Amanda N. Wavrin Week 3

Useful Links

 * My User Page
 * Week 3 Assignment Page

Previous HIV Virus Knowledge
The be honest, my previous knowledge of the HIV virus is limited. I know that HIV is a virus and that it is sexually transmitted. I also know that there is no cure for HIV and that it is extremely difficult to treat. The evolution of the HIV virus is a hot topic and I know much research has been conducted revolving around its evolution. I do know that its origins are said to be in Africa and it is prevelent in Africa to this day.

Three questions about HIV that I would like to have answered are:
 * 1) What is the origin of the HIV viurs? Do we know its evolution?
 * 2) What are the effects of the HIV virus on the human body? What are the symptoms?
 * 3) What is the human immune system's response to the HIV virus once infected?

Using PubMed

 * Begin by going to www.ncbi.nih.gov/entrez/
 * Search dUTPase
 * Clicking on the first article brings up a page with an abstract for the article
 * By clicking on the hyperlink available for the author(s) it will conduct a search on PubMed for that author
 * The screen shots shown for this page on PubMed today are different than those shown in the Bioinformatics for Dummies book used in lab.
 * [[Image:Pebmed1.jpg|thumb|upright=3.5|PubMed Screen Shot]]
 * As seen on the screen above, there are no drop down boxes such an a "display" or "show" box
 * Search by author name using the name Abergel
 * Restrict your search results by adding dUTPase next to Abergel
 * If large colored rectangle appear above the title, a journal offers free access to the full text for that paper
 * You can aslo search PubMed using fields
 * By clicking the drop down button next to the Display, you can click on MEDLINE
 * In your search, if you follow each term by the code that identifies its field (in brackets) it will modify your search
 * You can also limit your search by chosing the Advanced search link

Scholarly Review About the HIV Virus

 * I searched PubMed to find a scholarly review by using the Advanced search option
 * I selected the Review and English options to find this article:
 * 1) Paper1 pmid=19758442
 * 1) Paper1 pmid=19758442


 * When searching HIV Virus on Google Scholar I got different results than when using PubMed. The Advanced Search option on Google Scholar was not very helpful.  I did not get the same papers when I searched both sites but both resulted in interesting articles.
 * When searching ISI Web of Knowledge I searched HIV Virus and specified articles from 2000-present. Once again I got different results from when I searched Google Scholar and PubMed. ISI appeared nicely organized.

Terms and Definitions

 * Seroconversion- The change of a serologic test from negative to positive, indicating the development of antibodies in response to infection or immunisation.
 * Phyletic- Denoting the evolution of sequential changes in a line of descent by which one species is transformed into a new species.
 * Cohort- A cohort is a group of animals of the same species, indentified by a common characteristic, which are studied over a period of time as part of a scietific or medical investigation.
 * Epitopes- That part of an antigenic molecule to which the t cell receptor responds, a site on a large molecule against which an antibody will be produced and to which it will bind.
 * Epidemiology- The study of the distribution and determinants of health related states and events in populations and the control of health problems.
 * Hypervariable Region- The regions of the immunoglobulin molecule that contain most of the residues involved in the antibody binding site.
 * Virology- The study of viruses and viral diseases.
 * CD4 T cell- A form of T-lymphocyte with CD4 receptor on the cell surpface that recognizes antigens of a virus-infected cell.
 * Viral Load- The number of viral particles (usually HIV) in a sample of blood plasma.
 * PCR- Polymerase chain reaction. The first practical system for invitro amplification of DNA.

