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HIV is associated with an increased risk of age-related clonal hematopoiesis among older adults

Nature Medicine volume 27, pages 1006–1011 (2021)Cite this article

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Abstract

People with human immunodeficiency virus (HIV) have higher rates of certain comorbidities, particularly cardiovascular disease and cancer, than people without HIV1,2,3,4,5. In view of observations that somatic mutations associated with age-related clonal hematopoiesis (CH) are linked to similar comorbidities in the general population6,7,8,9,10, we hypothesized that CH may be more prevalent in people with HIV. To address this issue, we established a prospective cohort study, the ARCHIVE study (NCT04641013), in which 220 HIV-positive and 226 HIV-negative participants aged 55 years or older were recruited in Australia. Demographic characteristics, clinical data and peripheral blood were collected to assess the presence of CH mutations and to identify potential risk factors for and clinical sequelae of CH. In total, 135 CH mutations were identified in 100 (22.4%) of 446 participants. CH was more prevalent in HIV-positive participants than in HIV-negative participants (28.2% versus 16.8%, P = 0.004), overall and across all age groups; the adjusted odds ratio for having CH in those with HIV was 2.16 (95% confidence interval 1.34–3.48, P = 0.002). The most common genes mutated overall were DNMT3A (47.4%), TET2 (20.0%) and ASXL1 (13.3%). CH and HIV infection were independently associated with increases in blood parameters and biomarkers associated with inflammation. These data suggest a selective advantage for the emergence of CH in the context of chronic infection and inflammation related to HIV infection.

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Fig. 1: Characteristics of mutations found in study participants.
Fig. 2: Adjusted and unadjusted estimates with 95% CIs for the association between CH mutation and HIV status, age, gender, sexual orientation and smoking.

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Data availability

The data that support the findings of this study are available from the corresponding authors upon reasonable request. This study is part of an ongoing clinical trial. Requests for additional raw and analyzed data and materials will be first reviewed by the corresponding authors to ensure that ethics obligations and trial protocols are not breached. Specifically, patient-related data may be subject to confidentiality and any request for merged patient data, including clinical information, must also be approved by the ARCHIVE study steering committee.

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Acknowledgements

The authors thank all of the individuals who participated in this study. We also acknowledge the following clinical site study coordinators: T. Vincent, Holdsworth House Medical Practice; R. Rosario, East Sydney Doctors; H. Lau, Prahran Market Clinic; F. Bascombe, St Vincent’s Hospital Sydney; D. Smith, Albion Centre; S. Price, Alfred Hospital; J. O’Brien, Monash Health; H. T. L. Tan, Taylor Square Private Clinic; B. Sinclair, Department of Sexual Health Medicine, Sydney Local Health District. We also acknowledge K. Merlin, M. Starr, B. Catlett and the Clinical Trials & Biorepository/DBS Team at St Vincent’s Centre for Applied Medical Research. Finally, we acknowledge P. Blombery, M. McBean and H. N. Goh for their assistance with ASXL1 fragment-length analysis. The Kirby Institute receives funding from the Australian Government Department of Health and Ageing. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Australian Government. We thank the following funders for fellowship and grant support: NHMRC investigator grant (1196749 to. M.A.D.), Cancer Council Victoria Dunlop Fellowship (to M.A.D.), Howard Hughes Medical Institute international research scholarship (to M.A.D.), NHMRC investigator grant (1196755 to S.-J.D.), CSL Centenary fellowship (to S.-J.D.), NHMRC postgraduate scholarship (to N.J.D.), NHMRC fellowship (1110067 to M.N.P.), Cancer Institute of NSW Future Research Leader Fellowship (15-1-01 to M.N.P.), NHMRC/MRFF investigator grant (1195030 to P.Y.), Snowdome Foundation/Maddie Riewoldt’s vision (to P.Y.), George and Yolanda Klempfner AO fellowship (to P.Y.), Gilead (to P.Y.) and NHMRC project grants (1128984 (to S.-J.D. and M.A.D.) and 1213110).

