Michael R. Pina Week 3

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Contents

Article Summary

Introduction

  • Because the rate at which HIV replicates is so high, variants that are best suited to the environment arise and spread very quickly.
    • This is essentially extremely fast evolution.
  • Unstable host environments can have variable effects.
    • It could lead to a dynamic immune response that would lead to little diversity.
    • Or the immune response could target only the most numerous variants, leading to a broader diversity.
  • Previous studies did not examine sequence patterns, and did not analyze enough "time points" in each subject.
    • This study examines higher levels of diversity correlating with rapid CD4 T cell decline.

Methods

  • 15 participants were selected from those who participated in ALIVE (injection drug users.)
    • Blood was collected every 6 months for testing over 4 years.
      • Rapid progressors = fewer than 200 CD4 T cells
      • Moderate progressors = 200-650
      • Nonprogressors = above 650
  • 285 bp region of env was amplified from PBMC.
  • env primers were used for cloning purposes, to find certain sequences.
  • Plasma viral load was determined by reverse transcription–PCR
  • Phylogenetic trees were made using a computer package.
    • Taxon labels were used to show the time where each train was isolated and number of identical replicates.
  • Units of analysis were defined by pairs of visits from each individual.
    • 26 time points were collected from the 15 participants
    • Sequence data and CD4 T cell count were known 1 year later.
  • dS/dN ratios used the Jukes-Cantor correction method.
    • Summary of this data was used for all subsequent analysis.

Results

  • CD4 decline varied across participants
    • Nonprogressor groups generally had lower viral load.
  • Sequence analysis focused on env region because it is important in host-virus interaction and tolerates mutation
    • 873 clones were analyzed
  • Changes in HIV-1 sequences were defined by diversity at each visit and divergence.
  • Viruses from 13 of the participants were originally homogeneous; 2 were heterogenous.
  • Diversity and divergence increased over time in all progressor categories.
  • Diversity and divergence were negatively correlated with CD4 T cell count 1 year later.
  • Rapid and moderate progressors showed a dS/dN ratio of 0.4, which nonprogressors showed a ratio of 1.6.
    • A ratio of 1 indicates randomly occurring mutation
  • Phylogenetic trees did not show predominance of a single strain.

Discussion

  • Higher diversity and divergence are associated with a decline in CD4 T cells.
  • Strains found in nonprogressors showed a possible selection against amino acid change; those in progressors showed selection for change.
  • The relationship between CD4 T cell decline and increased diversity and divergence agrees with the hypothesis of Nowak.
    • For those subjects who contracted AIDS, diversity and divergence continued to increase
  • Optimum environment for the virus could be continually changing because of different immune responses.
  • A more effective immune response may be seen in the nonprogressors.

Definitions

  1. Seroconversion: Seroconversion is the development of detectable specific antibodies to microorganisms in the blood serum as a result of infection or immunization. Serology (the testing for antibodies) is used to determine antibody positivity.
  2. Virology:the branch of medical science that studies viruses and viral diseases
  3. Cohort: age group: a group of people having approximately the same age
  4. Phylogenetic tree: A phylogenetic tree or evolutionary tree is a tree showing the evolutionary relationships among various biological species or other entities that are known to have a common ancestor
  5. Taxon: taxonomic group: animal or plant group having natural relation
  6. Jukes - Cantor Correction: As the time of divergence between two sequences increases the probability of a second substitution at any one nucleotide site increases and the increase in the count of differences is slowed. This makes these counts not a desirable measure of distance. In some way, this slow down must be accounted for. The solution to this problem was first noted by Jukes and Cantor.
  7. Preponderance: superiority in power or influence; "the preponderance of good over evil"; "the preponderance of wealth and power"
  8. Stratification: the condition of being arranged in social strata or classes within a group
  9. Chemostat: A chemostat (from Chemical environment is static) is a bioreactor to which fresh medium is continuously added, while culture liquid is continuously removed to keep the culture volume constant. By changing the rate with which medium is added to the bioreactor the growth rate of the microorganism can be easily controlled.
  10. Co-receptor: A co-receptor is a cell surface receptor that binds a signalling molecule in addition to a primary receptor in order to facilitate ligand recognition and initiate a biological process, such as entry of a pathogen into a host cell.


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