HIV-1 compartmentalization in the central nervous system during cryptococcal meningitis: Analysis of viral, fungal, and host factors
10 affiliations
- 1Intramural Clinical Management and Operations Branch, Office of the Clinical Director, National Institute of Allergy and Infectious Disease (NIAID), NIH, Bethesda, Maryland, United States of America
- 2Clinical Retrovirology Section, HIV Dynamics and Replication Program, National Cancer Institute, National Institutes of Health, Frederick, Maryland, United States of America
- 3HENYIDA LLC, Lewes, Delaware, United States of America
- 4Office of Biostatistics Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America
- 5AIDS and Cancer Virus Program, Frederick National Laboratory for Cancer Research, Frederick, Maryland, United States of America
- 6Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, North Carolina, United States of America
- 7Virus Isolation and Serology Laboratory, Frederick National Laboratory for Cancer Research, Frederick, Maryland, United States of America
- 8Department of Medicine, School of Medicine, College of Health Sciences Makerere University, Kampala, Uganda
- 9Department of Medicine and International Health, University of Minnesota, Minneapolis, Minnesota, United States of America
- 10Laboratory of Immunoregulation, Division of Intramural Research, National Institute of Allergy and Infectious Disease (NIAID), NIH, Bethesda, Maryland, United States of America
Abstract
Opportunistic infections in the central nervous system (CNS), such as cryptococcal meningitis (CM) have profound consequences for people living with HIV-1 (PWH), including blood-brain barrier impairment and neuroinflammation. To investigate how CM may shape the HIV-1 populations in the CNS, we characterized viral variants in the blood and cerebrospinal fluid (CSF) compartments in PWH with active CM. Thirty-nine participants with CM had paired plasma and CSF viral load measurements prior to the start of anti-retroviral therapy (pre-ART), with overall significantly higher HIV-1 viral loads in plasma compared to the CSF. Among those with CSF pleocytosis, CSF viral loads were relatively higher and CCR5 coreceptor-utilizing HIV-1 were more frequently detected. To investigate whether these differences were due to sustained HIV-1 replication in the CNS that generated genetically distinct viral lineages in the CSF (i.e., viral compartmentalization), we characterized pre-ART HIV-1 env populations in a subgroup of eighteen PWH with CSF HIV-1 RNA levels > blood (N = 9) and CSF RNA levels < blood (N = 9). Compartmentalization between CSF and plasma viral populations was detected in participants from both groups and was associated with higher interleukin-2 (IL-2) levels in CSF. In some cases, HIV-1 populations in CSF were compartmentalized from plasma, were exclusively macrophage-tropic and reached levels exceeding 105 copies/ml CSF. In other cases, HIV-1 infected cells trafficking across the plasma and CSF compartments seemed the most likely source of virus in the CSF. Post-ART analysis in one participant demonstrated emergence of distinct HIV-1 populations. This study demonstrates that opportunistic infections may have diverse effects in shaping HIV-1 viral populations. Author summary: Cryptococcal meningitis (CM) is an infection that disrupts the blood-brain-barrier, providing a useful model to investigate host and fungal factors influencing HIV-1 populations in this critical anatomic compartment. In this study, we assessed viral characteristics (e.g., HIV-1 subtype, levels of viral RNA in CSF and blood, env entry phenotype), fungal attributes (cryptococcal antigen levels) and host features (soluble and cellular immune biomarkers) to determine their relationship to HIV-1 compartmentalization during cryptococcal meningitis. We studied paired plasma and cerebrospinal fluid (CSF) in a Ugandan cohort prior to initiation of ART, including a substantial proportion of PWH with highly pathogenic HIV-1 Subtype D. We found that HIV-1 compartmentalization during CM and prior to ART initiation (pre-ART) was associated with elevated CSF interleukin-2. Compartmentalized HIV-1 in the CSF may consist of macrophage-tropic HIV-1. We also studied one participant who initiated and then stopped ART; although the genetic composition of their rebound plasma viremia was related to pre-ART CSF and blood populations, the post-ART CSF rebound viruses were genetically distinct. These findings suggest that cryptococcal meningitis may influence CNS HIV-1 populations prior to ART initiation, potentially impacting the dynamics of viral reservoirs.
Related
- Aseptic Meningitis Unmasking Coccidioidomycosis of the Central Nervous System Outside an Endemic Region
- Meningitis, encephalitis, and beyond: A practical intensive care unit guide to severe central nervous system infections.
- Invasive Cryptococcal Meningitis: A Sequelae of Primary Intestinal Lymphangiectasia
- Rare Fatal Event of Multidrug-resistant Shigella Septicemia and Cryptococcal Meningitis in an Immunocompromised Host
- Cryptococcal meningitis-associated cerebrovascular injury presenting with sequential multifocal cerebral infarctions and prominent autonomic dysfunction in a non-HIV patient: a case report and focused literature review.
