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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
Journal Club Presentation
BIOL368/F16: Bioinformatics Laboratory
September 13 and 20, 2016
Outline
• The envelope protein gp120 is used by the
virus to infect cells during the HIV life cycle.
• Evolution by natural selection applies to HIV.
• The purpose of the Markham et al. (1998)
study is…
• The main results of the study are…
• The limitations and future directions of the
study are…
Outline
• The envelope protein gp120 is used by the
virus to infect cells during the HIV life cycle.
• Evolution by natural selection applies to HIV.
• The purpose of the Markham et al. (1998)
study is…
• The main results of the study are…
• The limitations and future directions of the
study are…
HIV Is a Retrovirus that Has Nine Genes
Donovan & Weisstein (2004)
The env gene codes for the gp120 and gp41 proteins.
gp120 and gp41 Are Expressed
on the Surface of the Virus
Donovan & Weisstein (2004)
The Envelope Protein Binds to the Cell Surface Receptor CD4
and Co-receptors CCR5 or CXCR3 during Infection
Donovan & Weisstein (2004)
• V3 region of gp120
‒ 285 base pairs long
‒ highly variable
‒ involved in host cell and antibody recognition
Many Stages of the HIV Life Cycle are Targeted
by Antiretroviral Drugs
Laskey & Siliciano (2014)
Outline
• The envelope protein gp120 is used by the
virus to infect cells during the HIV life cycle.
• Evolution by natural selection applies to HIV.
• The purpose of the Markham et al. (1998)
study is…
• The main results of the study are…
• The limitations and future directions of the
study are…
How Evolution Applies to HIV
• Evolution is a genetically-based change in the
characteristics of a population over time.
• A genetically-based change is a change in
allele frequencies in a population.
• The population is all of the HIV viruses in an
affected individual.
• In this example, each variant of the HIV env
gene is an allele.
• New variants (new alleles) are being
generated by mutation of the virus.
Which Evolutionary Forces Apply to HIV?
•
•
•
•
Mutation
Migration
Genetic drift
Nonrandom mating
– sexual selection combines elements of nonrandom
mating with natural selection
• Natural selection
– only force that increases fitness
– only force that leads to adaptations to the
environment
– the environment in this case is the host immune
system and any antiretroviral therapy
Natural Selection Applies to HIV
1. Individuals in a population vary in their traits.
2. The traits are heritable; they can be passed onto
offspring.
3. More offspring are produced than can survive.
4. The subset of offspring that survive and reproduce
is not a random sample.
Individuals with certain traits are more likely to survive and
reproduce, or produce more offspring.
Natural Selection Applies to HIV
1. Individuals in a population vary in their traits.
Viruses encode different versions of the envelope proteins.
Enabled by error-prone reverse transcriptase
2. The traits are heritable; they can be passed onto
offspring.
The variations are encoded in the viral genome and packaged
into viral particles.
3. More offspring are produced than can survive.
Many copies of the HIV virus are produced.
4. Individuals with certain traits are more likely to
survive and reproduce, or produce more offspring.
Viruses that can escape the host immune system produce
more offspring viruses.
Viral resevoirs exist in the body, even when viral count is
undetectable in the blood
Outline
• The envelope protein gp120 is used by the
virus to infect cells during the HIV life cycle.
• Evolution by natural selection applies to HIV.
• The purpose of the Markham et al. (1998)
study is…
• The main results of the study are…
• The limitations and future directions of the
study are…
The Introduction Justifies Why the Scientists
Performed the Study
• The importance or significance
of this work is...
• The limitations in previous
studies that led them to perform
this work are...
• This study overcame these
limitations by...
• The main result presented in the
paper is...
Outline
• The envelope protein gp120 is used by the
virus to infect cells during the HIV life cycle.
• Evolution by natural selection applies to HIV.
• The purpose of the Markham et al. (1998)
study is…
• The main results of the study are…
• The limitations and future directions of the
study are…
CD4 T Cell Trajectory Relates to gp120 V3 Sequence
Diversity and Divergence in Three Progressor Groups
Data for Individual Subjects Supports their
Classificaton into Three Progressor Groups
Diversity and Divergence Are Highest
in the Rapid Progressor Group
Viruses from Subject 9 Show a
Pattern of Limited Progression
along a Single Branch...
...Followed by a Return to Strains
Related to an Earlier Visit
• Sequences are identified by subject,
visit, and clone number.
• Clones are color-coded by visit.
Viral Sequences in Four “Randomly” Selected
Individuals Show a Pattern of Interruped Evolution
Outline
• The envelope protein gp120 is used by the
virus to infect cells during the HIV life cycle.
• Evolution by natural selection applies to HIV.
• The purpose of the Markham et al. (1998)
study is…
• The main results of the study are…
• The limitations and future directions of the
study are…
The Discussion Places the Results of This Study
in the Context of Other Research
• The main results of this study are…
• How do these results compare to other studies?
• How do these results fit with explanatory models?
• The main limitations of this study are...
• What future work do you suggest?
Summary
• The envelope protein gp120 is used by the
virus to infect cells during the HIV life cycle.
• Evolution by natural selection applies to HIV.
• The purpose of the Markham et al. (1998)
study is…
• The main results of the study are…
• The limitations and future directions of the
study are…
References
• Markham RB, Wang WC, Weisstein AE, Wang Z, Munoz A, Templeton
A, Margolick J, Vlahov D, Quinn T, Farzadegan H, Yu XF (1998)
Patterns of HIV-1 evolution in individuals with differing rates of CD4
T cell decline. Proc Natl Acad Sci USA 95: 12568-12573.
DOI: 10.1073/pnas.95.21.12568
• Donovan S and Weisstein AE (2003) Exploring HIV Evolution: An
Opportunity for Research. In Jungck JR, Fass MR, and Stanley ED,
eds. Microbes Count! West Chester, Pennsylvania: Keystone Digital
Press.
• Laskey SB and Siliciano, RF (2014) A mechanistic theory to explain
the efficacy of antiretroviral therapy. Nature Reviews Microbiology,
12(11), 772-780. DOI: 10.1038/nrmicro3351