Limited HIV-2 reservoirs in central-memory CD4 T-cells associated to CXCR6 co-receptor expression in attenuated HIV-2 infection

PLoS Pathog. 2019 May 16;15(5):e1007758. doi: 10.1371/journal.ppat.1007758. eCollection 2019 May.

Abstract

The low pathogenicity and replicative potential of HIV-2 are still poorly understood. We investigated whether HIV-2 reservoirs might follow the peculiar distribution reported in models of attenuated HIV-1/SIV infections, i.e. limited infection of central-memory CD4 T lymphocytes (TCM). Antiretroviral-naive HIV-2 infected individuals from the ANRS-CO5 (12 non-progressors, 2 progressors) were prospectively included. Peripheral blood mononuclear cells (PBMCs) were sorted into monocytes and resting CD4 T-cell subsets (naive [TN], central- [TCM], transitional- [TTM] and effector-memory [TEM]). Reactivation of HIV-2 was tested in 30-day cultures of CD8-depleted PBMCs. HIV-2 DNA was quantified by real-time PCR. Cell surface markers, co-receptors and restriction factors were analyzed by flow-cytometry and multiplex transcriptomic study. HIV-2 DNA was undetectable in monocytes from all individuals and was quantifiable in TTM from 4 individuals (median: 2.25 log10 copies/106 cells [IQR: 1.99-2.94]) but in TCM from only 1 individual (1.75 log10 copies/106 cells). HIV-2 DNA levels in PBMCs (median: 1.94 log10 copies/106 PBMC [IQR = 1.53-2.13]) positively correlated with those in TTM (r = 0.66, p = 0.01) but not TCM. HIV-2 reactivation was observed in the cells from only 3 individuals. The CCR5 co-receptor was distributed similarly in cell populations from individuals and donors. TCM had a lower expression of CXCR6 transcripts (p = 0.002) than TTM confirmed by FACS analysis, and a higher expression of TRIM5 transcripts (p = 0.004). Thus the low HIV-2 reservoirs differ from HIV-1 reservoirs by the lack of monocytic infection and a limited infection of TCM associated to a lower expression of a potential alternative HIV-2 co-receptor, CXCR6 and a higher expression of a restriction factor, TRIM5. These findings shed new light on the low pathogenicity of HIV-2 infection suggesting mechanisms close to those reported in other models of attenuated HIV/SIV infection models.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antiviral Restriction Factors
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / metabolism*
  • CD4-Positive T-Lymphocytes / virology
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Case-Control Studies
  • Cells, Cultured
  • Female
  • HIV Infections / immunology
  • HIV Infections / metabolism*
  • HIV Infections / virology
  • HIV-2 / genetics
  • HIV-2 / immunology*
  • Humans
  • Immunologic Memory / immunology*
  • Leukocytes, Mononuclear / immunology
  • Leukocytes, Mononuclear / metabolism*
  • Leukocytes, Mononuclear / virology
  • Male
  • Middle Aged
  • Receptors, CXCR6 / genetics
  • Receptors, CXCR6 / metabolism*
  • Transcriptome
  • Tripartite Motif Proteins
  • Ubiquitin-Protein Ligases

Substances

  • Antiviral Restriction Factors
  • CXCR6 protein, human
  • Carrier Proteins
  • Receptors, CXCR6
  • Tripartite Motif Proteins
  • TRIM5 protein, human
  • Ubiquitin-Protein Ligases

Grants and funding

This work was supported in part by the ANRS (France Recherche Nord&Sud Sida-hiv Hépatites), the Institut National de la Santé et de la Recherche Médicale, the Université Pierre et Marie Curie, Paris, the University Paris7, Paris Diderot, France and the French Government's Investissement d'Avenir program, Laboratoires d'Excellence "Integrative Biology of Emerging Infectious Diseases" (ANR-10-LABX-62-IBEID). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript