Delineating the effect of sex hormone intake on immunity in cis and trans women with HIV

Although sex hormones are recognized to induce immune variations, little is known on the effect of exogenous sex hormone intake on immune responses in cis and trans women. Here, we aimed at quantifying how sex hormone intake affects HIV-1 immune markers in cis women (CW) and trans women (TW) with HIV. We considered measurements of key HIV-1 immune markers (CD4, CD8, lymphocyte counts, and CD4:CD8 ratio) from cis men (CM), CW, and TW enrolled in the Swiss HIV Cohort Study. We modeled immune markers using linear mixed-effects models with an interaction between the variables "group" (CW, TW) and "with sex hormones intake" (yes/no). We conducted serum proteomics measurements of 92 inflammation markers on samples from 31 TW before and after sex hormone intake to assess the inflammation environment. We included 54'141 measurements from 3'092 CW and 83 TW sampled between 2015 and 2022, and 147'298 from 8'611 CM. Sex hormone intake was associated with significant distinct effects on CD4 and CD4:CD8 ratio between the different groups of women (p=0.0025 and 0.015). TW with sex hormone intake had significantly higher CD4 counts (median = 772 (1Q-3Q=520-1'006)) than without (median = 617 (1Q-3Q=426-892)). This increase was similar in magnitude to the difference in CD4 counts between CW and CM. None of the serum inflammation proteins showed significant concentration difference before and after sex hormone intake in TW. This study highlights the need to consider the potential role of sex hormones intake in modulating the immune system among other biological and social factors, especially in TW in HIV. ### Competing Interest Statement IAA has received honoraria from MSD and Sanofi, a travel grant from Gilead Sciences, and a grant from the Promedica foundation. RDK has received research fundings from Gilead unrelated to this work. AH's institution has received travel grants, congress and advisory fees from MSD, Viiv and Gilead, unrelated to this work. KAP's institution has received travel grants and advisory fees from MSD, Gilead and ViiV healthcare unrelated to this work. HFG has received grants from the SNF; SHCS; Yvonne Jacob Foundation; University of Zurich's Clinical Research Priority Program, viral disease; Zurich Primary HIV Infection; Systems.X; National Institutes of Health; Gilead Sciences; and Roche; and personal fees from Merck, Gilead Sciences, ViiV, GSK, Janssen, Johnson and Johnson and Novartis, for consultancy or DSMB membership and a travel grant from Gilead. ### Funding Statement This work has been financed within the framework of the Swiss HIV Cohort Study, supported by the Swiss National Science Foundation (grant #201369), by SHCS project #882 and by the SHCS research foundation. The data were gathered by the 5 Swiss university hospitals, 2 cantonal hospitals, 15 affiliated hospitals, and 36 private physicians (listed at http://www.shcs.ch/180-health-care-providers). IAA is supported by a research grant of the Promedica Foundation. CP is supported by a Fellowship from the Collegium Helveticum. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The SHCS was approved by the local ethical committees of the participating centres: Ethikkommission beider Basel ("Die Ethikkommission beider Basel hat die Dokumente zur Studie zustimmend zur Kenntnis genommen und genehmigt."); Kantonale Ethikkommission Bern (21/88); Comite departemental d'ethique des specialites medicales et de medecine communautaire et de premier recours, Hopitaux Universitaires de Geneve (01-142); Commission cantonale d'ethique de la recherche sur l'etre humain, Canton de Vaud (131/01); Comitato etico cantonale, Repubblica e Cantone Ticino (CE 813); Ethikkommission des Kantons St. Gallen (EKSG 12/003); Kantonale Ethikkommission Zurich (KEK-ZH-NR: EK-793), and written informed consent was obtained from all participants. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The individual level datasets generated or analyzed during the current study do not fulfill the requirements for open data access: 1) The SHCS informed consent states that sharing data outside the SHCS network is only permitted for specific studies on HIV infection and its complications, and to researchers who have signed an agreement detailing the use of the data and biological samples; and 2) the data is too dense and comprehensive to preserve patient privacy in persons living with HIV. According to the Swiss law, data cannot be shared if data subjects have not agreed or data is too sensitive to share. Investigators with a request for selected data should send a proposal to the respective SHCS address (www.shcs.ch/contact). The provision of data will be considered by the Scientific Board of the SHCS and the study team and is subject to Swiss legal and ethical regulations, and is outlined in a material and data transfer agreement.