Dataset Information

Pleocytosis is associated with disruption of HIV compartmentalization between blood and cerebral spinal fluid viral populations.

ABSTRACT:

Introduction

We hypothesized that pleocytosis, which is a marker of central nervous system (CNS) inflammation, would result in viral genetic equilibration or de-compartmentalization between HIV populations in the blood and cerebrospinal fluid (CSF), suggesting viral trafficking.

Methods

Study subjects, who started or interrupted their antiretroviral treatment, had viral loads measured and clonal viral env sequences generated from HIV RNA extracted from paired blood and CSF samples. White blood counts in CSF were also measured at each timepoint. Degree of inter-compartment segregation was calculated by posterior probability using linear discriminant analysis and multidimensional scaling. Co-receptor usage was determined using a trained support vector machine.

Results

Pleocytosis was strongly associated with disruption of viral compartmentalization.

Conclusions

Inflammation in the CNS, marked by pleocytosis, allows HIV populations to mix between blood and CSF, which may increase the overall viral genetic diversity within the CSF.

SUBMITTER: Smith DM

PROVIDER: S-EPMC2794037 | biostudies-literature | 2009 Mar

REPOSITORIES: biostudies-literature

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Publications

Pleocytosis is associated with disruption of HIV compartmentalization between blood and cerebral spinal fluid viral populations.

Smith Davey M DM Zárate Selene S Shao Hai H Pillai Satish K SK Letendre Scott L SL Wong Joseph K JK Richman Douglas D DD Frost Simon D W SD Ellis Ronald J RJ

Virology 20081218 1

<h4>Introduction</h4>We hypothesized that pleocytosis, which is a marker of central nervous system (CNS) inflammation, would result in viral genetic equilibration or de-compartmentalization between HIV populations in the blood and cerebrospinal fluid (CSF), suggesting viral trafficking.<h4>Methods</h4>Study subjects, who started or interrupted their antiretroviral treatment, had viral loads measured and clonal viral env sequences generated from HIV RNA extracted from paired blood and CSF samples ...[more]

PMID: 19100592

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Project description:One challenge in conducting DNA methylation-based epigenome-wide association study (EWAS) is the appropriate cleaning and quality-checking of data to minimize biases and experimental artifacts, while simultaneously retaining potential biological signals. These issues are compounded in studies that include multiple tissue types, and/or tissues for which reference data are unavailable to assist in adjusting for cell-type mixture, for example cerebral spinal fluid (CSF). For our study that evaluated blood and CSF taken from aneurysmal subarachnoid hemorrhage (aSAH) patients, we developed a protocol to clean and quality-check genome-wide methylation levels and compared the methylomic profiles of the two tissues to determine whether blood is a suitable surrogate for CSF. CSF samples were collected from 279 aSAH patients longitudinally during the first 14 days of hospitalization, and a subset of 88 of these patients also provided blood samples within the first 2 days. Quality control (QC) procedures included identification and exclusion of poor performing samples and low-quality probes, functional normalization, and correction for cell-type heterogeneity via surrogate variable analysis (SVA). Significant differences in rates of poor sample performance was observed between blood (1.1% failing QC) and CSF (9.12% failing QC; p = 0.003). Functional normalization increased the concordance of methylation values among technical replicates in both CSF and blood. SVA improved the asymptotic behavior of the test of association in a simulated EWAS under the null hypothesis. To determine the suitability of blood as a surrogate for CSF, we calculated the correlations of adjusted methylation values at each CpG between blood and CSF globally and by genomic regions. Overall, mean within-CpG correlation was low (r < 0.26), suggesting that blood is not a suitable surrogate for global methylation in CSF. However, differences in the magnitude of the correlation were observed by genomic region (CpG island, shore, shelf, open sea; p < 0.001 for all) and orientation with respect to nearby genes (3' UTR, transcription start site, exon, body, 5' UTR; p < 0.01 for all). In conclusion, the correlation analysis and QC pipelines indicated that DNA extracted from blood was not, overall, a suitable surrogate for DNA from CSF in aSAH methylomic studies.

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Project description:BACKGROUND:Compartmentalization of HIV-1 between the genital tract and blood was noted in half of 57 women included in 12 studies primarily using cell-free virus. To further understand differences between genital tract and blood viruses of women with chronic HIV-1 infection cell-free and cell-associated virus populations were sequenced from these tissues, reasoning that integrated viral DNA includes variants archived from earlier in infection, and provides a greater array of genotypes for comparisons. METHODOLOGY/PRINCIPAL FINDINGS:Multiple sequences from single-genome-amplification of HIV-1 RNA and DNA from the genital tract and blood of each woman were compared in a cross-sectional study. Maximum likelihood phylogenies were evaluated for evidence of compartmentalization using four statistical tests. Genital tract and blood HIV-1 appears compartmentalized in 7/13 women by >/=2 statistical analyses. These subjects' phylograms were characterized by low diversity genital-specific viral clades interspersed between clades containing both genital and blood sequences. Many of the genital-specific clades contained monotypic HIV-1 sequences. In 2/7 women, HIV-1 populations were significantly compartmentalized across all four statistical tests; both had low diversity genital tract-only clades. Collapsing monotypic variants into a single sequence diminished the prevalence and extent of compartmentalization. Viral sequences did not demonstrate tissue-specific signature amino acid residues, differential immune selection, or co-receptor usage. CONCLUSIONS/SIGNIFICANCE:In women with chronic HIV-1 infection multiple identical sequences suggest proliferation of HIV-1-infected cells, and low diversity tissue-specific phylogenetic clades are consistent with bursts of viral replication. These monotypic and tissue-specific viruses provide statistical support for compartmentalization of HIV-1 between the female genital tract and blood. However, the intermingling of these clades with clades comprised of both genital and blood sequences and the absence of tissue-specific genetic features suggests compartmentalization between blood and genital tract may be due to viral replication and proliferation of infected cells, and questions whether HIV-1 in the female genital tract is distinct from blood.

Dataset Information

Pleocytosis is associated with disruption of HIV compartmentalization between blood and cerebral spinal fluid viral populations.

Introduction

Methods

Results

Conclusions

Publications

Pleocytosis is associated with disruption of HIV compartmentalization between blood and cerebral spinal fluid viral populations.

Similar Datasets

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