Compartmentalized Replication of R5 T Cell-Tropic HIV-1 in the Central Nervous System Early in the Course of Infection
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{"title"=>"Compartmentalized Replication of R5 T Cell-Tropic HIV-1 in the Central Nervous System Early in the Course of Infection", "type"=>"journal", "authors"=>[{"first_name"=>"Christa Buckheit", "last_name"=>"Sturdevant", "scopus_author_id"=>"55548365300"}, {"first_name"=>"Sarah B.", "last_name"=>"Joseph", "scopus_author_id"=>"7202289965"}, {"first_name"=>"Gretja", "last_name"=>"Schnell", "scopus_author_id"=>"26022613000"}, {"first_name"=>"Richard W.", "last_name"=>"Price", "scopus_author_id"=>"7403295986"}, {"first_name"=>"Ronald", "last_name"=>"Swanstrom", "scopus_author_id"=>"7004358853"}, {"first_name"=>"Serena", "last_name"=>"Spudich", "scopus_author_id"=>"9278487100"}], "year"=>2015, "source"=>"PLoS Pathogens", "identifiers"=>{"issn"=>"15537374", "pui"=>"603612659", "pmid"=>"25811757", "isbn"=>"1553-7366", "doi"=>"10.1371/journal.ppat.1004720", "sgr"=>"84926474784", "scopus"=>"2-s2.0-84926474784"}, "id"=>"37ebcc2d-c0ca-3b7f-a1a3-c53850b248c6", "abstract"=>"Compartmentalized HIV-1 replication within the central nervous system (CNS) likely provides a foundation for neurocognitive impairment and a potentially important tissue reservoir. The timing of emergence and character of this local CNS replication has not been defined in a population of subjects. We examined the frequency of elevated cerebrospinal fluid (CSF) HIV-1 RNA concentration, the nature of CSF viral populations compared to the blood, and the presence of a cellular inflammatory response (with the potential to bring infected cells into the CNS) using paired CSF and blood samples obtained over the first two years of infection from 72 ART-naïve subjects. Using single genome amplification (SGA) and phylodynamics analysis of full-length env sequences, we compared CSF and blood viral populations in 33 of the 72 subjects. Independent HIV-1 replication in the CNS (compartmentalization) was detected in 20% of sample pairs analyzed by SGA, or 7% of all sample pairs, and was exclusively observed after four months of infection. In subjects with longitudinal sampling, 30% showed evidence of CNS viral replication or pleocytosis/inflammation in at least one time point, and in approximately 16% of subjects we observed evolving CSF/CNS compartmentalized viral replication and/or a marked CSF inflammatory response at multiple time points suggesting an ongoing or recurrent impact of the infection in the CNS. Two subjects had one of two transmitted lineages (or their recombinant) largely sequestered within the CNS shortly after transmission, indicating an additional mechanism for establishing early CNS replication. Transmitted variants were R5 T cell-tropic. Overall, examination of the relationships between CSF viral populations, blood and CSF HIV-1 RNA concentrations, and inflammatory responses suggested four distinct states of viral population dynamics, with associated mechanisms of local viral replication and the early influx of virus into the CNS. This study considerably enhances the generalizability of our results and greatly expands our knowledge of the early interactions of HIV-1 in the CNS.", "link"=>"http://www.mendeley.com/research/compartmentalized-replication-r5-t-celltropic-hiv1-central-nervous-system-early-course-infection", "reader_count"=>42, "reader_count_by_academic_status"=>{"Unspecified"=>1, "Professor > Associate Professor"=>3, "Librarian"=>1, "Researcher"=>7, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>13, "Other"=>2, "Student > Master"=>4, "Student > Bachelor"=>6, "Lecturer"=>1, "Professor"=>2}, "reader_count_by_user_role"=>{"Unspecified"=>1, "Professor > Associate Professor"=>3, "Librarian"=>1, "Researcher"=>7, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>13, "Other"=>2, "Student > Master"=>4, "Student > Bachelor"=>6, "Lecturer"=>1, "Professor"=>2}, "reader_count_by_subject_area"=>{"Unspecified"=>2, "Biochemistry, Genetics and Molecular Biology"=>6, "Nursing and Health Professions"=>2, "Mathematics"=>1, "Agricultural and Biological Sciences"=>12, "Medicine and Dentistry"=>9, "Neuroscience"=>2, "Psychology"=>1, "Social Sciences"=>1, "Immunology and