Host genetic and immune factors drive evasion of HIV-1 pathogenesis in viremic non-progressors

Ángel Bayón-Gil; Inmaculada Hernández; Judith Dalmau; Juan C. Nieto; Víctor Urrea; Lidia Garrido-Sanz; Ginevra Caratú; Maria C. García-Guerrero; Cristina Gálvez; María Salgado; Itziar Erkizia; Fernando Laguía; Patricia Resa-Infante; Marta Massanella; Raúl Tonda; Jordi Morata; Kai Ying Hong; Jane Koshy; Aaron R. Goldman; Leila Giron; Mohamed Abdel-Mohsen; Holger Heyn; Javier Martinez-Picado; Maria C. Puertas

doi:10.1016/j.medj.2024.09.007

Host genetic and immune factors drive evasion of HIV-1 pathogenesis in viremic non-progressors

Ángel Bayón-Gil, Inmaculada Hernández, Judith Dalmau, Juan C. Nieto, Víctor Urrea, Lidia Garrido-Sanz, Ginevra Caratú, Maria C. García-Guerrero, Cristina Gálvez, María Salgado, Itziar Erkizia, Fernando Laguía, Patricia Resa-Infante, Marta Massanella, Raúl Tonda, Jordi Morata, Kai Ying Hong, Jane Koshy, Aaron R. Goldman, Leila GironMohamed Abdel-Mohsen, Holger Heyn, Javier Martinez-Picado^*, Maria C. Puertas^*

^*Corresponding author for this work

Medicine, Infectious Diseases Division

Research output: Contribution to journal › Article › peer-review

3 Scopus citations

Abstract

Background: Viremic non-progressors (VNPs) represent an exceptional and uncommon subset of people with HIV-1, characterized by the remarkable preservation of normal CD4⁺ T cell counts despite uncontrolled viral replication—a trait reminiscent of natural hosts of simian immunodeficiency virus. The mechanisms orchestrating evasion from HIV-1 pathogenesis in human VNPs remain elusive, primarily due to the absence of integrative studies. Methods: We implemented a novel single-cell and multiomics approach to comprehensively characterize viral, genomic, transcriptomic, and metabolomic factors driving this exceedingly rare disease phenotype in 16 VNPs and 29 HIV+ progressors. Findings: Genetic predisposition to the VNP phenotype was evidenced by a higher prevalence of CCR5Δ32 heterozygosity, which was associated with lower levels of CCR5 expression and a lower frequency of infected cells in peripheral circulation. We also observed reduced levels of plasma markers of intestinal disruption and attenuated interferon responses in VNPs. These factors potentially drive the other phenotypic traits of immune preservation in this population, including the unaltered tryptophan metabolic profile, reduced activation of cytotoxic lymphocytes, and reduced bystander CD4⁺ T cell apoptosis. Conclusions: In summary, our comprehensive analysis identified intricate factors collectively associated with the unique immunovirological equilibrium in VNPs, shedding light on potential avenues for therapeutic exploration in managing HIV pathogenesis. Funding: The work was supported by funding from the Spanish Ministry of Science and Innovation and the National Institutes of Health (NIH).

Original language	English (US)
Article number	100518
Journal	Med
Volume	6
Issue number	2
DOIs	https://doi.org/10.1016/j.medj.2024.09.007
State	Published - Feb 14 2025

Funding

We would like to thank Eulalia Grau and the Sample Processing and Storage Service at IrsiCaixa for their coordination in the access to clinical samples. We would like to thank M.A. Fern\u00E1ndez at the Flow Cytometry Service of IGTP (Institute Germans Trias i Pujol, Badalona, Spain) for his help and counseling with flow cytometry and sorting experiments. This work was financially supported by Spanish Ministry of Science, Innovation and Universities grant FPU17/04766 (A.B.-G.); Spanish Ministry of Science and Innovation contract RYC2020-028934-I (M.M.); Spanish Ministry of Science and Innovation contract CP22/00038 (M.S.); National Institutes of Health Cancer Center Support grant CA010815 (Wistar Proteomics and Metabolomics Shared Resource); National Institutes of Health grant S10 OD023586 (The Wistar Institute); Spanish Ministry of Science and Innovation grants PID2019-109870RB-I00 and CB21/13/00063 (J.M.-P. laboratory); and National Institutes of Health - National Institute of Allergy and Infectious Diseases grants 1 UM1 AI164561-01 and 1P01AI178376-01 (J.M.-P. laboratory). L.G.-S. received financial support from grant SLT02823 000257 , funded by the \u201CStrategic plan for research and innovation in health\u201D (PERIS), from the Catalan Department of Health . We would like to thank Eulalia Grau and the Clinical Sample Service at IrsiCaixa for their coordination in the access to clinical samples. We would like to thank M.A. Fern\u00E1ndez at the Flow Cytometry Service of IGTP (Institute Germans Trias i Pujol, Badalona, Spain) for his help and counseling with flow cytometry and sorting experiments. This work was financially supported by Spanish Ministry of Science, Innovation and Universities grant FPU17/04766 (A.B.-G.); Spanish Ministry of Science and Innovation contract RYC2020-028934-I (M.M.); Spanish Ministry of Science and Innovation contract CP22/00038 (M.S.); National Institutes of Health Cancer Center Support grant CA010815 (Wistar Proteomics and Metabolomics Shared Resource); National Institutes of Health grant S10 OD023586 (The Wistar Institute); Spanish Ministry of Science and Innovation grants PID2019-109870RB-I00 and CB21/13/00063 (J.M.-P. laboratory); and National Institutes of Health - National Institute of Allergy and Infectious Diseases grants 1 UM1 AI164561-01 and 1P01AI178376-01 (J.M.-P. laboratory). L.G.-S. received financial support from grant SLT02823 000257, funded by the \u201CStrategic plan for research and innovation in health\u201D (PERIS), from the Catalan Department of Health.

