Clinical and immunological correlates of CXCR4 coreceptor use in people with HIV-1 receiving antiretroviral therapy in the Netherlands: a multicentre cohort study.

BACKGROUND: CXCR4-using (X4) viruses are associated with faster disease progression in untreated HIV-1 infection, although their clinical, virological, and immunological correlates during suppressive antiretroviral therapy are not well characterised. We aimed to assess the associations between X4 coreceptor use and clinical outcomes, HIV persistence, and immunological profiles in people with HIV-1 receiving suppressive antiretroviral therapy.

METHODS: In this multicentre cohort study, asymptomatic adults with HIV receiving suppressive antiretroviral therapy were enrolled from four HIV treatment centres in the Netherlands between Oct 16, 2019, and Oct 27, 2021 and followed up for 2 years. Clinical data were obtained from structured questionnaires and electronic health records. HIV-1 coreceptor use was predicted from triplicate env sequencing with Geno2pheno, and participants were classified as having CCR5-using (R5), X4, or mixed virus. HIV-1 subtype was assigned using env and pol sequences. Total and intact HIV DNA in CD4 T cells were quantified using multiplex digital PCR. Plasma proteomics, bulk peripheral blood mononuclear cell transcriptomics, and high-dimensional flow cytometry were used for systems-level profiling. Associations between predicted coreceptor use and clinical outcomes, HIV-reservoir measures, and immunological profiles were assessed using adjusted regression models and discovery and validation cohorts.

FINDINGS: Coreceptor use was assigned in 1724 participants; 1222 had R5 virus, 336 had X4 virus, and 166 had mixed classifications. Primary clinical analyses included 1494 participants, of whom 1172 were in the R5 group and 322 were in the X4 group. Compared with the R5 group, the X4 group had a lower CD4 nadir, a higher prevalence of previous AIDS-defining events, poorer immunological recovery, and more comorbidities, particularly type 2 diabetes and non-affective psychiatric disorders. The median total HIV DNA was 1051 copies per 10 CD4 T cells in the X4 group versus 599 copies per 10 CD4 T cells in the R5 group, and the median intact HIV DNA was 23 copies per 10 CD4 T cells versus 15 copies per 10 CD4 T cells. No significant differences were observed in plasma inflammatory proteins. Participants in the X4 group had higher frequencies of activated CD4 T cells and PD-1 regulatory T cells, and transcriptomic analyses identified downregulation of two validated transcripts involved in transcriptional repression and lipid hydrolysis.

INTERPRETATION: Among people with HIV receiving suppressive antiretroviral therapy, infection with X4 virus was associated with markers of more advanced previous HIV disease, impaired immune recovery, larger HIV reservoirs, and selected comorbidities despite viral suppression. Coreceptor use might therefore help to contextualise clinical, virological, and immunological heterogeneity in treated HIV-1 infection and could be relevant to future HIV cure studies.

FUNDING: ViiV Healthcare.

Copyright © 2026 The Author(s). Published by Elsevier Ltd.. All rights reserved.

PMID: 42956782