Cdominguez Week 3

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Assignment Page Individual Journal Entries Class Journal
BIOL368/S20:Week 1 user:cdominguez BIOL368/S20:Class Journal Week 1
BIOL368/S20:Week 2 cdominguez Week 2 BIOL368/S20:Class Journal Week 2
BIOL368/S20:Week 3 cdominguez Week 3 BIOL368/S20:Class Journal Week 3
BIOL368/S20:Week 4 cdominguez Week 4 BIOL368/S20:Class Journal Week 4
BIOL368/S20:Week 5 cdominguez Week 5 BIOL368/S20:Class Journal Week 5
BIOL368/S20:Week 6 cdominguez Week 6 BIOL368/S20:Class Journal Week 6
BIOL368/S20:Week 8 cdominguez Week 8 BIOL368/S20:Bibliography
BIOL368/S20:Week 10 cdominguez Week 10 BIOL368/S20:Class Journal Week 10
BIOL368/S20:Week 11 cdominguez Week 11 BIOL368/S20:Class Journal Week 11
BIOL368/S20:Week 13 cdominguez Week 13 BIOL368/S20:Class Journal Week 13
BIOL368/S20:Week 14 cdominguez Week 14 BIOL368/S20:Class Journal Week 14

Purpose

To understand the evolutionary adaption of HIV in the body in accordance with the human immune response, specifically CD4 T cells, and how this relates to its infection of the body over time.

Definitions

  1. seroconversion: test result of negative to positive for a virus indicated by presence of antibodies (Biology Online)
  2. peripheral: outside/surface of the body away from the center (Biology Online)
  3. mononuclear: having one nucleus (Biology Online)
  4. preponderance: superior in weight or excess (Oxford Reference)
  5. nested:the systematic truncation of a DNA molecule from one end to produce a series of fragments that have an identical sequence at one end and different sequences at the other (Oxford Reference)
  6. monophyletic: a taxonomic group that holds characters descended from a single common ancestor (Biology Online)
  7. serum:clear liquid of blood with no clotting factor (Biology Online)
  8. hypervariable: complementarity‐determining region (Biology Online)
  9. homogeonous: consisting of or composed of similar elements or ingredients, of a uniform quality throughout (Biology Online)
  10. epitopes: the antigenic determinant on an antigen to which the paratope on an antibody binds (Oxford Reference)

Outline

What is the importance or significance of this work?

The importance of this work is to examine more closely the evolutionary persistence of HIV in the body. HIV affects millions of people and attacks the immune system. This study places importance on understanding CD4 T cell decline as well as examining divergence and diversity in order to better understand the relationship and mechanism between the virus and our immune system.

What were the limitations in previous studies that led them to perform this work?

Other studies did not have a big study population thus limiting greater application of results and findings. These studies also used less sophisticated methods by not examining sequence patterns as well as only using very few time points of their subjects.

How did they overcome these limitations?

This study included 15 subjects of which they followed fro 4 years allowing them to have a bigger study population and more time points to conduct research. They also included direct examination of sequence patterns in order to make more conclusive statements on diversity and divergence changes over time.

What is the main result presented in this paper?

Between their subjects of which they categorized as nonprogressor, moderately progressing, or rapidly progressing, there was a relationship between decline in CD4 T cells and greater diversity and divergence. This was seen in conjunction with the various groups and thus amount of CD4 T cells and resulting diversity and divergence over a 4 year period.

What were the methods used in the study?

Study Population 15 subjects were selected from AIDS Linked to Intravenous Experiences (ALIVE) that identified as injection drug users and categorized as nonprogressors, moderate progressors, or rapid progressors. 6 month interval visits were done where blood was taken for 4 years.

Sequencing of HIV-1 enc Genes PCR amplified env gene from peripheral blood mononuclear cells (PBNC). 35 PCR cycles of the samples were run followed by cloning into pUC19 and sequencing.

Plasma Viral Load Reverse transcription-PCR was used to analyze plasma viral load.

Generation of Phylogenetic Trees Using the MEGA computer package, taxon were labeled as time isolated and number of identical replicates and grouped according to color of time observed.

