Model with two types of CTL regulation and experiments on CTL dynamics.

Recently, we developed a mathematical model of interaction between the HIV and the immune system to match various dynamic experiments carried out in HIV-infected humans and SIV-infected macaques. The model includes helper cell-dependent and helper cell-independent cytotoxic lymphocytes (CTLs) and predicts two stable steady states, a state with a high virus load and few helper cells, and another state with a low virus load and many helper cells. Here we upgrade the model to take into account recent reports on the link between the activation status of infected cells and their ability to produce virus, the effect of helper cells at the time of priming on CTL differentiation, and virus dynamics in unvaccinated macaques with a broad genetic background acutely infected with SIVmac251. We also discuss in detail the experimental justification of the CTL block and the robustness of model predictions with respect to the hypothesis of two CTL subtypes.

Interpreting the effect of vaccination on steady state infection in animals challenged with Simian immunodeficiency virus.

A representative vaccinated macaque challenged with SIVmac251 establishes a persistent infection with a lower virus load, higher CTL frequencies, and much higher helper cell frequencies, than a representative control animal. The reasons for the difference are not fully understood. Here we interpret this effect using a mathematical model we developed recently to explain results of various experiments on virus and CTL dynamics in SIV-infected macaques and HIV-infected humans. The model includes two types of cytotoxic lymphocytes (CTLs) regulated by antigen-activated helper cells and directly by infected cells, respectively, and predicts the existence of two steady states with different viremia, helper cell and CTL levels. Depending on the initial level of CTL memory cells and helper cells, a representative animal ends up in either the high-virus state or the low-virus state, which accounts for the observed differences between the two animal groups. Viremia in the low-virus state is proportional to the antigen sensitivity threshold of helper cells. Estimating the infectivity ratio of activated and resting CD4 T cells at 200-300, the correct range for the critical memory cell percentage and the viremia peak suppression is predicted. However, the model does not explain why viremia in the "low-virus state" is surprisingly high , relative to vaccinated animals infected with SHIV, and broadly distributed among challenged animals. We conclude that the model needs an update explaining extremely low sensitivity of uninfected helper cells to antigen in vaccinated animals.

Two types of cytotoxic lymphocyte regulation explain kinetics of immune response to human immunodeficiency virus.

The organization of the cytotoxic T lymphocyte (CTL) response at organismal level is poorly understood. We propose a mathematical model describing the interaction between HIV and its host that explains 20 quantitative observations made in HIV-infected individuals and simian immunodeficiency virus-infected monkeys, including acute infection and response to various antiretroviral therapy regimens. The model is built on two modes of CTL activation: direct activation by infected cells and indirect activation by CD4 helper cells activated by small amounts of virus. Effective infection of helper cells by virus leads to a stable chronic infection at high virus load. We assume that CTLs control virus by killing infected cells. We explain the lack of correlation between the CTL number and the virus decay rate in therapy and predict that individuals with a high virus load can be switched to a low-viremia state that will maintain stability after therapy, but the switch requires fine adjustment of therapy regimen based on the model and individual parameters.

[The dynamic function of the motor apparatus of the respiratory system during maximal voluntary hyperventilation under hypoxia and hypercapnia]. / Dinamika funktsional'nogo sostoianiia motornogo apparata sistemy dykhaniia v protsesse maksimal'noi proizvol'noi giperventiliatsii v usloviiakh gipoksii i giperkapnii.

The working ability in the course of hyperventilation can be divided into three stages: the adaptation, stable working ability, the fatigue. Hypoxia decreased the duration and intensity of voluntary hyperventilation. During hypercapnia, the hyperventilation is more intensive and shorter. The data obtained suggest a co-operation of one's own will and chemoreceptor stimuli under hypoxia and hypercapnia.