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.
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
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.
Marcus, J. L. et al. Comparison of overall and comorbidity-free life expectancy between insured adults with and without HIV Infection, 2000-2016. JAMA Netw. Open 3, e207954 (2020).
Schouten, J. et al. Cross-sectional comparison of the prevalence of age-associated comorbidities and their risk factors between HIV-infected and uninfected individuals: the AGEhIV cohort study. Clin. Infect. Dis. 59, 1787–1797 (2014).
Hasse, B. et al. Morbidity and aging in HIV-infected persons: the Swiss HIV Cohort Study. Clin. Infect. Dis. 53, 1130–1139 (2011).
Rosenson, R. S. et al. Excess risk for atherosclerotic cardiovascular outcomes among US adults with HIV in the current era. J. Am. Heart Assoc. 9, e013744 (2020).
Shiels, M. S. & Engels, E. A. Evolving epidemiology of HIV-associated malignancies. Curr. Opin. HIV AIDS 12, 6–11 (2017).
Genovese, G. et al. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N. Engl. J. Med. 371, 2477–2487 (2014).
Jaiswal, S. et al. Age-related clonal hematopoiesis associated with adverse outcomes. N. Engl. J. Med. 371, 2488–2498 (2014).
Xie, M. et al. Age-related mutations associated with clonal hematopoietic expansion and malignancies. Nat. Med. 20, 1472–1478 (2014).
Abelson, S. et al. Prediction of acute myeloid leukaemia risk in healthy individuals. Nature 559, 400–404 (2018).
Desai, P. et al. Somatic mutations precede acute myeloid leukemia years before diagnosis. Nat. Med. 24, 1015–1023 (2018).
Autenrieth, C. S. et al. Global and regional trends of people living with HIV aged 50 and over: estimates and projections for 2000–2020. PLoS ONE 13, e0207005 (2018).
Gueler, A. et al. Life expectancy in HIV-positive persons in Switzerland: matched comparison with general population. AIDS 31, 427–436 (2017).
Feinstein M. J., et al. Characteristics, prevention and management of cardiovascular disease in people living with HIV: a scientific statement from the American Heart Association. Circulation 140, e98–e124 (2019).
Deeks, S. G. Immune dysfunction, inflammation and accelerated aging in patients on antiretroviral therapy. Top. HIV Med. 17, 118–123 (2009).
Jalbert, E. et al. IL-1β-enriched monocytes mount massive IL-6 responses to common inflammatory triggers among chronically HIV-1 infected adults on stable anti-retroviral therapy at risk for cardiovascular disease. PLoS ONE 8, e75500 (2013).
Cassol, E. et al. Persistent microbial translocation and immune activation in HIV-1-infected South Africans receiving combination antiretroviral therapy. J. Infect. Dis. 202, 723–733 (2010).
Chow, F. C., Bacchetti, P., Kim, A. S., Price, R. W. & Hsue, P. Y. Effect of CD4+ cell count and viral suppression on risk of ischemic stroke in HIV infection. AIDS 28, 2573–2577 (2014).
Triant, V. A. et al. Association of immunologic and virologic factors with myocardial infarction rates in a US healthcare system. J. Acquir. Immune Defic. Syndr. 55, 615–619 (2010).
Friis-Moller, N. et al. Combination antiretroviral therapy and the risk of myocardial infarction. N. Engl. J. Med. 349, 1993–2003 (2003).
Subbaraman, R., Chaguturu, S. K., Mayer, K. H., Flanigan, T. P. & Kumarasamy, N. Adverse effects of highly active antiretroviral therapy in developing countries. Clin. Infect. Dis. 45, 1093–1101 (2007).
Kuller, L. H. et al. Inflammatory and coagulation biomarkers and mortality in patients with HIV infection. PLoS Med. 5, e203 (2008).
Neuhaus, J. et al. Markers of inflammation, coagulation and renal function are elevated in adults with HIV infection. J. Infect. Dis. 201, 1788–1795 (2010).
Fuster, J. J. et al. Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice. Science 355, 842–847 (2017).
Jaiswal, S. et al. Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease. N. Engl. J. Med. 377, 111–121 (2017).
Steensma, D. P. Clinical consequences of clonal hematopoiesis of indeterminate potential. Blood Adv. 2, 3404–3410 (2018).
Frick, M. et al. Role of donor clonal hematopoiesis in allogeneic hematopoietic stem-cell transplantation. J. Clin. Oncol. 37, 375–385 (2019).
Bick, A. G. et al. Genetic interleukin-6 signaling deficiency attenuates cardiovascular risk in clonal hematopoiesis. Circulation 141, 124–131 (2020).
Kaner, J. D. et al. HIV portends a poor prognosis in myelodysplastic syndromes. Leuk. Lymphoma 60, 3529–3535 (2019).
Sallman, D. A. et al. The first-in-class anti-CD47 antibody magrolimab (5F9) in combination with azacitidine is effective in MDS and AML patients: ongoing phase 1b results. Blood 134, 569 (2019).
Borate, U. et al. Phase Ib study of the anti-TIM-3 antibody MBG453 in combination with decitabine in patients with high-risk myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Blood 134, 570 (2019).
Fenaux, P. et al. Luspatercept in patients with lower-risk myelodysplastic syndromes. N. Engl. J. Med. 382, 140–151 (2020).
Busque, L. et al. High-sensitivity C-reactive protein is associated with clonal hematopoiesis of indeterminate potential. Blood Adv. 4, 2430–2438 (2020).
Pietras, E. M. et al. Chronic interleukin-1 exposure drives haematopoietic stem cells towards precocious myeloid differentiation at the expense of self-renewal. Nat. Cell Biol. 18, 607–618 (2016).
Pietras, E. M. et al. Re-entry into quiescence protects hematopoietic stem cells from the killing effect of chronic exposure to type I interferons. J. Exp. Med. 211, 245–262 (2014).
Bogeska R., et al. Hematopoietic stem cells fail to regenerate following inflammatory challenge. Preprint at bioRxiv https://doi.org/10.1101/2020.08.01.230433 (2020).
Cai, Z. et al. Inhibition of inflammatory signaling in Tet2 mutant preleukemic cells mitigates stress-induced abnormalities and clonal hematopoiesis. Cell Stem Cell 23, 833–49 (2018).
Meisel, M. et al. Microbial signals drive pre-leukaemic myeloproliferation in a Tet2-deficient host. Nature 557, 580–584 (2018).
Grund, B. et al. Relevance of interleukin-6 and D-dimer for serious non-AIDS morbidity and death among HIV-positive adults on suppressive antiretroviral therapy. PLoS One 11, e0155100 (2016).
Micromedex. https://www.micromedexsolutions.com (Accessed 19 March 2021).
Centers for Disease Control and Prevention. Defining adult overweight and obesity. CDC.gov https://www.cdc.gov/obesity/adult/defining.html (Accessed 19 March 2021).
Yeh, P. et al. Molecular disease monitoring using circulating tumor DNA in myelodysplastic syndromes. Blood 129, 1685–1690 (2017).
Doig, K. D. et al. PathOS: a decision support system for reporting high-throughput sequencing of cancers in clinical diagnostic laboratories. Genome Med. 9, 38 (2017).
Richards, S. et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet. Med. 17, 405–424 (2015).
Yannakou, C. K. et al. ASXL1 c.1934dup;p.Gly646Trpfs*12—a true somatic alteration requiring a new approach. Blood Cancer J. 7, 656 (2017).
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).
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.
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.
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.
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.
About this article
Cite this article
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