Microbiology"=>6}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>9}, "Neuroscience"=>{"Neuroscience"=>2}, "Social Sciences"=>{"Social Sciences"=>1}, "Psychology"=>{"Psychology"=>1}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>6}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>12}, "Nursing and Health Professions"=>{"Nursing and Health Professions"=>2}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>6}, "Mathematics"=>{"Mathematics"=>1}, "Unspecified"=>{"Unspecified"=>2}}, "reader_count_by_country"=>{"United Kingdom"=>1, "South Africa"=>1, "France"=>1, "India"=>1}, "group_count"=>0}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1990150"], "description"=>"<p>Values shown are medians (interquartile ranges) except where noted</p><p><sup>a</sup>Subjects with sufficient viral RNA loads in the CSF (>1,000 copies of viral RNA/ml; to ensure adequate sampling) for further SGA analysis at one or more time points within the first two years.</p><p>Background demographic and clinical characteristics of study participants at baseline.</p>", "links"=>[], "tags"=>["sample pairs", "Infection Compartmentalized HIV", "subject", "csf", "rna", "CNS replication", "sga"], "article_id"=>1357152, "categories"=>["Biological Sciences"], "users"=>["Christa Buckheit Sturdevant", "Sarah B. Joseph", "Gretja Schnell", "Richard W. Price", "Ronald Swanstrom", "Serena Spudich"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1004720.t001", "stats"=>{"downloads"=>0, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Background_demographic_and_clinical_characteristics_of_study_participants_at_baseline_/1357152", "title"=>"Background demographic and clinical characteristics of study participants at baseline.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2015-03-26 03:52:34"}
  • {"files"=>["https://ndownloader.figshare.com/files/1990147"], "description"=>"<p>Single-cycle infection of HIV-1 Env-pseudotyped reporter viruses on CD4<sup>low</sup>CCR5<sup>high</sup> 293-Affinofile cells [<a href=\"http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1004720#ppat.1004720.ref028\" target=\"_blank\">28</a>]. Receptor expression was measured as follows: CD4<sup>low</sup> = 972 receptors/cell, CD4<sup>high</sup> = 72,041 receptors/cell, CCR5<sup>high</sup> = 15,636 receptors/cell. The data are averaged from triplicate wells for each of 2 to 3 <i>env</i> clones that were generated per indicated amplicon. Amplicons were selected for cloning to represent different portions of the phylogenetic tree. Subjects with no evidence of CNS compartmentalization (i.e. equilibrated) are shown in panel (A); and subjects with CNS compartmentalization at one or more time points are in panel (B). Longitudinal time points are indicated (T1, T2, T3, etc.) and samples with marked pleocytosis are noted (*).</p>", "links"=>[], "tags"=>["sample pairs", "Infection Compartmentalized HIV", "subject", "csf", "rna", "CNS replication", "sga"], "article_id"=>1357149, "categories"=>["Biological Sciences"], "users"=>["Christa Buckheit Sturdevant", "Sarah B. Joseph", "Gretja Schnell", "Richard W. Price", "Ronald Swanstrom", "Serena Spudich"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1004720.g005", "stats"=>{"downloads"=>0, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_All_viruses_required_high_levels_of_CD4_for_efficient_entry_indicative_of_primarily_being_selected_for_replication_in_CD4_T_cells_/1357149", "title"=>"All viruses required high levels of CD4 for efficient entry, indicative of primarily being selected for replication in CD4+ T cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-03-26 03:52:34"}
  • {"files"=>["https://ndownloader.figshare.com/files/1990145"], "description"=>"<p>Neighbor-joining phylogenetic trees showing how compartmentalization can: (A) be persistent with multiple clonal expansions allowing recombination; (B) consist of sequential transient clonal expansions; and (C) be established with a transmitted variant. <i>env</i> sequences from the CSF are labeled with circles (C, colors designated in figure) and <i>env</i> sequences from the blood plasma are labeled with triangles (P, colors designated in figure). Days p.i. are noted. Bootstrap values ≥ 50 are indicated (*) at the appropriate nodes to highlight the more significant branch points. Genetic distance is indicated at the top of each phylogenetic tree (0.001, number of nucleotide substitutions per site between <i>env</i> sequences.) Compartmentalized populations are indicated at the appropriate node by an open circle and emphasized using a blue bar. BEAST-generated TMRCAs of the entire viral population are noted adjacent to the subject ID, and the TMRCAs of the different compartmentalized linages (subject 9040 and 9021) and transmitted parental lineages (subject 7146) are also noted.