Alex A. Cardenas Week 5

Assignment 5

Continued Research Project

• 3 main points
  • Why did 6 of the 15 subjects develop AIDS and who has them? What did they have in common and what did they not have in common with subjects who did not develop AIDS?
  • The dS/dN ratios are used in hoping to prove whether or not the subject will develop AIDS depending on the low and high ratios.
  • Determine which subjects have AIDS and distinguish common factors for why each may have developed AIDS. From there we will compare them to subjects who do not have AIDS and see if they are on their way to develop AIDS.

Methods (From week 4)

• 15 injection drug users were observed in ALIVE study. Blood was taken and sampled every 6 months.
  • After seroconversion, theses patients were followed and their CD4 T cell count is seen in this graph.
• Subjects were placed into 3 groups:
  • Have AIDS: 1, 3, 4, 20, 22, 25
  • Leaning toward AIDS: 7, 8, 9, 14
    • These are 4 of the 6 moderate progressors that are leaning toward AIDS.
  • Subjects who don't have AIDS: 2, 5, 6, 12, 13

Research Article

• A Statistical Characterization of Consistent Patterns of Human Immunodeficiency Virus Evolution Within Infected Patients by Scott Williamson, Steven M. Perry, Carlos D. Bustamante, Maria E. Orive, Miles N. Stearns and John K. Kelly
• This article was used to support some of the claims made last week regarding our research.
• From the introduction there are 3 main stages
  • In the first stage, there was a linear increase in both env divergence and diversity from the population.
  • The next stage lasts 2 years on average and it was shown that there was a stabilization or decline in nucleotide diversity but the divergence continues.
  • Divergence stabilizes in the last stage meaning that "env sequence evolution nearly comes to a halt" A statistical Characterization of Consistent Patterns of HIV Evolution Within infected patients September 28, 2011.
    • Usually beings one year before the onset of clinical AIDS and as stated, CD4+ T Cell counts are below 300 cells.
• An indicator of disease progression was the CD4 T cell count and emergence of X4 viral genotype.
  • Peak diversity = initial emergence of X4 virus
  • Divergence stabilization = X4 reaching highest frequency.
• Hypothesis #2 - evolutionary rates slow due to infection disrupting the immune system.
• If max likelihood divergence stabilization model > (significantly) max likelihood of constant rate model = evolutionary slowdown.
• Two different versions of divergence stabilization.
  • First poses that disease progression is related to divergence stabilization.
    • Divergence stabilization takes on formula Tp + a in which Tp=time of disease progression and a=constant across all patients.
• Tp is the time which CD4 T cell count dropped below 300 cells/ml.
• Integration was as follows: started with homogeneous population of 2N sequences of L length. --> ancestral population.
• Recombination occurred at rate r per sequence per generation

Conclusion

• Relaxation of positive selection causes divergence stabilization.
• The synonymous sites for the constant-rate model were accepted but not for nonsynonymous sites.
• Only for nonsynonomous sites did Single-a sites with individual patients separate analyses share a relationship between time of divergences stabilization and disease progression.
  • Predicted by the immune relaxation hypothesis.
• Immune-Relaxation Hypothesis poses common ideas about HIV evolution.
  • Primary agent of positive selection in C2-V5 region of env is immune system
  • HIV disrupts immune system function that control infection.
• Virus infects HIV-specific CD4+ T cells.
  • This viral specificity adds to uncontrolled viral replication in which leads to the progression of AIDS.
  • Altering the course of viral evolution is found in the interaction between the virus and HIV-specific immune effectors
• A decrease in the dN/dS ratio of the env gene V3 loop in time with an infected subject.
  • Over the course of infection, there was a reduction in selection intensity.
• Since there is a homogenous population, it takes some time for mutations to become spread at a noticeable frequency.

Presentation

• My part of the presentation can be found here: Media:Presentation1.pptx
• Final Presentation can be found here: Media:Final_Presentation.ppt

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