Keywords

CCR5
CTL activation
HIV reservoir
HIV-1 pathogenesis
Translation to patients
VNP
interferon
single-cell RNA sequencing
tryptophan
viremic non-progressor
zonulin

ASJC Scopus subject areas

General Medicine

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.medj.2024.09.007

Cite this

Bayón-Gil, Á., Hernández, I., Dalmau, J., Nieto, J. C., Urrea, V., Garrido-Sanz, L., Caratú, G., García-Guerrero, M. C., Gálvez, C., Salgado, M., Erkizia, I., Laguía, F., Resa-Infante, P., Massanella, M., Tonda, R., Morata, J., Hong, K. Y., Koshy, J., Goldman, A. R., ... Puertas, M. C. (2025). Host genetic and immune factors drive evasion of HIV-1 pathogenesis in viremic non-progressors. Med, 6(2), Article 100518. https://doi.org/10.1016/j.medj.2024.09.007

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title = "Host genetic and immune factors drive evasion of HIV-1 pathogenesis in viremic non-progressors",

abstract = "Background: Viremic non-progressors (VNPs) represent an exceptional and uncommon subset of people with HIV-1, characterized by the remarkable preservation of normal CD4+ T cell counts despite uncontrolled viral replication—a trait reminiscent of natural hosts of simian immunodeficiency virus. The mechanisms orchestrating evasion from HIV-1 pathogenesis in human VNPs remain elusive, primarily due to the absence of integrative studies. Methods: We implemented a novel single-cell and multiomics approach to comprehensively characterize viral, genomic, transcriptomic, and metabolomic factors driving this exceedingly rare disease phenotype in 16 VNPs and 29 HIV+ progressors. Findings: Genetic predisposition to the VNP phenotype was evidenced by a higher prevalence of CCR5Δ32 heterozygosity, which was associated with lower levels of CCR5 expression and a lower frequency of infected cells in peripheral circulation. We also observed reduced levels of plasma markers of intestinal disruption and attenuated interferon responses in VNPs. These factors potentially drive the other phenotypic traits of immune preservation in this population, including the unaltered tryptophan metabolic profile, reduced activation of cytotoxic lymphocytes, and reduced bystander CD4+ T cell apoptosis. Conclusions: In summary, our comprehensive analysis identified intricate factors collectively associated with the unique immunovirological equilibrium in VNPs, shedding light on potential avenues for therapeutic exploration in managing HIV pathogenesis. Funding: The work was supported by funding from the Spanish Ministry of Science and Innovation and the National Institutes of Health (NIH).",

keywords = "CCR5, CTL activation, HIV reservoir, HIV-1 pathogenesis, Translation to patients, VNP, interferon, single-cell RNA sequencing, tryptophan, viremic non-progressor, zonulin",

author = "{\'A}ngel Bay{\'o}n-Gil and Inmaculada Hern{\'a}ndez and Judith Dalmau and Nieto, \{Juan C.\} and V{\'i}ctor Urrea and Lidia Garrido-Sanz and Ginevra Carat{\'u} and Garc{\'i}a-Guerrero, \{Maria C.\} and Cristina G{\'a}lvez and Mar{\'i}a Salgado and Itziar Erkizia and Fernando Lagu{\'i}a and Patricia Resa-Infante and Marta Massanella and Ra{\'u}l Tonda and Jordi Morata and Hong, \{Kai Ying\} and Jane Koshy and Goldman, \{Aaron R.\} and Leila Giron and Mohamed Abdel-Mohsen and Holger Heyn and Javier Martinez-Picado and Puertas, \{Maria C.\}",

note = "Publisher Copyright: {\textcopyright} 2024 The Author(s)",

year = "2025",

month = feb,

day = "14",

doi = "10.1016/j.medj.2024.09.007",

language = "English (US)",

volume = "6",

journal = "Med",

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Bayón-Gil, Á, Hernández, I, Dalmau, J, Nieto, JC, Urrea, V, Garrido-Sanz, L, Caratú, G, García-Guerrero, MC, Gálvez, C, Salgado, M, Erkizia, I, Laguía, F, Resa-Infante, P, Massanella, M, Tonda, R, Morata, J, Hong, KY, Koshy, J, Goldman, AR, Giron, L , Abdel-Mohsen, M, Heyn, H, Martinez-Picado, J & Puertas, MC 2025, 'Host genetic and immune factors drive evasion of HIV-1 pathogenesis in viremic non-progressors', Med, vol. 6, no. 2, 100518. https://doi.org/10.1016/j.medj.2024.09.007

TY - JOUR

T1 - Host genetic and immune factors drive evasion of HIV-1 pathogenesis in viremic non-progressors

AU - Bayón-Gil, Ángel

AU - Hernández, Inmaculada

AU - Dalmau, Judith

AU - Nieto, Juan C.