</p>", "links"=>[], "tags"=>["sample pairs", "Infection Compartmentalized HIV", "subject", "csf", "rna", "CNS replication", "sga"], "article_id"=>1357148, "categories"=>["Biological Sciences"], "users"=>["Christa Buckheit Sturdevant", "Sarah B. Joseph", "Gretja Schnell", "Richard W. Price", "Ronald Swanstrom", "Serena Spudich"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1004720.g004", "stats"=>{"downloads"=>0, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Compartmentalization_can_persist_and_evolve_independently_within_the_CSF_over_time_/1357148", "title"=>"Compartmentalization can persist and evolve independently within the CSF over time.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-03-26 03:52:34"}
  • {"files"=>["https://ndownloader.figshare.com/files/1990143"], "description"=>"<p>Examination of longitudinal relationships early during infection for 20 subjects with multiple time points where at least one time point was analyzed for viral populations. This group did not differ significantly from the 17 subjects with longitudinal samples available but not analyzed (due to low CSF viral load) in the average number of samples per person or the time span covered. Within individual subjects, the days post infection for each sample is indicated using circles, which represent the following: open light blue circle, sample not analyzed due to CSF viral load (VL) < 1,000 copies/ml (NA (low CSF VL)); open royal blue circle; sample not analyzed but CSF VL > 1,000 copies/ml (NA (high CSF VL)); closed dark blue circle, equilibrated with minimal CSF pleocytosis (CSF WBC <10 cells/μl) (Equilibrated (−)); closed pink circle, equilibrated with marked CSF pleocytosis (CSF WBC ≥10 cells/μl) (Equilibrated (+)); and closed red circle, compartmentalized. (A) Subjects with all analyzed time points equilibrated with minimal to no pleocytosis and remaining time points not analyzed. (B) Subjects with pleocytosis or compartmentalization in one time point (above dotted line) and subjects with pleocytosis, or compartmentalization in at least two time points (below dotted line). In every subject the compartmentalized (C) viral sequence population changed between sampling time points, indicated by different subscript numbers.</p>", "links"=>[], "tags"=>["sample pairs", "Infection Compartmentalized HIV", "subject", "csf", "rna", "CNS replication", "sga"], "article_id"=>1357145, "categories"=>["Biological Sciences"], "users"=>["Christa Buckheit Sturdevant", "Sarah B. Joseph", "Gretja Schnell", "Richard W. Price", "Ronald Swanstrom", "Serena Spudich"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1004720.g003", "stats"=>{"downloads"=>0, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_An_assessment_of_the_viral_populations_in_the_two_compartments_longitudinally_/1357145", "title"=>"An assessment of the viral populations in the two compartments longitudinally.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-03-26 03:52:34"}
  • {"files"=>["https://ndownloader.figshare.com/files/1990142"], "description"=>"<p>(A) Pie charts grouping the samples by days p.i. and showing the percentage of samples in each phylogenetic state as a function of time: 0–4 months (‘acute’), 5–12 months (‘early’), and 13–24 (‘established’). States represented include: Not Analyzed by SGA, due to CSF viral load <1,000 copies/ml; Equilibrated (−), CSF WBC <10 cells/μl; Equilibrated (+), CSF WBC ≥10 cells/μl; and Compartmentalized. We used a cut-off of 10 WBC/μl to define a state of substantial CSF pleocytosis because this is two-times the upper limit of normal value of CSF WBC (0 to 5 cells/μl) [<a href=\"http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1004720#ppat.1004720.ref022\" target=\"_blank\">22</a>] ensuring that the measured