HLA-mediated control and CD8+ T cell response mechanisms in persistent viral infections

Background: There are many viruses that result in persistent infections affecting millions of people worldwide. Although our immune system deploys different strategies to eliminate them, many times they prove unsuccessful and call for a better understanding of the host-virus interplay. One important weapon of the immune system is CD8+ T cells which identify infected cells and limit the spread of infection using different effector mechanisms. Aim: The aim of this study is two-fold; the investigation of 1) the impact of immunogenetic factors such as HLA class I molecules and Killer cell immunoglobulin-like receptors (KIRs) on CD8+ T cell responses and 2) the efficiency of lytic and non-lytic CD8+ T cell responses and how they shape viral escape dynamics. Methods: The methods used to address the aims include statistical models, high-throughput sequence analysis, ordinary differential equation models and agent-based models. Results: We find that HLA class I molecules explain a small percentage of the heterogeneity observed in the outcome of HCV, HTLV-1 and HIV infections. However, we show that an inhibitory KIR, namely KIR2DL2, can enhance both protective and detrimental HLA class I-restricted anti-viral immunity, for both HCV and HTLV-1 infections and in a manner compatible with the modulation of CD8+ T cell downstream responses. Furthermore, for HIV/SIV infection, we show that the CD8+ T cell control of the infection can be consistent with a non-lytic mechanism. Additionally, we find that lytic CD8+ T cell responses are more efficient than non-lytic responses which can lead to slower and less frequent viral escape explained by spatial factors. Conclusions: We conclude that KIRs can play an important role in shaping HLA class-I mediated immunity and suggest that this occurs in synergy with CD8+ T cells whose lytic and non-lytic effector functions can differ in efficiency and lead to variable viral escape rates

Why Don't CD8+ T Cells Reduce the Lifespan of SIV-Infected Cells In Vivo?

In January 2010 two groups independently published the observation that the depletion of CD8+ cells in SIV-infected macaques had no detectable impact on the lifespan of productively infected cells. This unexpected observation led the authors to suggest that CD8+ T cells control SIV viraemia via non-lytic mechanisms. However, a number of alternative plausible explanations, compatible with a lytic model of CD8+ T cell control, were proposed. This left the field with no consensus on how to interpret these experiments and no clear indication whether CD8+ T cells operated primarily via a lytic or a non-lytic mechanism. The aim of this work was to investigate why CD8+ T cells do not appear to reduce the lifespan of SIV-infected cells in vivo

A Differential Network Approach to Exploring Differences between Biological States: An Application to Prediabetes

Background: Variations in the pattern of molecular associations are observed during disease development. The comprehensive analysis of molecular association patterns and their changes in relation to different physiological conditions can yield insight into the biological basis of disease-specific phenotype variation. Methodology: Here, we introduce a formal statistical method for the differential analysis of molecular associations via network representation. We illustrate our approach with extensive data on lipoprotein subclasses measured by NMR spectroscopy in 4,406 individuals with normal fasting glucose, and 531 subjects with impaired fasting glucose (prediabetes). We estimate the pair-wise association between measures using shrinkage estimates of partial correlations and build the differential network based on this measure of association. We explore the topological properties of the inferred network to gain insight into important metabolic differences between individuals with normal fasting glucose and prediabetes. Conclusions/Significance: Differential networks provide new insights characterizing differences in biological states. Based on conventional statistical methods, few differences in concentration levels of lipoprotein subclasses were found between individuals with normal fasting glucose and individuals with prediabetes. By performing the differential analysis of networks, several characteristic changes in lipoprotein metabolism known to be related to diabetic dyslipidemias were identified. The results demonstrate the applicability of the new approach to identify key molecular changes inaccessible to standard approaches

The Efficiency of the Human CD8+ T Cell Response: How Should We Quantify It, What Determines It, and Does It Matter?

Multidisciplinary techniques, in particular the combination of theoretical and experimental immunology, can address questions about human immunity that cannot be answered by other means. From the turnover of virus-infected cells in vivo, to rates of thymic production and HLA class I epitope prediction, theoretical techniques provide a unique insight to supplement experimental approaches. Here we present our opinion, with examples, of some of the ways in which mathematics has contributed in our field of interest: the efficiency of the human CD8+ T cell response to persistent viruses

Local Increase of Arginase Activity in Lesions of Patients with Cutaneous Leishmaniasis in Ethiopia

The leishmaniases are a complex of diseases caused by Leishmania parasites. Currently, the diseases affect an estimated 12 million people in 88 countries, and approximately 350 million more people are at risk. The leishmaniases belong to the most neglected tropical diseases, affecting the poorest populations, for whom access to diagnosis and effective treatment are often not available. Leishmania parasites infect cells of the immune system called macrophages, which have the capacity to eliminate the intracellular parasites when they receive the appropriate signals from other cells of the immune system. In nonhealing persistent leishmaniasis, lymphocytes are unable to transmit the signals to macrophages required to kill the intracellular parasites. The local upregulation of the enzyme arginase has been shown to impair lymphocyte effector functions at the site of pathology. In this study, we tested the activity of this enzyme in skin lesions of patients presenting with localized cutaneous leishmaniasis. Our results show that arginase is highly upregulated in these lesions. This increase in arginase activity coincides with lower expression of a signalling molecule in lymphocytes, which is essential for efficient activation of these cells. These results suggest that increased arginase expression in the localized cutaneous lesions might contribute to persistent disease in patients presenting with cutaneous leishmaniasis

Can Non-lytic CD8+T Cells Drive HIV-1 Escape?

