Frequency and Dynamics of Transmitted Polymorphisms and their Impact on Early Pathogenesis in Heterosexual Couples in Zambia

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1 Frequency and Dynamics of Transmitted Polymorphisms and their Impact on Early Pathogenesis in Heterosexual Couples in Zambia 8 th International Workshop on HIV Transmission Principles of Intervention Barcelona, 4-5 October 2013 Daniela C. Mónaco, PhD Emory Vaccine Center, Atlanta, U.S.A.

2 Selection of escape mutations to the cellular immune response HLA Class I/CD8+ T Cells

3 Selection of escape mutations to the cellular immune response Transmission? HLA Class I/CD8+ T Cells Donor Recipient

4 Zambia-Emory HIV Research Project (ZHERP) Established by Susan Allen in 1994 Identified 169 epidemiologically-linked couples (median EDI=45.5 days) Baseline 6M 12M 18M 24M Couple is identified as HIV serodiscordant Negative partner is tested once per month Negative partner seroconverts Plasma collected from D and LR gag, pol and nef PCR amplified and sequenced from D and LR Plasma collected from LR gag, pol and nef PCR amplified and sequenced from LR

5 Zambia-Emory HIV Research Project (ZHERP) Established by Dr. Susan Allen in 1994 Identified 169 epidemiologically-linked couples (median EDI=45.5 days) Baseline 6M 12M 18M 24M Couple is identified as HIV serodiscordant Negative partner is tested once per month Negative partner seroconverts Plasma collected from D and LR gag, pol and nef PCR amplified and sequenced from D and LR Plasma collected from LR gag, pol and nef PCR amplified and sequenced from LR

6 Zambia-Emory HIV Research Project (ZHERP) Established by Dr. Susan Allen in 1994 Identified 169 epidemiologically-linked couples (median EDI=45.5 days) Baseline 6M 12M 18M 24M Couple is identified as HIV serodiscordant Negative partner is tested once per month Negative partner seroconverts Plasma collected from D and LR gag, pol and nef PCR amplified and sequenced from D and LR Plasma collected from LR gag, pol and nef PCR amplified and sequenced from LR

7 Questions of the Study 1. What is the prevalence of Gag, Pol and Nef polymorphisms circulating in the chronically-infected Zambia population? 2. How frequently are these polymorphisms transmitted? 3. Are the transmitted polymorphisms relevant to the newly infected individual s HLA-I alleles? 4. How does these transmitted polymorphisms affect early pathogenesis?

8 1. What is the prevalence of Gag, Pol and Nef polymorphisms circulating in the chronicallyinfected Zambia population? Sequence analysis - Obtained the Zambia consensus for Gag, Pol and Nef using the donor sequences - Identified any change from consensus as a polymorphism

9 1. What is the prevalence of Gag, Pol and Nef polymorphisms circulating in the chronicallyinfected Zambia population? Nef (11.0) > Gag (7.1) > Pol (4.1) (p<0.001)

10 1. What is the prevalence of Gag, Pol and Nef polymorphisms circulating in the chronicallyinfected Zambia population? Nef (11.0) > Gag (7.1) > Pol (4.1) (p<0.001) Pol (41.0) > Gag (35.5) > Nef (23.0) (p<0.001)

11 2. How frequently are these polymorphisms transmitted? All positions

12 2. How frequently are these polymorphisms transmitted? Single amino acid positions All positions p=4e-21 Mixture positions p<0.01

13 3. Are the transmitted polymorphisms relevant to the newly infected individual s HLA-I alleles? Escape Wild type HLA A02 + HLA A02 - HLA association - HLA-linked polymorphisms: we identified positions using donor and NYT (not-yet transmitters) sequences and considered any polymorphism present in that position - A-list Epitope: we considered any polymorphism located on the defined CTL epitopes

14 3. Are the transmitted polymorphisms relevant to the newly infected individual s HLA-I alleles? Donor Gag Pol Nef HLA-associated Polymorphisms: Gag (26.5%) > Pol (23.5%)=Nef (23.1%) (p=0.0132) HLA-linked: Gag=Pol=Nef A-list Epitopes: Gag=Pol > Nef (p<0.0001)

15 3. Are the transmitted polymorphisms relevant to the newly infected individual s HLA-I alleles? LR Gag Pol Nef HLA-associated Polymorphisms: Gag (19.3%)=Nef (18.2%) > Pol (15.2%) (p=0.0002) HLA-linked: Gag > Pol=Nef (p=0.0017) A-list Epitopes: Gag=Pol=Nef

16 4. How does these transmitted polymorphisms affect early pathogenesis? Total number of polymorphisms Set point VL (Nadir VL during the 3-9 months post-edi) CD4 count (Up to two years post-edi) p= Pol p=0.05

17 4. How does these transmitted polymorphisms affect early pathogenesis? LR HLA-linked polymorphisms (q<0.01) Set point VL (Nadir VL during the 3-9 months post-edi) CD4 count (Up to two years post-edi) Gag HLA-linked p=0.03 Gag HLA-associated p=0.04 p=0.006

18 4. How does these transmitted polymorphisms affect early pathogenesis? Donor HLA-linked polymorphisms (q<0.01) Set point VL (Nadir VL during the 3-9 months post-edi) CD4 count (Up to five years post-edi) p=0.003 p= p=0.0004

19 Conclusions The Zambian HIV + population shows a high frequency of polymorphisms in Gag, Pol and Nef proteins but only a small proportion of them are relevant to the individual s own HLA-I alleles. This could be explained by: (1) their high probability of transmission, even when a bias for transmission of consensus residues is evidenced; (2) their low rate of reversion, even in the absence of the selecting HLA in the newly-infected individual. This facts would also explain the high amount of relevant HLAlinked polymorphisms transmitted to the newly-infected individual.

20 Conclusions In the newly infected individual, transmission of polymorphisms has two opposite effects on early pathogenesis, depending on weather they are linked to the patient s HLA or not: (1) total number of polymorphisms transmitted is associated with a reduction in set point VL and a slower CD4 decline, which could be due to their effect on viral fitness; (2) proportion of HLA-linked polymorphisms is associated with an increase in set point VL and a faster CD4 decline, which would show that transmission of pre-escaped virus can lead to a faster disease progression.

21 Next step Fitness (total polymorphisms) CTL-escape (HLA-linked polymorphisms) Disease Progression

22 Acknowledgments Emory University Eric Hunter Cindy Derdeyn Malinda Schaefer Jessica Prince Dan Claiborne Dario Dilernia Paul Farmer Kristine Dennis University of Alabama- Birmingham Paul Goepfert Richard Kaslow James Tang Oxford Univeristy Philip Goulder John Frater Rodney Philips Philippa Matthews Emily Adland Ragon Institute Bruce Walker University of KwaZulu-Natal Thumbi Ndung'u ZEHRP cohort The Staff and Participants Susan Allen Elwyn Chomba William Kilembe Joseph Mulenga Amanda Tichacek Nicole Luisi Microsoft Research David Heckerman Jonathan Carlson Bloemfontein Oxford Collaborative Group Cloete van Vuuren Dominique Goedhals Gary Huang Dewald Steyn Havard School of Public Health Roger Shapiro