Journal Club Presentation BIOL368/F16: Bioinformatics Laboratory 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.

on the Surface of the Virus 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 Individuals in a population vary in their traits. The traits are heritable; they can be passed onto offspring. More offspring are produced than can survive. 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 Individuals in a population vary in their traits. Viruses encode different versions of the envelope proteins. Enabled by error-prone reverse transcriptase The traits are heritable; they can be passed onto offspring. The variations are encoded in the viral genome and packaged into viral particles. More offspring are produced than can survive. Many copies of the HIV virus are produced. 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

...Followed by a Return to Strains Related to an Earlier Visit 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