Transcript CD4 T-cell count associated with diversity and

Patterns of HIV-1 evolution in individuals
with differing rates of CD4 T cell decline
Markham RB, Wang WC, Weisstein AE, Wang Z,
Munoz A, Templeton A, Margolick J, Vlahov D, Quinn
T, Farzadegan H, Yu XF
(1998) Proc Natl Acad Sci USA 95: 12568-12573
Michael Pina, Salomon Garcia
Journal Club Presentation
BIOL398-01/S10: Bioinformatics Laboratory
March 2, 2010
Outline
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Introduction to the Markham et al. paper
Our question about the article
Methods
Results
Conclusion
CD4 T-cell count associated with
diversity and divergence
• The evolution of the HIV-1 gene was
studied in 15 seroconverting participants
(intravenous drug users)
• They were selected for differences in the
rate of their CD4 T-cell decline
• Rates of diversity and divergence both
showed a pattern of increase among the
progressor groups
Evolution of the HIV-1 virus in
the participants
• Viral evolution among the progressor
groups showed a selection for
nonsynonymous mutants
• Nonprogressors with low viral loads
selected against nonsynonymous
mutations
• For the progressor groups, this may have
resulted in higher reproduction rates of the
virus
HIV-1 variants over the course of
the study
• No single variant was dominant across all
participants
• Evolution away from a variant was
followed by evolution towards a variant
• This may show selection against a
predominant strain or the product of
independent evolutions within different
host environments
The importance of CD4 T-cells
• Differences of CD4 T-cell count reflect not
only the quantity of mutations, but
differences in the mutations that may be
best suited to the host environment
CD4 T cell trajectory, diversity, and divergence over
time since first seropositive visit (t = 0) in each of the
15 subjects
Taking a closer look at the paper
• We wanted to know how the amino acid
changes are affecting the interaction
between the virus and host environment
• “The overall pattern is one in which viral
strains from nonprogressors showed
possible selection against amino acid
change, while those from progressors
showed selection for such change (or
against the absence of change).”
Our question regarding the paper
• Is the Ds/Dn ratio more of a determinant
on the progressor categories than the rate
of CD4 T cell decline?
• We know from previous examination that
the different categories are somewhat
arbitrary
Methods to find an answer
• Subjects 10 and 13 were chosen because of
their quintessential qualities as “rapid
progressor” and “nonprogressor”, respectively
– They have nearly the same amount of data points
collected over a similar time span
• All of their DNA sequences were obtained from
the Bedrock website, in addition to other data
from the study
• The online Biology Workbench tools were used
for a variety of tasks
Statistical calculations
Subject
# clones
S
Theta
Min Diff
Max Diff
10
74
16.3
1.14
20.0
13
24
6.43
1.14
9.12
Using the Biology Workbench
• CLUSTALW was used for multiple
sequences alignments for all available
sequences of subjects 10 and 13
– Phylogenetic trees were also generated
• CLUSALDIST was used to generate a
distance matrix
Phylogenetic trees for subject 10
and 13
Subject 10
Subject 13
dS-dN values
10
.5
• Converted to log
scale for consistency
among data values
• Negative value
indicates synonymous
mutations
• Positive value
indicates
nonsynonymous
mutations
-
13
n/a
1
-0.118
-0.861
2
0.530
n/a
3
-
-0.333
4
-0.133
1.724
5
-0.447
0.479
6
0.785
7
-
-
8
n/a
-
9
n/a
-
10
n/a
-
11
n/a
-
12
n/a
-
13
n/a
-
An answer to our question
• It was determined that subjects 10 and 13
do indeed differ in their diversity and
divergence as represented visually in their
phylogenetic trees and also in our
statistical calculations
• The dS-dN values are so similar and
limited that it is difficult to say whether or
not progressors show a selection for
amino acid change
A more recent article
• Functional diversity of HIV-1 envelope
proteins expressed by contemporaneous
plasma viruses.
• “…clones carrying unique mutations in V3
often displayed low infectivity”
• No correlation was observed between viral
infectivity and sensitivity to entry inhibitors