The CD8+ T cell effector mechanisms that mediate control of HIV-1 and SIV infections remain poorly understood. Recent work suggests that the mechanism may be primarily non-lytic. This is in apparent conflict with the observation that SIV and HIV-1 variants that escape CD8+ T cell surveillance are frequently selected. Whilst it is clear that a variant that has escaped a lytic response can have a fitness advantage compared to the wild-type, it is less obvious that this holds in the face of non-lytic control where both wild-type and variant infected cells would be affected by soluble factors. In particular, the high motility of T cells in lymphoid tissue would be expected to rapidly destroy local effects making selection of escape variants by non-lytic responses unlikely. The observation of frequent HIV-1 and SIV escape poses a number of questions. Most importantly, is the consistent observation of viral escape proof that HIV-1- and SIV-specific CD8+ T cells lyse infected cells or can this also be the result of non-lytic control? Additionally, the rate at which a variant strain escapes a lytic CD8+ T cell response is related to the strength of the response. Is the same relationship true for a non-lytic response? Finally, the potential anti-viral control mediated by non-lytic mechanisms compared to lytic mechanisms is unknown. These questions cannot be addressed with current experimental techniques nor with the standard mathematical models. Instead we have developed a 3D cellular automaton model of HIV-1 which captures spatial and temporal dynamics. The model reproduces in vivo HIV-1 dynamics at the cellular and population level. Using this model we demonstrate that non-lytic effector mechanisms can select for escape variants but that outgrowth of the variant is slower and less frequent than from a lytic response so that non-lytic responses can potentially offer more durable control

The variation in outcome that can be explained by individual HLA class I alleles in HIV-1, HTLV-1 and HCV infections.

<p>The explained fraction (EF) was calculated following Nelson <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002381#pcbi.1002381-Nelson1" target="_blank">[82]</a>; data for HCV and HTLV-1 were taken from <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002381#pcbi.1002381-SeichAlBasatena1" target="_blank">[56]</a>, and data for HIV-1 were taken from <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002381#pcbi.1002381-Pereyra1" target="_blank">[40]</a>, <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002381#pcbi.1002381-Emu1" target="_blank">[83]</a>. 95% confidence intervals were estimated by bootstrapping the data 5,000 times, trimming the 5% extremes, and then calculating the range in which 95% of the remaining data lay. Due to linkage between the HLA alleles, the EF is not additive; so for instance, in HTLV-1 infection, the three alleles <i>HLA-A*02</i>, <i>C*08</i>, and <i>B*54</i> together only explain 6.6% of the outcome. The outcomes explained are HCV: spontaneous clearance v persistence; HTLV-1: asymptomatic carriage v HAM/TSP; HIV-1: elite control v viremic control v progression.</p

CD8+ T cells recognise virally infected cells via their T cell receptor (TCR).

<p>The TCR binds complexes of viral peptides and HLA class I molecules at the surface of virus-infected cells. Following CD8+ T cell recognition of the infected cell, the CD8+ T cell effector mechanisms are triggered. CD8+ effector mechanisms can be lytic (killing of the infected cell) and/or non-lytic (secretion of cytokines such as IFNg and TNFa which reduce the probability of cell infection and viral production).</p

The effect of genomic inversions on estimation of population genetic parameters from SNP data

In recent years it has emerged that structural variants have a substantial impact on genomic variation. Inversion polymorphisms represent a significant class of structural variant, and despite the challenges in their detection, data on inversions in the human genome are increasing rapidly. Statistical methods for inferring parameters such as the recombination rate and the selection coefficient have generally been developed without accounting for the presence of inversions. Here we exploit new software for simulating inversions in population genetic data, invertFREGENE, to assess the potential impact of inversions on such methods. Using data simulated by invertFREGENE, as well as real data from several sources, we test whether large inversions have a disruptive effect on widely applied population genetics methods for inferring recombination rates, for detecting selection, and for controlling for population structure in genome-wide association studies (GWAS). We find that recombination rates estimated by LDhat are biased downward at inversion loci relative to the true contemporary recombination rates at the loci but that recombination hotspots are not falsely inferred at inversion breakpoints as may have been expected. We find that the integrated haplotype score (iHS) method for detecting selection appears robust to the presence of inversions. Finally, we observe a strong bias in the genome-wide results of principal components analysis (PCA), used to control for population structure in GWAS, in the presence of even a single large inversion, confirming the necessity to thin SNPs by linkage disequilibrium at large physical distances to obtain unbiased results