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

Abstract

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.

Recombination-mediated escape from primary CD8+ T cells in acute HIV-1 infection

“…HIV-1 is highly recombinogenic [26] and HIV-1 recombination has been observed in patients infected with multiple viruses within weeks-months of infection [12,14,15,17]. Although none of these acute-phase studies have experimentally linked the emergence of recombinants to immune responses, several mathematical models have suggested that recombination may impact escape from CD8+ T cell responses [27,28]. Such associations have been suggested in one study of superinfection during the chronic stage of HIV-1 infection [29].…”

Evolutionary Analysis of Human Immunodeficiency Virus Type 1 Therapies Based on Conditionally Replicating Vectors

“…In peripheral blood of untreated HIV-1 patients, the frequencies of multiple infection among all infected CD4 + T cells are 2.6% and 7.0% for acute and chronic infection, respectively [60]. Substituting our model parameters into a model for HIV-1 superinfection following the approach developed in a recent study [59], we obtain a prediction that 2.6% of all infected cells will be multiply infected, indicating that our assumed superinfection rate maps onto the lower range of observed values (Text S1). In our simulations, the frequency of T cells dually infected by HIV-1 and TIP among all infected cells is around 0.4%, which is much lower than the predicted value.…”

Multiscale modeling of virus replication and spread

“…Several extensions to the standard model have been made to account for additional processes, such as intracellular delay , multiple infection of target cells , and viral mutations . Some of the model extensions including more sophisticated approximations of the intracellular replication cycle allowed a theoretical analysis of expected infection dynamics and disease progression while not being appropriate to quantitate actual processes. These models helped to identify conditions under which drug resistant mutants arise , and identified appropriate targets for drug treatment .…”

“…Some of the model extensions including more sophisticated approximations of the intracellular replication cycle allowed a theoretical analysis of expected infection dynamics and disease progression while not being appropriate to quantitate actual processes. These models helped to identify conditions under which drug resistant mutants arise , and identified appropriate targets for drug treatment . Further extensions to the standard model allowed the analysis and quantitation of intracellular processes in more detail.…”