HIV-1 evolution in response to immune selection pressures

BISC 441 guest lecture

Zabrina Brumme, Ph.D.

Assistant Professor, Faculty of Health Sciences

Simon Fraser University

http://www3.niaid.nih.gov/topics/HIVAIDS/Understanding/Biology/structure.htm

On an individual level….

Time since infection

HIV evolution in a single individual: 12 year period

eg:: Shankarappa et al, J Virol 1999

BD Walker, BT Korber, Nat Immunol 2001

On a global level…

HIV subtypes are differentially distributed throughout the world

http://www.hiv.lanl.gov

1. High mutation rate

HIV reverse transcriptase makes 1 error per replication cycle

Recombination

Host factors: APOBEC 3G

2. High replication rate

~up to 1010 virions/day in untreated infection

3. Lifelong infection

4. High numbers of infected individuals worldwide

5. Multitude of selection pressures:

- antiretroviral drugs

- immune selection pressures

Why does HIV evolution and diversification occur so rapidly?

My research program combines molecular biology and computational approaches to:

Study HIV-1 evolution in response to selection pressures imposed by cellular immune responses* (“immune escape”)

Use this information to identify characteristics of effective anti-HIV immune responses and other information that may be

useful to vaccine design

*humoral (antibody) responses are important too!

HLA class I alleles present HIV-derived peptide epitopes on the infected cell surface, thus alerting CTL to the presence of infection

CTL

HLA

HLA class I alleles act as a selective force shaping HIV evolution through the selection of immune escape mutations

“CTL Escape Mutant”

CTL

CTL

HLA

HLA genetic diversity protects us against diverse infectious diseases

CBA

Population:

HLA-A = 1757 alleles*

HLA-B = 2338 alleles*

HLA-C = 1304 alleles*

*as of January 2012. http://hla.alleles.org/nomenclature/stats.html

Individual:

HIV adapts to the HLA class I alleles of each host it passes through

Moore et al Science 2002; Bhattacharya et al Science 2007, Brumme et al PLoS Pathogens 2007; Rousseau et al J Virol 2008; Kawashima et al Nature 2009

Immune escape pathways are broadly predictable based on host HLA

Mapping sites of immune escape across the HIV-1 genome:

…first, a brief primer on techniques and challenges…

Identifying patterns of host-

mediated evolution in HIV

Brumme laboratory

Identifying patterns of host-

mediated evolution in HIV

Assemble large cohort of HIV-infected individuals

Brumme laboratory

Identifying patterns of host-

mediated evolution in HIV

Assemble large cohort of HIV-infected individuals

Undertake host (HLA class I) and HIV genotyping

Brumme laboratory

Identifying patterns of host-

mediated evolution in HIV

Assemble large cohort of HIV-infected individuals

Undertake host (HLA class I) and HIV genotyping

Apply statistical methods to identify patterns of HIV adaptation

Brumme laboratory

Identifying patterns of host-

mediated evolution in HIV

Assemble large cohort of HIV-infected individuals

Undertake host (HLA class I) and HIV genotyping

Apply statistical methods to identify patterns of HIV adaptation

*

*

*Note: these steps are

harder and more complicated than they

appear

*Brumme laboratory

00 44

44 00not B*57not B*57

B*57B*57

NNTT

p = 0.03 p = 0.03

Pt1: ..TSNLQEQIGW.. B*57+Pt2: ..TSTLQEQIGW.. B*57-Pt3: ..TSNLQEQIGW.. B*57+Pt4: ..TSTLQEQIGW.. B*57-Pt5: ..TSTLQEQIGW.. B*57-Pt6: ..TSNLQEQIAW.. B*57+Pt7: ..TSTLQEQITW.. B*57-Pt8: ..TSNLQEQIGW.. B*57+

B*57

TW10 epitope

HIV-1 Gag:

Immune escape map

Susceptible

Adapted

Are escape mutations in HIV-1 accumulating at the population level?

Transmission and reversion of escape mutations

non-B*57 B*57

selection

non-B*57

reversion

Failure to revert leads to accumulation of escape variant at the population level

non-B*51 B*51

non-B*51

Example: escape in B*51-TI8 epitope

B*51-associated I135X mutation

HIV Reverse Transcriptase

% HLA-B*51 Prevalence

75

50

25

0 10 20

R=0.91p=0.0006

% I

135X

in B

*51-

Kumamoto

London

Vancouver

Perth

Oxford

Barbados

LusakaDurban

Gaberone

Increased prevalence of I135X in populations with high B*51 prevalence

Kawashima et al, Nature 2009

Is it possible that HIV-1 is acting as a selective pressure on humans??

Vertical transmission of HIV (and genetic inheritance of HLA)

non-B*57B*57

50% chance B*57

Mothers with protective HLA alleles less likely to

transmit HIV to childnon-B*57B*57

If B*57 improved survival

HIV-infected children who inherit protective alleles have improved chances of survival

Summary and Conclusions

- Strong evidence of HLA-associated immune selection on HIV

- HIV Immune escape pathways are broadly predictable based on host HLA

- Characterization of sites, pathways, kinetics of immune escape mutations will help identify regions for inclusion in vaccine design

- Information on common escape pathways can be incorporated into immunogen design to block “preferred” mutational escape pathways

- Evidence for accumulation of escape mutations in contemporary HIV-1 sequences

- Potential for HIV-1 selection on humans??