pleocytosis was a robust marker for an inflammatory response. (B) Pie chart showing the percent of samples in each phylogenetic state exhibiting substantial CSF pleocytosis (CSF WBC ≥10 cells/μl). (C) Relationship between plasma and CSF HIV-1 RNA concentrations for not analyzed samples with minimal pleocytosis (NA (−); CSF WBC <10 cells/μl) and equilibrated samples with minimal pleocytosis (Eq (−), CSF WBC <10 cells/μl). Spearman’s rank correlation coefficient and <i>P</i>-value are indicated. Samples with undetectable CSF HIV-1 RNA (<50 copies/ml; limit of detection) were not included in the correlation analysis. (D) Relationship between CSF viral loads for equilibrated with minimal pleocytosis (Eq (−); CSF WBC <10 cells/μl); equilibrated with marked pleocytosis (Eq (+); CSF WBC ≥10 cells/μl); and compartmentalized (Comp) samples. Significant <i>P</i> values (Mann-Whitney Test) comparing relationships between groups are indicated. Samples with evidence of marked pleocytosis (CSF WBC ≥10 cells/μl) are indicated using open circles, while samples with minimal to no pleocytosis are indicated by solid circles.</p>", "links"=>[], "tags"=>["sample pairs", "Infection Compartmentalized HIV", "subject", "csf", "rna", "CNS replication", "sga"], "article_id"=>1357144, "categories"=>["Biological Sciences"], "users"=>["Christa Buckheit Sturdevant", "Sarah B. Joseph", "Gretja Schnell", "Richard W. Price", "Ronald Swanstrom", "Serena Spudich"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1004720.g002", "stats"=>{"downloads"=>0, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Correlates_of_CSF_HIV_1_RNA_levels_CNS_inflammation_and_CNS_phylogenetic_state_/1357144", "title"=>"Correlates of CSF HIV-1 RNA levels, CNS inflammation, and CNS phylogenetic state.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-03-26 03:52:34"}
  • {"files"=>["https://ndownloader.figshare.com/files/1990140"], "description"=>"<p>Neighbor-joining phylogenetic trees depicting sequence relationships from subjects with (A) equilibrated and (B) compartmentalized viral populations. <i>env s</i>equences from the CSF (blue circles) and blood plasma (red triangles) are shown. Bootstrap values ≥35 are included (*) at the appropriate nodes. Genetic distance is indicated at the bottom of each figure (0.001, number of nucleotide substitutions per site between <i>env</i> sequences). Compartmentalized CNS populations are designated by an open circle at the appropriate node and a solid blue bracket. Clonal amplification is indicated by a solid black bar.</p>", "links"=>[], "tags"=>["sample pairs", "Infection Compartmentalized HIV", "subject", "csf", "rna", "CNS replication", "sga"], "article_id"=>1357142, "categories"=>["Biological Sciences"], "users"=>["Christa Buckheit Sturdevant", "Sarah B. Joseph", "Gretja Schnell", "Richard W. Price", "Ronald Swanstrom", "Serena Spudich"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1004720.g001", "stats"=>{"downloads"=>0, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_HIV_1_blood_and_CSF_populations_early_during_infection_can_be_equilibrated_or_compartmentalized_/1357142", "title"=>"HIV-1 blood and CSF populations early during infection can be equilibrated or compartmentalized.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-03-26 03:52:34"}
  • {"files"=>["https://ndownloader.figshare.com/files/1990154", "https://ndownloader.figshare.com/files/1990155", "https://ndownloader.figshare.com/files/1990156", "https://ndownloader.figshare.com/files/1990157", "https://ndownloader.figshare.com/files/1990158", "https://ndownloader.figshare.com/files/1990159"], "description"=>"<div><p>Compartmentalized HIV-1 replication within the central nervous system (CNS) likely provides a foundation for neurocognitive impairment and a potentially important tissue reservoir. The timing of emergence and character of this local CNS replication has not been defined in a population of subjects. We examined the frequency of elevated cerebrospinal fluid (CSF) HIV-1 RNA concentration, the nature of CSF viral populations compared to the blood, and the presence of a cellular inflammatory response (with the potential to bring infected cells into the CNS) using paired CSF and blood samples obtained over the first two years of infection from 