BibTeX
@article{manion2026hiv1,
title = {{HIV-1 compartmentalization in the central nervous system during cryptococcal meningitis: Analysis of viral, fungal, and host factors}},
author = {Maura Manion and Camille M. Lange and Ana M. Ortega-Villa and Christine M. Fennessey and Brandon F. Keele and Matthew Moeser and Helene Highbarger and Kristi Huik and Natalie Lindo and Christian Gonsalves and James Virga and David B. Meya and Sarah B. Joseph and David R. Boulware and Irini Sereti and Frank Maldarelli},
journal = {PLOS Pathogens},
year = {2026},
month = oct,
doi = {10.1371/journal.ppat.1014697},
url = {https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014697},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - HIV-1 compartmentalization in the central nervous system during cryptococcal meningitis: Analysis of viral, fungal, and host factors
AU - Maura Manion
AU - Camille M. Lange
AU - Ana M. Ortega-Villa
AU - Christine M. Fennessey
AU - Brandon F. Keele
AU - Matthew Moeser
AU - Helene Highbarger
AU - Kristi Huik
AU - Natalie Lindo
AU - Christian Gonsalves
AU - James Virga
AU - David B. Meya
AU - Sarah B. Joseph
AU - David R. Boulware
AU - Irini Sereti
AU - Frank Maldarelli
PY - 2026
DA - 2026/10/01
JO - PLOS Pathogens
DO - 10.1371/journal.ppat.1014697
UR - https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014697
AB - Opportunistic infections in the central nervous system (CNS), such as cryptococcal meningitis (CM) have profound consequences for people living with HIV-1 (PWH), including blood-brain barrier impairment and neuroinflammation. To investigate how CM may shape the HIV-1 populations in the CNS, we characterized viral variants in the blood and cerebrospinal fluid (CSF) compartments in PWH with active CM. Thirty-nine participants with CM had paired plasma and CSF viral load measurements prior to the start of anti-retroviral therapy (pre-ART), with overall significantly higher HIV-1 viral loads in plasma compared to the CSF. Among those with CSF pleocytosis, CSF viral loads were relatively higher and CCR5 coreceptor-utilizing HIV-1 were more frequently detected. To investigate whether these differences were due to sustained HIV-1 replication in the CNS that generated genetically distinct viral lineages in the CSF (i.e., viral compartmentalization), we characterized pre-ART HIV-1 env populations in a subgroup of eighteen PWH with CSF HIV-1 RNA levels > blood (N = 9) and CSF RNA levels < blood (N = 9). Compartmentalization between CSF and plasma viral populations was detected in participants from both groups and was associated with higher interleukin-2 (IL-2) levels in CSF. In some cases, HIV-1 populations in CSF were compartmentalized from plasma, were exclusively macrophage-tropic and reached levels exceeding 105 copies/ml CSF. In other cases, HIV-1 infected cells trafficking across the plasma and CSF compartments seemed the most likely source of virus in the CSF. Post-ART analysis in one participant demonstrated emergence of distinct HIV-1 populations. This study demonstrates that opportunistic infections may have diverse effects in shaping HIV-1 viral populations. Author summary: Cryptococcal meningitis (CM) is an infection that disrupts the blood-brain-barrier, providing a useful model to investigate host and fungal factors influencing HIV-1 populations in this critical anatomic compartment. In this study, we assessed viral characteristics (e.g., HIV-1 subtype, levels of viral RNA in CSF and blood, env entry phenotype), fungal attributes (cryptococcal antigen levels) and host features (soluble and cellular immune biomarkers) to determine their relationship to HIV-1 compartmentalization during cryptococcal meningitis. We studied paired plasma and cerebrospinal fluid (CSF) in a Ugandan cohort prior to initiation of ART, including a substantial proportion of PWH with highly pathogenic HIV-1 Subtype D. We found that HIV-1 compartmentalization during CM and prior to ART initiation (pre-ART) was associated with elevated CSF interleukin-2. Compartmentalized HIV-1 in the CSF may consist of macrophage-tropic HIV-1. We also studied one participant who initiated and then stopped ART; although the genetic composition of their rebound plasma viremia was related to pre-ART CSF and blood populations, the post-ART CSF rebound viruses were genetically distinct. These findings suggest that cryptococcal meningitis may influence CNS HIV-1 populations prior to ART initiation, potentially impacting the dynamics of viral reservoirs.
SN - 1553-7374
SN - 1553-7366
ER -