Estimating the Impact of Vaccination on Acute Simian-Human Immunodeficiency Virus/Simian Immunodeficiency Virus Infections

Complex Systems in Biology Group, Centre for Vascular Research, University of New South Wales 2052, New South Wales, Australia.
Journal of Virology (Impact Factor: 4.44). 10/2008; 82(23):11589-98. DOI: 10.1128/JVI.01596-08
Source: PubMed


The dynamics of HIV infection have been studied in humans and in a variety of animal models. The standard model of infection
has been used to estimate the basic reproductive ratio of the virus, calculated from the growth rate of virus in acute infection.
This method has not been useful in studying the effects of vaccination, since, for the vaccines developed so far, early growth
rates of virus do not differ between control and vaccinated animals. Here, we use the standard model of viral dynamics to
derive the reproductive ratio from the peak viral load and nadir of target cell numbers in acute infection. We apply this
method to data from studies of vaccination in SHIV and SIV infection and demonstrate that vaccination can reduce the reproductive
ratio by 2.3- and 2-fold, respectively. This method allows the comparison of vaccination efficacies among different viral
strains and animal models in vivo.

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    • "For example, the number of uninfected (and infected) cells in the lungs or respiratory tracts of macaques, ferrets and mice that were experimentally infected with influenza could be measured [30,31,34]. Using the CXCR4-tropic SHIV/macaque model, both target cell densities (naïve and memory CD4 T cells) and viral loads from PB have been measured [14,16,26-28]. The target cells of simian immunodeficiency virus (SIV), or CCR5-tropic SHIV infection (memory CD4 T cells expressing CCR5), have been measured from gastrointestinal mucosa samples [15]. "
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    ABSTRACT: Background Mathematical modeling of virus dynamics has provided quantitative insights into viral infections such as influenza, the simian immunodeficiency virus/human immunodeficiency virus, hepatitis B, and hepatitis C. Through modeling, we can estimate the half-life of infected cells, the exponential growth rate, and the basic reproduction number (R0). To calculate R0 from virus load data, the death rate of productively infected cells is required. This can be readily estimated from treatment data collected during the chronic phase, but is difficult to determine from acute infection data. Here, we propose two new models that can reliably estimate the average life span of infected cells from acute-phase data, and apply both methods to experimental data from humanized mice infected with HIV-1. Methods Both new models, called as the reduced quasi-steady state (RQS) model and the piece-wise regression (PWR) model, are derived by simplification of a standard model for the acute-phase dynamics of target cells, viruses and infected cells. By having only a limited number of parameters, both models allow us to reliably estimate the death rate of productively infected cells. Simulated datasets with plausible parameter values are generated with the standard model to compare the performance of the new models with that of the major previous model (i.e., the simple exponential model). Finally, we fit models to time course data from HIV-1 infected humanized mice to estimate the several important parameters characterizing their acute infection. Results and conclusions The new models provided much better estimates than the previous model because they more precisely capture the de novo infection process. Both models describe the acute phase of HIV-1 infected humanized mice reasonably well, and we estimated an average death rate of infected cells of 0.61 and 0.61, an average exponential growth rate of 0.69 and 0.76, and an average basic reproduction number of 2.30 and 2.38 in the RQS model and the PWR model, respectively. These estimates are fairly close to those obtained in humans.
    Full-text · Article · May 2014 · Theoretical Biology and Medical Modelling
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    • "Target cells drop to the nadir Tmin, then partly recover, and settle at the steady-state value T*. The nadir of target cells in the standard model applied to SHIV is the solution of the equation [28] "
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    ABSTRACT: Identifying early predictors of infection outcome is important for the clinical management of HIV infection, and both viral load and CD4+ T cell level have been found to be useful predictors of subsequent disease progression. Very high viral load or extensively depleted CD4+ T cells in the acute phase often result in failure of immune control, and a fast progression to AIDS. It is usually assumed that extensive loss of CD4+ T cells in the acute phase of HIV infection prevents the establishment of robust T cell help required for virus control in the chronic phase. We tested this hypothesis using viral load and CD4+ T cell number of SHIV-infected rhesus macaques. In acute infection, the lowest level of CD4+ T cells was a good predictor of later survival; animals having less than 3.3% of baseline CD4+ T cells progressed to severe disease, while animals with more than 3.3% of baseline CD4+ T cells experienced CD4+ T cell recovery. However, it is unclear if the disease progression was caused by early depletion, or was simply a result of a higher susceptibility of an animal to infection. We derived a simple relationship between the expected number of CD4+ T cells in the acute and chronic phases for a constant level of host susceptibility or resistance. We found that in most cases, the depletion of CD4+ T cells in chronic infection was consistent with the prediction from the acute CD4+ T cell loss. However, the animals with less than 3.3% of baseline CD4 T cells in the acute phase were approximately 20% more depleted late in the infection than expected based on constant level of virus control. This suggests that severe acute CD4 depletion indeed impairs the immune response.
    Full-text · Article · Feb 2011 · PLoS ONE
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    • "In a recent paper [18], we have shown that in CXCR4-tropic SHIV-infected monkeys vaccination significantly reduced peak viral load and increased the lowest CD4+ T cell count in the acute phase of infection. Although we demonstrated the decrease in virus replication in vaccinated animals, we did not identify the specific mechanism (i.e. the CD8+ T cell effector function) responsible for this outcome. "
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    ABSTRACT: Many studies have shown that vaccines inducing CD8+ T cell responses can reduce viral loads and preserve CD4+ T cell numbers in monkey models of HIV infection. The mechanism of viral control by the vaccine-induced CD8+ T cells is usually assumed to be cytolysis of infected cells. However, in addition to cytolysis of infected cells, CD8+ T cells secrete a range of soluble factors that suppress viral replication. We have studied the dynamics of virus and CD4+ T cells in a successful vaccination-challenge model of SHIV infection. We find that better viral control in the acute phase of infection is associated with slower decay of peak viral load. Comparing viral and CD4+ T cell dynamics in acute infection, we find that a cytolytic mode of viral control with direct killing of infected cells is inconsistent with the observed trends. On the other hand, comparison of the predicted effects of noncytolytic CD8+ effector function with the experimental data shows that non-cytolytic control provides a better explanation of the experimental results. Our analysis suggests that vaccine-induced CD8+ T cells control SHIV infection by non-cytolytic means.
    Full-text · Article · Nov 2010 · PLoS ONE
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