72 ART-naïve subjects. Using single genome amplification (SGA) and phylodynamics analysis of full-length <i>env</i> sequences, we compared CSF and blood viral populations in 33 of the 72 subjects. Independent HIV-1 replication in the CNS (compartmentalization) was detected in 20% of sample pairs analyzed by SGA, or 7% of all sample pairs, and was exclusively observed after four months of infection. In subjects with longitudinal sampling, 30% showed evidence of CNS viral replication or pleocytosis/inflammation in at least one time point, and in approximately 16% of subjects we observed evolving CSF/CNS compartmentalized viral replication and/or a marked CSF inflammatory response at multiple time points suggesting an ongoing or recurrent impact of the infection in the CNS. Two subjects had one of two transmitted lineages (or their recombinant) largely sequestered within the CNS shortly after transmission, indicating an additional mechanism for establishing early CNS replication. Transmitted variants were R5 T cell-tropic. Overall, examination of the relationships between CSF viral populations, blood and CSF HIV-1 RNA concentrations, and inflammatory responses suggested four distinct states of viral population dynamics, with associated mechanisms of local viral replication and the early influx of virus into the CNS. This study considerably enhances the generalizability of our results and greatly expands our knowledge of the early interactions of HIV-1 in the CNS.</p></div>", "links"=>[], "tags"=>["sample pairs", "Infection Compartmentalized HIV", "subject", "csf", "rna", "CNS replication", "sga"], "article_id"=>1357156, "categories"=>["Biological Sciences"], "users"=>["Christa Buckheit Sturdevant", "Sarah B. Joseph", "Gretja Schnell", "Richard W. Price", "Ronald Swanstrom", "Serena Spudich"], "doi"=>["https://dx.doi.org/10.1371/journal.ppat.1004720.s001", "https://dx.doi.org/10.1371/journal.ppat.1004720.s002", "https://dx.doi.org/10.1371/journal.ppat.1004720.s003", "https://dx.doi.org/10.1371/journal.ppat.1004720.s004", "https://dx.doi.org/10.1371/journal.ppat.1004720.s005", "https://dx.doi.org/10.1371/journal.ppat.1004720.s006"], "stats"=>{"downloads"=>30, "page_views"=>13, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Compartmentalized_Replication_of_R5_T_Cell_Tropic_HIV_1_in_the_Central_Nervous_System_Early_in_the_Course_of_Infection_/1357156", "title"=>"Compartmentalized Replication of R5 T Cell-Tropic HIV-1 in the Central Nervous System Early in the Course of Infection", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2015-03-26 03:52:34"}
  • {"files"=>["https://ndownloader.figshare.com/files/1990151"], "description"=>"<p><sup>a</sup>Time point(s) beyond 2 years p.i. analyzed for subject 9018 and 9040 were not included in any overall population analyses.</p><p><sup>b</sup>Estimated.</p><p><sup>c,d</sup>VL, viral load; HIV-1 RNA (log<sub>10</sub> copies/ml).</p><p><sup>e</sup>Cells/μl.</p><p><sup>f</sup>CSF white blood cell (WBC) count, cell/μl.</p><p><sup>g</sup>CSF/plasma albumin ratio.</p><p><sup>h</sup>Three statistical analyses of genetic compartmentalization between viral populations in the blood plasma and CSF: Slatkin-Maddison test (SM) [<a href=\"http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1004720#ppat.1004720.ref018\" target=\"_blank\">18</a>], Wright’s measure of population subdivision (F<sub>st</sub>) [<a href=\"http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1004720#ppat.1004720.ref019\" target=\"_blank\">19</a>,<a href=\"http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1004720#ppat.1004720.ref020\" target=\"_blank\">20</a>] and the Nearest-neighbor statistic (S<sub>nn</sub>) [<a href=\"http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1004720#ppat.1004720.ref021\" target=\"_blank\">21</a>]. <i>P</i> values <0.05 indicated statistically significant genetic compartmentalization.</p><p><sup>i</sup>HIV-1 population characteristics in the CSF compartment (compart). Eq, equilibrated blood plasma and CSF populations; Cp (compartmentalized), significant compartmentalization by three compartmentalization analyses; Ap, clonal amplification of ≥3 variants detected in the CSF.