Correlation Analysis The data included 76 times points for one year. Stratification of CD4 T cell count was used to determine if diversity/divergence changed based on T cell count.

Determination of dS/dN Ratios Jukes-Cantor correction resolved any bias in random mutations or sample size based on categorization of synonymous or nonsynonymous.

Examination of Source of Greater Initial Visit Diversity in Subjects 9 and 15 High variation of two subjects was examined through phylogenetic tree analysis.

Comparison of the Rate of Change of Divergence and Diversity Regression lines and slopes for each subject were combined according to progression classification in order to use random effects models

Briefly state the result shown in each of the figures and tables, not just the ones you are presenting.

Figure 1 CD4 T cell decline was variable in accordance with diversity and divergence.

Table 1 Data of all 15 subjects which show viral load as well as annual change, slope of divergence, and slope of change. This showed that 13/15 subjects' virus were homogenous while 2/15 were more heterogenous.

Figure 2 Diversity and divergence were seen to increase regardless of progressor category. Rapid progresser had faster change in divergence as compared to nonprogressor as well as in diversity for all categories.

Figure 3 There was a pattern of "limited progression" and no dominant strain that persisted in phylogenetic tree.

Figure 4 Reestablishes this pattern among all 15 subjects as shown in figure 3.

How do the results of this study compare to the results of previous studies (See Discussion).

A few studies showed results that are opposite of what they found- diversity in rapid progressors was less then slow progressors although divergence increased for both like this study found. However, differences in time followed and timeline of the disease. Another study also showed less diversity with quicker declining CD4 T cells, which was seen in 1 of their study subjects. They address this by calling it "exceptional".

How do the results of this study support published HIV evolution models?

They speak to the model of Nowak of which their study supported- this model CD4 T cell decline occurs with increasing diversity. This was shown in their subjects where as the disease progressed, they also saw more diversity and divergence due to lack of immune response in the host body as the virus develops evolutionarily.

What are the important implications of this work?

The important implications of this work involve using methods that look more closely at how HIV evolutionarily develops in the body in accordance with the human body immune response, specifically CD4 T cells. This is important in understanding how medical and drug research can also evolve to take the diversity and divergence of the virus into account when developing potential drugs to treat HIV. The study makes clear that it has yielded results that confirm and directly fit into the Nowak model that shows as CD4 T cells decline, diversity and divergence increase.

What future directions should the authors take?

It would be interesting for the authors to potentially take on the role of looking at how they can stop the increase in diversity or divergence. If this is not possible, then it would also be interesting to see which ways the immune response could be altered due to the high amount of variants that HIV develops into.

Give a critical evaluation of how well you think the authors supported their conclusions with the data they showed. Are there any limitations or major flaws to the paper?

The authors were full prove in supporting their conclusion. The paper did not have any ground breaking discoveries, but instead built upon a model of the HIV mechanism. It used more specific methods and greater study population in order to generalize their findings to how the virus evolves. I found their main conclusion to be that genetic diversity and divergence is persistant and ever-changing for the virus as it adapts to its environment. CD4 cells decline in relation to increase diversity which does not allow the human immune response to fully eradicate and attack all possible types and diverse array of the virus as the infection progresses. To this point, the paper did a good job at showing the results and demonstrating how they proved this point.

Conclusions

The Markham et. al. paper found, through examination of 15 subjects with HIV over a course of 4 years, that decline in CD4 T cells was correlated with increased in diversity and divergence. This demonstrates the rapid and persistant adaptation of HIV and its variant forms in the body over time. Due to this increase in diversity and divergence, the immune response mostly fails due to its inability to target all variants during the course of the infection. This paper added evidence and confirmed the Nowak model that also hypothesized this mechanism of HIV in the body.

Acknowledgments

  • I worked with user:kvescio for this assignment during class where we discussed the paper and definitions.
  • Except for what is noted above, this individual journal entry was completed by me and not copied from another source.

Cdominguez (talk) 16:28, 30 January 2020 (PST)

References

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