Author information

Author notes

  1. These authors contributed equally: Nila J. Dharan, Paul Yeh, Kathy Petoumenos, Sarah-Jane Dawson, Mark N. Polizzotto, Mark A. Dawson.

Authors and Affiliations

  1. Kirby Institute, University of New South Wales Sydney, Sydney, New South Wales, Australia

    Nila J. Dharan, Katherine Ognenovska, David J. Templeton, Nectarios Rose, Jolie Hutchinson, Kathy Petoumenos & Mark N. Polizzotto

  2. Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

    Paul Yeh, Miriam M. Yeung, Jerick Guinto, Sarah Ftouni, Sarah-Jane Dawson & Mark A. Dawson

  3. Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia

    Paul Yeh, Miriam M. Yeung, Sarah-Jane Dawson & Mark A. Dawson

  4. Holdsworth House Medical Practice, Sydney, New South Wales, Australia

    Mark Bloch & Trina Vincent

  5. East Sydney Doctors, Darlinghurst, New South Wales, Australia

    David Baker & Ricardo Rosario

  6. Prahran Market Clinic, Melbourne, Victoria, Australia

    Norman Roth & Helen Lau

  7. Albion Centre, South Eastern Sydney Local Hospital Network, Sydney, New South Wales, Australia

    Don Smith & Denise Smith

  8. School of Public Health and Community Medicine, University of New South Wales Sydney, Sydney, New South Wales, Australia

    Don Smith

  9. Department of Infectious Diseases, Alfred Hospital and Monash University, Melbourne, Victoria, Australia

    Jennifer F. Hoy & Sally Price

  10. Monash Infectious Diseases, Monash Health, Clayton, Victoria, Australia

    Ian Woolley & Jessica O’Brien

  11. Centre for Inflammatory Diseases, Monash University, Clayton, Victoria, Australia

    Ian Woolley

  12. Taylor Square Private Clinic, Darlinghurst, New South Wales, Australia

    Catherine Pell & Hooi Theng Lynn Tan

  13. Department of Sexual Health Medicine and Sexual Assault Medical Service, Sydney Local Health District, Sydney, New South Wales, Australia

    David J. Templeton & Bret Sinclair

  14. Discipline of Medicine, Central Clinical School, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia

    David J. Templeton

  15. Positive Life, Sydney, New South Wales, Australia

    Neil Fraser

  16. Centre for Cancer Research, University of Melbourne, Melbourne, Victoria, Australia

    Sarah-Jane Dawson & Mark A. Dawson

  17. St Vincent’s Hospital, Darlinghurst, New South Wales, Australia

    Mark N. Polizzotto & Florence Bascombe

Authors
  1. Nila J. Dharan
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Consortia

The ARCHIVE Study Group

  • Nila J. Dharan
  • , Paul Yeh
  • , Mark Bloch
  • , Trina Vincent
  • , David Baker
  • , Ricardo Rosario
  • , Norman Roth
  • , Helen Lau
  • , Don Smith
  • , Denise Smith
  • , Jennifer F. Hoy
  • , Sally Price
  • , Ian Woolley
  • , Jessica O’Brien
  • , Catherine Pell
  • , Hooi Theng Lynn Tan
  • , David J. Templeton
  • , Bret Sinclair
  • , Neil Fraser
  • , Kathy Petoumenos
  • , Sarah-Jane Dawson
  • , Mark N. Polizzotto
  • , Florence Bascombe
  •  & Mark A. Dawson

Contributions

N.J.D. and P.Y. are co-first authors and contributed equally to this article. K.P., S.-J.D., M.N.P. and M.A.D. are co-senior authors and contributed equally to this article. N.J.D., P.Y., K.P., S.-J.D., M.N.P. and M.A.D. designed the project and trial protocol, oversaw the management of the trial and wrote the final manuscript. M.B., D.B., N. Roth, D.S., J.F.H., I.W., C.P., D.J.T. and M.N.P. recruited partipants to the study. N.J.D. and K.O. supported study recruitment and coordination. N.F. provided community input for the trial design and conduct. Experimental work and genomic analysis were performed by P.Y., M.M.Y., J.G., S.F, S.-J.D. and M.A.D. Statistical analyses were completed by N.J.D., P.Y., N. Rose, J.H., K.P. and M.N.P. All authors reviewed and approved the final version of the manuscript.

