Evidence map›Paper›PMID 40088911›Full record

ArticleThe Lancet. Microbe2025

Association between HIV-1 Nef-mediated MHC-I downregulation and the maintenance of the replication-competent latent viral reservoir in individuals with virally suppressed HIV-1 in Uganda: an exploratory cohort study.

Mitchell J Mumby, Jessica L Prodger, Jada Hackman, Sharada Saraf, Xianming Zhu, Roux-Cil Ferreira, Stephen Tomusange, Samiri Jamiru, Aggrey Anok, Taddeo Kityamuweesi and 19 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in The Lancet. Microbe, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.

0numbers the graph read from it
0cells of the map it votes in
6citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

6 citing papers in PubMed.

  1. Review
  2. Review
  3. Review
  4. Review
  5. HIV Nef amplifies mechanical heterogeneity to promote immune evasion.bioRxiv : the preprint server for biology · 2025
    Article
  6. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

29 authors.

Mitchell J MumbyDepartment of Microbiology and Immunology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.
Jessica L ProdgerDepartment of Microbiology and Immunology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.
Jada HackmanLaboratory of Immunoregulation, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Baltimore, Maryland, USA.
Sharada SarafLaboratory of Immunoregulation, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Baltimore, Maryland, USA.
Xianming ZhuDepartment of Pathology, Johns Hopkins University, Baltimore, MA, USA.
Roux-Cil FerreiraDepartment of Pathology and Laboratory Medicine, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.
Stephen TomusangeRakai Health Sciences Program, Kalisizo, Uganda.
Samiri JamiruRakai Health Sciences Program, Kalisizo, Uganda.
Aggrey AnokRakai Health Sciences Program, Kalisizo, Uganda.
Taddeo KityamuweesiRakai Health Sciences Program, Kalisizo, Uganda.
Paul BuuleRakai Health Sciences Program, Kalisizo, Uganda.
Corby FinkDepartment of Microbiology and Immunology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.
Cassandra R EdgarDepartment of Microbiology and Immunology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.
Steven M TrothenDepartment of Microbiology and Immunology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.
Gregory A DekabanDepartment of Microbiology and Immunology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.
Erin E BrownLaboratory of Immunoregulation, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Baltimore, Maryland, USA.
Adam A CapoferriDepartment of Medicine, Johns Hopkins University, Baltimore, MA, USA.
Owen R BakerLaboratory of Immunoregulation, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Baltimore, Maryland, USA.
Ethan KlockDepartment of Medicine, Johns Hopkins University, Baltimore, MA, USA.
Jernelle C MillerDepartment of Medicine, Johns Hopkins University, Baltimore, MA, USA.
Charles KirbyDepartment of Pathology, Johns Hopkins University, Baltimore, MA, USA.
Briana LynchLaboratory of Immunoregulation, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Baltimore, Maryland, USA.
Aaron A R TobianDepartment of Pathology, Johns Hopkins University, Baltimore, MA, USA.
Art F Y PoonDepartment of Microbiology and Immunology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada; Department of Pathology and Laboratory Medicine, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.
Thomas C QuinnLaboratory of Immunoregulation, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Baltimore, Maryland, USA; Department of Medicine, Johns Hopkins University, Baltimore, MA, USA.
Ronald M GaliwangoRakai Health Sciences Program, Kalisizo, Uganda.
Steven J ReynoldsLaboratory of Immunoregulation, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Baltimore, Maryland, USA; Department of Medicine, Johns Hopkins University, Baltimore, MA, USA; Rakai Health Sciences Program, Kalisizo, Uganda.
Andrew D ReddLaboratory of Immunoregulation, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Baltimore, Maryland, USA; Department of Medicine, Johns Hopkins University, Baltimore, MA, USA; Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa.
Jimmy D DikeakosDepartment of Microbiology and Immunology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada. Electronic address: jimmy.dikeakos@uwo.ca.

Funding

REACH: Research Enterprise to Advance a Cure for HIVUM1AI164565 · NIAID · WEILL MEDICAL COLL OF CORNELL UNIV · PI Marina Caskey, R. Brad Jones · 2021 to 2026
$32.9M
Medical Scientist Training Program Training GrantT32GM145449 · NIGMS · DUKE UNIVERSITY · PI Christopher D Kontos · 2022 to 2026
$6.6M
Johns Hopkins HIV Epidemiology and Prevention Sciences Training ProgramT32AI102623 · NIAID · JOHNS HOPKINS UNIVERSITY · PI Shruti H Mehta · 2013 to 2026
$5.3M
NIAID NIH HHS T32 AI102623NIAID NIH HHS UM1 AI164565NIGMS NIH HHS T32 GM145449
6 · The paper itself

Abstract

backgroundThe persistence of a replication-competent latent viral reservoir (RC-LVR) during antiretroviral therapy (ART) is a barrier to the development of a cure for HIV-1, but the role of viral genes in influencing RC-LVR size is unclear. We aimed to assess whether the magnitude by which the HIV-1 accessory protein Nef evades the adaptive immune response by downregulating MHC-I or CD4, or both, from the surface of infected cells is associated with the rate at which the RC-LVR in people with HIV-1 changes during long-term ART (>1 year).

methodsWe conducted an exploratory cohort study in which nef genes were sequenced from outgrowth viruses derived from the quantitative viral outgrowth assay (QVOA) for a group of people with ART-suppressed HIV-1 in Uganda between 2015 and 2020. Study participants were selected from the Rakai Health Sciences Program (RHSP) LVR cohort, a cohort of 90 adults (aged ≥18 years) who were HIV-1 positive, receiving ART, and had maintained viral suppression for at least 1 year at the time of study enrolment. For this study, participants were required to have available p24

findings14 (15%) of 90 participants from the RHSP cohort met the inclusion criteria and were enrolled in this study. 49 nef sequences were isolated from these participants. We observed variability in participant-derived Nef-mediated cell surface MHC-I downregulation (median 114·88% [IQR 104·93-121·51] of the downregulation capacity of NL4-3 Nef) and CD4 downregulation (94·50% [84·05-100·16] of NL4-3 Nef). The estimated rate of change of the RC-LVR was positive for four participants. For one donor, the rate of change was significantly positive (7·4 × 10

interpretationNef-mediated MHC-I downregulation might contribute to HIV-1 persistence during long-term ART. Strategies to inhibit Nef-mediated MHC-I downregulation could represent a viable therapeutic avenue to reduce the size of the latent reservoir in vivo, improving treatment outcomes in people with HIV-1.

fundingCanadian Institutes of Health Research, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, and the REACH Martin Delaney Collaboratory.

Indexed as

Histocompatibility Antigens Class IHIV-1HIV Infectionsnef Gene Products, Human Immunodeficiency VirusVirus LatencyAdultCD4 AntigensCD4-Positive T-LymphocytesCohort StudiesDown-RegulationFemaleHumansMaleMiddle AgedUgandaViral LoadCD4 AntigensHistocompatibility Antigens Class Inef Gene Products, Human Immunodeficiency Virusnef protein, Human immunodeficiency virus 1

Identifiers

PMID40088911
PMCPMC12066219

What Socratic holds

Textmetadata
LicenceCC BY-NC-ND
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.