etch rate, selectivity, anisotropy, and self-bias voltage have been examined as a function of SF6 flow, O2 flow, CHF3 flow, pressure, and the RF power, using response surface methodology, in order to optimize anisotropic etching conditions. The effects of the variables on the measured responses are discussed. The anisotropic etch mechanism is based on ion-enhanced inhibitor etching. SF6 provides the reactive neutral etching species, O2 supplies the inhibitor film forming species, and SF6 and CHF3 generate ion species that suppress the formation of the inhibitor film at horizontal surfaces. Anisotropic etching of high aspect ratio structures with smooth etch surfaces has been achieved. The technique is applied to the fabrication of three-dimensional micromechanical structures