Bobak Seddighzadeh Week 5

Question

The question that my partner and I wanted to tackle for the HIV Evolution project is: what is or are the nucleotide sequences in the env region of the V3 domain that are responsible for the increased genetic diversity, divergence, and rate of CD4 T cell decline amongst rapid, moderate, and non-progressors. The question began with the general desire to know why a disparity exists in the rate of evolution amongst variants.

Prediction

My partner and I predict that the increased rate of CD4 decline, genetic divergence and diversity are directly related to two possible mechanism: A) HIV-1 variants termed rapid progressors selected for a structural mechanism that does not protect the genetic material against mutations as effectively B) or HIV-1 variants termed rapid progressors selected for a mechanism that induces mutations on its own DNA. I also predict that both these mechanism are related to nucleotide differences found in the env region of the V3 domain. As stated in the discussion, Markham concluded in his discussion that "higher levels of both genetic diversity and divergence in the HIV-1 variants present in a given individual were associated with a greater decline in CD4 T cells" (Markham et al., 1998). Therefore, we know that CD4 T cell decline is proportional to genetic diversity and divergence. Intuitively what led me to the prediction is genetic diversity and divergence are affected by the rate of mutations. I modeled my prediction after a possible mechanism that would increase the mutation rate of genetic material.

Plan of Attack

To approach this question properly, we need a set of data from subjects, visits, and clones in the env region of the V3 domain that possesses variable rates of divergence and diversity that can be classified as either a rapid or non progrogressor. For the rapid progressors, we have chosen 3-V6, 3-V7, 3-V8, 4-V5, 4-V6, 4-V7, 11-V7, 11-V8, 11-V9. Subjects 4, 10, and 11 were chosen because they had the highest rates of annual CD4 T cell decline. Having a high annual rate of CD4 T cell decline which is a potential good lead into specific nucleotide sequences that cause increased rates of diversity and divergence. For the group of non-progressors, we have chosen 2-V3, 2-V4, 2-V5, 12-V3, 12-V5, 12-V6, 13-V5, 13-V6, 13-V10. These subjects were chosen because they were the only recorded nonprogressors in the experiment. These visits were chosen because they had the highest CD4 T cell count among all visits. These clones will be analyzed for each visit to find a difference in the nucleotide sequence.