AU - Urrea, Víctor

AU - Garrido-Sanz, Lidia

AU - Caratú, Ginevra

AU - García-Guerrero, Maria C.

AU - Gálvez, Cristina

AU - Salgado, María

AU - Erkizia, Itziar

AU - Laguía, Fernando

AU - Resa-Infante, Patricia

AU - Massanella, Marta

AU - Tonda, Raúl

AU - Morata, Jordi

AU - Hong, Kai Ying

AU - Koshy, Jane

AU - Goldman, Aaron R.

AU - Giron, Leila

AU - Abdel-Mohsen, Mohamed

AU - Heyn, Holger

AU - Martinez-Picado, Javier

AU - Puertas, Maria C.

PY - 2025/2/14

Y1 - 2025/2/14

N2 - Background: Viremic non-progressors (VNPs) represent an exceptional and uncommon subset of people with HIV-1, characterized by the remarkable preservation of normal CD4+ T cell counts despite uncontrolled viral replication—a trait reminiscent of natural hosts of simian immunodeficiency virus. The mechanisms orchestrating evasion from HIV-1 pathogenesis in human VNPs remain elusive, primarily due to the absence of integrative studies. Methods: We implemented a novel single-cell and multiomics approach to comprehensively characterize viral, genomic, transcriptomic, and metabolomic factors driving this exceedingly rare disease phenotype in 16 VNPs and 29 HIV+ progressors. Findings: Genetic predisposition to the VNP phenotype was evidenced by a higher prevalence of CCR5Δ32 heterozygosity, which was associated with lower levels of CCR5 expression and a lower frequency of infected cells in peripheral circulation. We also observed reduced levels of plasma markers of intestinal disruption and attenuated interferon responses in VNPs. These factors potentially drive the other phenotypic traits of immune preservation in this population, including the unaltered tryptophan metabolic profile, reduced activation of cytotoxic lymphocytes, and reduced bystander CD4+ T cell apoptosis. Conclusions: In summary, our comprehensive analysis identified intricate factors collectively associated with the unique immunovirological equilibrium in VNPs, shedding light on potential avenues for therapeutic exploration in managing HIV pathogenesis. Funding: The work was supported by funding from the Spanish Ministry of Science and Innovation and the National Institutes of Health (NIH).

AB - Background: Viremic non-progressors (VNPs) represent an exceptional and uncommon subset of people with HIV-1, characterized by the remarkable preservation of normal CD4+ T cell counts despite uncontrolled viral replication—a trait reminiscent of natural hosts of simian immunodeficiency virus. The mechanisms orchestrating evasion from HIV-1 pathogenesis in human VNPs remain elusive, primarily due to the absence of integrative studies. Methods: We implemented a novel single-cell and multiomics approach to comprehensively characterize viral, genomic, transcriptomic, and metabolomic factors driving this exceedingly rare disease phenotype in 16 VNPs and 29 HIV+ progressors. Findings: Genetic predisposition to the VNP phenotype was evidenced by a higher prevalence of CCR5Δ32 heterozygosity, which was associated with lower levels of CCR5 expression and a lower frequency of infected cells in peripheral circulation. We also observed reduced levels of plasma markers of intestinal disruption and attenuated interferon responses in VNPs. These factors potentially drive the other phenotypic traits of immune preservation in this population, including the unaltered tryptophan metabolic profile, reduced activation of cytotoxic lymphocytes, and reduced bystander CD4+ T cell apoptosis. Conclusions: In summary, our comprehensive analysis identified intricate factors collectively associated with the unique immunovirological equilibrium in VNPs, shedding light on potential avenues for therapeutic exploration in managing HIV pathogenesis. Funding: The work was supported by funding from the Spanish Ministry of Science and Innovation and the National Institutes of Health (NIH).

KW - CCR5

KW - CTL activation

KW - HIV reservoir

KW - HIV-1 pathogenesis

KW - Translation to patients

KW - VNP

KW - interferon

KW - single-cell RNA sequencing

KW - tryptophan

KW - viremic non-progressor

KW - zonulin

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U2 - 10.1016/j.medj.2024.09.007

DO - 10.1016/j.medj.2024.09.007

M3 - Article

C2 - 39413785

AN - SCOPUS:85207774805

SN - 2666-6359

VL - 6

JO - Med

JF - Med

IS - 2

M1 - 100518

ER -

Host genetic and immune factors drive evasion of HIV-1 pathogenesis in viremic non-progressors

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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