[<a href=\"http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1004720#ppat.1004720.ref018\" target=\"_blank\">18</a>]</p><p><sup>j</sup>TMRCA (Time to Most Recent Common Ancestor) of the entire viral population, analyzed by BEAST [<a href=\"http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1004720#ppat.1004720.ref015\" target=\"_blank\">15</a>]. An asterisk (*) indicates transmission of > 1 variant.</p><p><sup>k</sup>TMRCA for the compartmentalized (Comp) CSF population for compartmentalized subjects.</p><p><sup>l</sup>Patient 9018 diagnosed with neurosyphilis at indicated date.</p><p><sup>m</sup>Significant compartmentalization scores were due to a compartmentalized lineage in the plasma. After removing this plasma lineage, the remaining plasma and CSF sequences were equilibrated.</p><p>Subject population virologic, clinical and phylogenetic characteristics.</p>", "links"=>[], "tags"=>["sample pairs", "Infection Compartmentalized HIV", "subject", "csf", "rna", "CNS replication", "sga"], "article_id"=>1357153, "categories"=>["Biological Sciences"], "users"=>["Christa Buckheit Sturdevant", "Sarah B. Joseph", "Gretja Schnell", "Richard W. Price", "Ronald Swanstrom", "Serena Spudich"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1004720.t002", "stats"=>{"downloads"=>0, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Subject_population_virologic_clinical_and_phylogenetic_characteristics_/1357153", "title"=>"Subject population virologic, clinical and phylogenetic characteristics.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2015-03-26 03:52:34"}
  • {"files"=>["https://ndownloader.figshare.com/files/1990149"], "description"=>"<p>Blood and CSF/CNS compartments are indicated. Blood plasma viral variants are represented by the red virus particles; and CNS viral variants are represented by the blue virus particles. CD4+ T cells are represented by open circles. Arrows indicate direction of virus movement between compartments. (A) State with a CSF HIV-1 RNA level 1–2% of the viral load in the blood and defined by minimal to no local CNS replication or inflammation, resulting in an equilibrated state between the two compartments (when CSF viral load high enough for analysis). Transparent infected CD4+ T cell represents potential local CNS replication that may be obscured by the import of virus into the CNS from the periphery. (B) State of equilibration between CSF and blood accompanied by high levels of pleocytosis, potentially caused by local CNS replication. Transparent infected CD4+ T cell represents potential local CNS replication likely obscured by the high levels of virus secreted by the infiltrating CD4+ T cells. (C) State of CSF/CNS clonal amplification of identical or nearly identical variants within CD4+ T cells. These clonally amplified populations are characterized by low diversity, signified by all CSF viruses in a single shade of blue. (D) State of genetically complex, compartmentalized viral replication within CD4+ T cells in the CSF/CNS indicative of persistent replication beyond a single clonal amplification event; this complexity is signified by CNS viral variants in multiple shades of blue.</p>", "links"=>[], "tags"=>["sample pairs", "Infection Compartmentalized HIV", "subject", "csf", "rna", "CNS replication", "sga"], "article_id"=>1357151, "categories"=>["Biological Sciences"], "users"=>["Christa Buckheit Sturdevant", "Sarah B. Joseph", "Gretja Schnell", "Richard W. Price", "Ronald Swanstrom", "Serena Spudich"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1004720.g006", "stats"=>{"downloads"=>0, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Four_states_can_define_the_relationship_between_virus_in_the_CSF_CNS_and_blood_early_during_infection_/1357151", "title"=>"Four states can define the relationship between virus in the CSF/CNS and blood early during infection.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-03-26 03:52:34"}

PMC Usage Stats | Further Information

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  • {"unique-ip"=>"10", "full-text"=>"10", "pdf"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"2", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2020", "month"=>"10"}

Relative Metric

{"start_date"=>"2015-01-01T00:00:00Z", "end_date"=>"2015-12-31T00:00:00Z", "subject_areas"=>[]}
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