{ "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.", "abstract_shown": true, "affiliations": [ "Intramural 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", "Clinical Retrovirology Section, HIV Dynamics and Replication Program, National Cancer Institute, National Institutes of Health, Frederick, Maryland, United States of America", "HENYIDA LLC, Lewes, Delaware, United States of America", "Office of Biostatistics Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America", "AIDS and Cancer Virus Program, Frederick National Laboratory for Cancer Research, Frederick, Maryland, United States of America", "Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, North Carolina, United States of America", "Virus Isolation and Serology Laboratory, Frederick National Laboratory for Cancer Research, Frederick, Maryland, United States of America", "Department of Medicine, School of Medicine, College of Health Sciences Makerere University, Kampala, Uganda", "Department of Medicine and International Health, University of Minnesota, Minneapolis, Minnesota, United States of America", "Laboratory of Immunoregulation, Division of Intramural Research, National Institute of Allergy and Infectious Disease (NIAID), NIH, Bethesda, Maryland, United States of America" ], "article_type": "Research Article", "arxiv": null, "author_total": 16, "authors": [ { "affs": [ 0 ], "name": "Maura Manion" }, { "affs": [ 1 ], "name": "Camille M. Lange" }, { "affs": [ 2 ], "name": "Ana M. Ortega-Villa" }, { "affs": [ 3 ], "name": "Christine M. Fennessey" }, { "affs": [ 4 ], "name": "Brandon F. Keele" }, { "affs": [ 5 ], "name": "Matthew Moeser" }, { "affs": [ 6 ], "name": "Helene Highbarger" }, { "affs": [ 7 ], "name": "Kristi Huik" }, { "affs": [ 8 ], "name": "Natalie Lindo" }, { "affs": [ 9 ], "name": "Christian Gonsalves" }, { "name": "James Virga" }, { "name": "David B. Meya" }, { "name": "Sarah B. Joseph" }, { "name": "David R. Boulware" }, { "name": "Irini Sereti" }, { "name": "Frank Maldarelli" } ], "bibtex": "https://research.draconitic.com/paper/bnb41t2xr84m6.bib", "cited_by": 0, "doi": "10.1371/journal.ppat.1014697", "fulltext_url": "https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014697", "id": "bnb41t2xr84m6", "issns": [ "1553-7374", "1553-7366" ], "landing_url": "https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014697", "language": "eng", "licence": "CC-BY-4.0", "licence_label": "CC BY 4.0", "licence_source": "journal", "licence_url": "https://creativecommons.org/licenses/by/4.0/", "metadata_licence": null, "native_subjects": [ [ "openalex", "2406|HIV Research and Treatment" ], [ "plos", "/Biology and life sciences/Anatomy/Body fluids/Blood/Blood plasma" ], [ "plos", "/Biology and life sciences/Anatomy/Body fluids/Cerebrospinal fluid" ], [ "plos", "/Biology and life sciences/Anatomy/Nervous system/Central nervous system" ], [ "plos", "/Biology and life sciences/Anatomy/Nervous system/Cerebrospinal fluid" ], [ "plos", "/Biology and life sciences/Evolutionary biology/Population genetics" ], [ "plos", "/Biology and life sciences/Genetics/Population genetics" ], [ "plos", "/Biology and life sciences/Microbiology/Medical microbiology/Microbial pathogens/Viral pathogens/Immunodeficiency viruses/HIV/HIV-1" ], [ "plos", "/Biology and life sciences/Microbiology/Medical microbiology/Microbial pathogens/Viral pathogens/Retroviruses/Lentivirus/HIV/HIV-1" ], [ "plos", "/Biology and life sciences/Microbiology/Virology/Viral transmission and infection/Viral load" ], [ "plos", "/Biology and life sciences/Organisms/Viruses/Immunodeficiency viruses/HIV/HIV-1" ], [ "plos", "/Biology and life sciences/Organisms/Viruses/RNA viruses/Retroviruses/Lentivirus/HIV/HIV-1" ], [ "plos", "/Biology and life sciences/Organisms/Viruses/Viral pathogens/Immunodeficiency viruses/HIV/HIV-1" ], [ "plos", "/Biology and life sciences/Organisms/Viruses/Viral pathogens/Retroviruses/Lentivirus/HIV/HIV-1" ], [ "plos", "/Biology and life sciences/Physiology/Body fluids/Blood/Blood plasma" ], [ "plos", "/Biology and life sciences/Physiology/Body fluids/Cerebrospinal fluid" ], [ "plos", "/Biology and life sciences/Population biology/Population genetics" ], [ "plos", "/Medicine and health sciences/Anatomy/Body fluids/Blood/Blood plasma" ], [ "plos", "/Medicine and health sciences/Anatomy/Body fluids/Cerebrospinal fluid" ], [ "plos", "/Medicine and health sciences/Anatomy/Nervous system/Central nervous system" ], [ "plos", "/Medicine and health sciences/Anatomy/Nervous system/Cerebrospinal fluid" ], [ "plos", "/Medicine and health sciences/Medical conditions/Infectious diseases/Infectious diseases of the nervous system/Cryptococcal meningitis" ], [ "plos", "/Medicine and health sciences/Medical conditions/Infectious diseases/Opportunistic infections" ], [ "plos", "/Medicine and health sciences/Neurology/Infectious diseases of the nervous system/Cryptococcal meningitis" ], [ "plos", "/Medicine and health sciences/Pathology and laboratory medicine/Pathogens/Microbial pathogens/Viral pathogens/Immunodeficiency viruses/HIV/HIV-1" ], [ "plos", "/Medicine and health sciences/Pathology and laboratory medicine/Pathogens/Microbial pathogens/Viral pathogens/Retroviruses/Lentivirus/HIV/HIV-1" ] ], "openalex": "W7222100436", "pdf_url": "https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1014697&type=printable", "pmcid": "PMC13671554", "pmid": null, "published": "2026-10-01", "publisher": "Public Library of Science", "ris": "https://research.draconitic.com/paper/bnb41t2xr84m6.ris", "sources": [ { "first_seen": "2026-10-30T12:17:23Z", "native_id": "10.1371/journal.ppat.1014697", "source": "plos", "url": "https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014697" }, { "first_seen": "2026-10-30T12:18:29Z", "native_id": "PMC:PMC13671554", "source": "europepmc", "url": "https://europepmc.org/article/PMC/PMC13671554" } ], "subjects": [ { "field": "medicine", "origin": "plos:anatomy", "subfield": "physiology" } ], "title": "HIV-1 compartmentalization in the central nervous system during cryptococcal meningitis: Analysis of viral, fungal, and host factors", "title_text": "HIV-1 compartmentalization in the central nervous system during cryptococcal meningitis: Analysis of viral, fungal, and host factors", "type": "peer-reviewed", "updated_at": "2026-10-30T12:18:29Z", "url": "https://research.draconitic.com/paper/bnb41t2xr84m6", "venue": "PLOS Pathogens", "versions": [] }