Corresponding authors

Correspondence to Kathy Petoumenos, Sarah-Jane Dawson, Mark N. Polizzotto or Mark A. Dawson.

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Competing interests

M.A.D. has been a member of advisory boards for CTX CRC, Storm Therapeutics, Celgene and Cambridge Epigenetix. S.-J.D has been a member of advisory boards for AstraZeneca. The laboratory of S.-J.D. received funding from CTx CRC and Genentech. The laboratory of M.A.D. received research funding from CTx CRC. N.J.D. received research support from Gilead Sciences. D.S. received research support and consultancy fees from Gilead Sciences, Janssen pharmaceuticals and Merck. J.H.’s institution received reimbursement for her involvement in Advisory Boards for Gilead Sciences, Merck, Sharp & Dohme and ViiV Healthcare. M.B. received support for medical advisory boards, lecturing and attendance at scientific conferences from Gilead Sciences, ViiV Healthcare and AbbVie, and his institution has received research support from Gilead Sciences, ViiV Healthcare, GSK, AbbVie, MSD, Amgen and Eli Lilly.

Additional information

Peer review information Nature Medicine thanks Hossein Khiabanian, Beibei Guo, Frederik Damm and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Michael Basson was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Extended Data Fig. 1 ARCHIVE study recruitment and analysis.

a. Participant enrolment and inclusion in the final analysis. In total 446 participants (220 HIV positive and 226 HIV negative) were assessed for CH. b. Study analysis design. Genomic analysis for CH was performed blinded to the HIV status of the participant. Unblinding of HIV status and statistical analysis was performed once genomic analysis by targeted deep sequencing was complete.

Extended Data Fig. 2 Correlation between duration of HIV and variant allele fraction of CH mutation and presence of two or more CH mutations.

No significant association was found between the duration of HIV in years and 1) the variant allele fraction of the CH mutation1 (figure); and 2) the presence of two or more CH mutations (OR [CI] = 0.99 [0.96–1.02], p = 0.58). 1Mean average variant allele fraction was calculated if there was more than one CH mutation present.

Extended Data Fig. 3 Box plots of the distribution of Interleukin-6 by IL6R p. Asp358Ala status.

Interleukin-6 levels when separated by IL6R Asp358Ala polymorphism status showed no statistical difference across a. CH mutation status and b. HIV status. The centre line of the box depicts the mean IL-6 value with the lower and upper bounds of the boxes representing the 25th and 75th percentile values, respectively. The lower bound of the whisker indicates the minimum, defined as the 25th percentile minus 1.5x the interquartile range, and the upper bound of the whisker indicates the maximum, defined as the 75th percentile plus 1.5x the interquartile range. Overall p-values (figure inset) were generated using the Kruskal-Wallis test. Tests for significant differences in the median across groups were done by generating p-values using post-hoc pairwise two-sided multiple comparison analysis (Dwass, Steel, Critchlow-Fligner Method). Outliers have been removed for box plot presentation only; p-values were calculated including outliers. Outliers were defined as values greater than 1.5 times the IQR above the third quartile.

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Dharan, N.J., Yeh, P., Bloch, M. et al. HIV is associated with an increased risk of age-related clonal hematopoiesis among older adults. Nat Med 27, 1006–1011 (2021). https://doi.org/10.1038/s41591-021-01357-y

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