Alex J. George Week 3

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Week 3: HIV Introduction

  1. My knowledge about HIV is definitely limited to what I hear in the news and media. I know HIV stands for the "Human Immunodeficiency Virus". Also, I know that you must be HIV + in order to contract AIDS. My understanding is that being exposed to the blood of an HIV + is enough to become HIV + yourself. Other than this basic information, I am not very knowledgeable about the biology of HIV.
  2. Questions concerning HIV:
    • Is it possible to be born HIV + without your mother being HIV +?
    • What is the biological affect of being HIV + on humans? What is physically/chemically changed in a human between HIV-/HIV+?
    • Has HIV been attributed to any particular gene/chromosome? What is the most we know about the HIV virus?

PubMed Activity

  • Pubmed's Menu is a little different than the text (There are no tabs in the newer version)
  • Searching "dUTPase" turns up multiple results, but few define what it is. So, I clicked on the suggested search "human dUTPase" under the "Also Try" menu

HIV Article

  • In order to find a useful HIV article on Pubmed, I searched "Human Immunodeficiency Virus" to search for articles with exactly that phrase. Since I only was interested in Full Text articles, I clicked on "Free Full Text" along the right side of the page.
  • I found a related article that defines the HIV virus by skimming the titles and abstracts. The article I found was the 24th result, Alternative paths in HIV-1 targeted human signal transduction pathways.
  • In order to see the full text for this article, scroll down, click on "LinkOut- more resources", then select one of the links under the "Full Text Sources" Header:

Comparison to Google Scholar and ISI Web of Science

  • The results for a Google Scholar search "Human Immunodeficiency Virus" seem to be more relevant than the results in Pubmed. The third result explains the expression of HIV in T Cells. The format of Google Scholar, however is worse than PubMed. The search results don't seem categorized and aren't as easy to distinguish.

However, I do like the "Related articles" link under each result which makes it easier to find relevant information. Also, there seem to be more full text articles within Google Scholar. Overall, I like the results given by Google scholar, but it is much harder to navigate.

  • The ISI Web of Knowledge Database is much more organized and makes much more sense to the user. I love the bar on the side to limit results. This provides a lot of options to limit or expand results. A simple "Human Immunodeficiency Virus" search under "Topic" can be limited to Review articles.

Overall, this is my favorite database. I feel like it is much easier to find what you are looking for.

Markham Article

  • Since it's Publication, the article was cited 52 times.

Definitions

  1. Seroconverting- development of detectable specific antibodies to microorganisms in the blood serum as a result of infection or immunization
  2. Virology- the study of viruses and viral diseases
  3. Nested PCR- (Polymerase Chain Reaction)- technique to magnify and copy pieces of DNA; nested is intended to reduce contamination
  4. Peripheral- constituting the outer boundary
  5. CD4 T cell- recognizes antigens on the surface of a virus-infected cell and secretes lymphokines that stimulate B cells and killer T cells; AIDS knocks out these cells
  6. Sanger Chain Termination method- method of sequencing DNA using modified bases to stop replication
  7. pUC19- plasmid cloning vector in which DNA can be inserted
  8. Plasma viral load- measure of the severity of a viral infection, especially HIV
  9. Monophyletic- common descent from a single ancestor
  10. epidemiology- the study of factors that affect the health and illness of populations

Summary

Introduction

  • High mutation/replication rates of HIV-1 lead to rapid adaptation
    • In stable conditions, most viable ("fit") mutant will be most prevalent
  • If unstable environment exists, either variable mutants are selected against or the dominant strain is selected against
    • If the dominant strain is selected against, then the diversity of mutants increases too much, such that the immune system can't control it
  • In HIV, the study looks at the forces against HIV that cause diversity and look at how the virus is adapting to forces

Limitations of Previous Work

  • Didn't look at sequence patterns
  • Subject pools were too small
  • The McDonald study didn't follow subjects from seroconversion and had limited "time point" for analysis

Methods

  • Study Population
    • Took 15 participants who were known injection users
    • Collected blood every 6 months and categorized participants as "Rapid progressors", "moderate progressors" and "non-progressors"
  • Sequencing HIV-1 Genes
    • Amplified 285-bp region of "env" gene from PBMC (peripheral blood mononuclear cells)
    • Used primers to find distinct sequences
  • Phylogenetic Trees
    • Constructed using a computer program
    • Indicates time when each strain was isolated and the number of identical replicated sampled
    • Shows independent segregation of clones
  • Correlation Analysis
    • Analyzed correlation between Genetic Diversity vs. CD4 Cell count and Mutational Divergence vs. CD4 cell count

Figures

  • Figure 1: shows the diversity, divergence, and CD4 cell count for each participant over time
  • Figure 2: Shows "mean slope" of diversity and divergence of each progressor category and indicates significant differences
  • Table 1: Summary of data on all subjects
  • Figures 3 & 4: Phylogenetic trees of subjects 5,7,8,9, and 14. Shows evolution is not sustained along single branch


Results

  • Main result: The more genetic diversity of the HIV-1 virus, the more rapid decline is in CD4 T-cell count
  • CD4 decline was variable
  • Sequence analysis performed on V3 domain (which is important for host-virus interaction)
  • Diversity and divergence increased over time
  • Diversity and divergence significantly negatively correlated to CD4 cell count
  • The dS/dN ration for Rapid and Moderate progressors was .4, indicating an advantage for nonsynonymous changes
  • For both divergence and diversity, rapid progressors differed significantly from nonprogressors
  • Phylogenetic trees gave no evidence of predominance by single strain

Discussion

  • Increase in diversity and divergence in HIV-1 variants led to CD4 decline
  • Nonprogressor viral strains showed possible selection against amino acid change, whereas moderate/rapid progressors selected for amino acid change
  • For subjects who contracted AIDS, their diversity and divergence continued to increase
  • To control infection, the host cell must control it at an organismal level due to high diversity of virus mutants
  • The importance of this work is that it reveals an more logical route to attacking HIV in patients who have already been diagnosed with the virus.
  • Results were consistent with that of M.A. Nowak, but differed with two other recent studies conducted by McDonald and Wolinsky et al.
  • McDonald's study showed that rapid progressors had less diversity than nonprogressors
  • Wolinsky also observed less diversity in 2 subjects with the most rapidly declining CD4 T-cell count


Individual Journals

  1. No Week 1 Journal
  2. Alex J. George Week 2
  3. Alex J. George Week 3
  4. Alex J. George Week 4
  5. Alex J. George Week 5
  6. Alex J. George Week 6
  7. Alex J. George Week 7
  8. Alex J. George Week 8
  9. Alex J. George Week 9
  10. Alex J. George Week 10
  11. Alex J. George Week 11
  12. Alex J. George Week 12
  13. Alex J. George Week 13

Shared Journals

  1. Week 2
  2. Week 3
  3. Week 4
  4. Week 5
  5. Week 6
  6. Week 7
  7. Week 8
  8. Week 9
  9. Week 11
  10. Week 12
  11. Week 13
  12. Week 14
  13. Week 15

Links

Course Home Page

Alex George

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