Dictionary used: http://www.biology-online.org/dictionary/Main_Page

Overview

 * HIV-1 has high mutation and replication rates, which allows them to adapt to a rapidly changing host environment
 * The patterns of HIV-1 evolution was studied in 15 different individuals. These individuals were selected for their differences in the CDT4 T cell decline. The 15 subjects fell into three groups: rapid progressors, moderate progressors, and non progressors
 * In a stable environmant, the "best fit" virus will be predominate. This has been observed in other systems.
 * An unstable host environment could have several different effects on the virus pool
 * Diversity could be reduced to the few surviving variants
 * Or, if only the most numerous viral variants were targeted, there would be a significant reduction in viral numbers but not in the genetic diversity

Previous Studies

 * Previous studies looked at smaller groups of infected subjects
 * They used techniques that did not directly examin sequence patterns
 * Analyzed a smaller number of time points per subject

Methods

 * Study Population
 * 15 individuals were chosen who were known injection drug users participating in the ALIVE (AIDS Linked to Intravenous Experiences) study
 * The participants had different levels of CD4 T cells: put into 1 of 3 categories- rapid, moderate, and non progressors
 * Every six months blood was obtained for studies
 * Sequencing of HIV-1
 * Nested PCR was used on a region of the env gene from PBMC
 * External env primers and nested primers were used
 * Plasma Viral Load
 * Determined by reverse transcription
 * Generation of Phylogenetic Trees
 * Trees constructed by using MEGA computer software
 * Taxon labels were used to show the time at which the strain was isolated and the amount of identical replicates used
 * They sare colored ti indicate the time at which they were observed
 * Correlation Analysis
 * Analyzed the correlation between genetic diversity and CD4 T cell count a year later
 * Also analyzed the correlation between mutational divergence and CD4 T cell count after a year
 * Determination of dS/dN Raios
 * Starin differences were classified as synonymous or nonsynonymous
 * The Jukes-Cantor correction was used for multiple hits
 * The resulting dS, dN, and dS/dN values were averaged
 * Examination of Source of Greater Initial Visit Diversity in Subjects 9 and 15
 * 9 and 15 had high genetic variation
 * These individuals may have been infected with two different viruses
 * Exclusion of number 15 did not change the dS/dN analysis conclusion
 * Comparison of the Rate of Change of Divergence and Diversity
 * The slope of the regression line of the ratio of divergence/diversity over time for each subject was found

Results

 * CD4 T cell decline was variable among the subjects
 * Non progressor group had low viral loads
 * The viral load data did not distinguish betwen the moderate and rapid progressor groups
 * V3 is an important site of host-virus interaction and was the region that sequence analysis was focused on
 * Diversity and divergence were negatively correlated with the CD4 T cell count over a year
 * The greater the diversity and divergence of a subject's virus, the more likely they were to have a greater CD4 T cell decline over the next year
 * Mylogenetic trees showed no evidence of the predominance of a single strain

Discussion

 * Both genetic diversity and divergence were higher in individuals with a greater CD4 T cell decline
 * Synonymous substitution rates were comparable in all three subject groups
 * Nonsynonymous rates in progressors were three times those in non progressors
 * Viral strains for non progressors selected against amino acid changes
 * Viral strains from progressors selected for amino acid change
 * McDonald's study found greater genetic diversity in slow progressors then in rapid progressors
 * Wolinksy observed less diversity in subjects with rapidly declining CD4 T cell counts
 * Virus' from 80% of Markham's rapid progressors showed high diversity and divergence
 * In general, the observed relationship between an increase in genetic diversity/divergence and the decline of CD4 T cells in these subjects was consistent with the model of Nowak
 * The importance of this work is that is it working towards finding a way to stop the HIV virus. The goal would be to beat/stop the genetic mutations and diversity of the virus.

Figures and Tables

 * Fig. 1- Shows the CD4 T cell trajectory, diversity, and divergence over time for the subjects in each of the three groups
 * Table 1- Shows a summary of the data on the 15 seroconverters
 * Fig. 2- Shows the mean slope of the genetic diversity/divergence in the different progressor groups
 * Fig. 3- Is a phylogenetic tree of evolution from subject 4
 * Fig. 4- Are phylogenetic trees of four other randomly selected subjects (subjects 5, 7, 8, 14)