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Mutational profiling of HIV+ diffuse large B-cell lymphoma reveals distinct mutational features with evidence of

Sophia M Roush1, Samantha Beck1, Jenny Coelho1

  • 1Department of Pathology and Laboratory Medicine, School of Medicine, University of North Carolina (UNC), Chapel Hill, NC, USA.

AIDS (London, England)
|January 20, 2026
PubMed

Insights

People with HIV (Human Immunodeficiency Virus) and diffuse large B-cell lymphoma (DLBCL) show distinct tumor mutations. Prior antiretroviral therapy correlates with higher tumor mutational burden and neoantigen load in HIV+ DLBCL.

Area of Science:

  • Oncology
  • Genetics
  • Virology

Background:

  • Diffuse large B-cell lymphoma (DLBCL) is a significant cause of cancer mortality in people with HIV (PWH).
  • PWH are underrepresented in molecular studies and clinical trials for DLBCL.
  • Understanding DLBCL in PWH is crucial for improving outcomes.

Purpose of the Study:

  • To investigate the molecular landscape of DLBCL in a Malawian cohort with both HIV-positive (HIV+) and HIV-negative (HIV-) individuals.
  • To identify distinct genetic alterations and mutational patterns in HIV+ DLBCL compared to HIV- DLBCL.
  • To explore the impact of prior antiretroviral therapy on DLBCL tumor characteristics.

Main Methods:

  • Whole-exome sequencing was performed on 30 DLBCL tumors from a Malawian cohort.
  • Tumors from both HIV+ and HIV- individuals were analyzed.
  • Data was integrated with a published HIV+ DLBCL dataset for comprehensive analysis.

Main Results:

  • KMT2D, BIRC6, TP53, and ARID1A were frequently mutated genes.
  • HIV+ DLBCL tumors showed enrichment for KMT2D mutations compared to HIV- DLBCL.
  • Prior antiretroviral therapy was associated with increased tumor mutational burden (TMB) and neoantigen load.
  • Five HIV+ DLBCL tumors exhibited microsatellite instability (MSI), linked to DNA repair pathways.
  • ARID1A mutations were found in MSI samples and tumors with MSH2 loss.
  • Recurrent driver mutations (LILRB1, MYD88, NRAS) and negative prognostic PTEN mutations were identified in integrated analysis.

Conclusions:

  • Distinct tumorigenic mechanisms are evident in HIV+ DLBCL.
  • Mutational profiling of HIV+ DLBCL cohorts is essential for identifying biomarkers.
  • Targeted therapies may be developed based on identified molecular alterations.
Abstract

Keywords:
AfricaHIVantiretroviral therapybiomarkersdiffuse large B-cell lymphomagenomicsmicrosatellite instabilityneoantigen

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