Blocking formation of the stable HIV reservoir: A new perspective for HIV-1 cure

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  • Goonetilleke, N.
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
  • Clutton, G.
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
  • Swanstrom, R.
    • Affiliation: School of Medicine, Department of Biochemistry and Biophysics
  • Joseph, S.B.
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
Abstract
  • Recent studies demonstrate that the stable HIV-1 reservoir in resting CD4+ T cells is mostly formed from viruses circulating when combination antiretroviral therapy (ART) is initiated. Here we explore the immunological basis for these observations. Untreated HIV-1 infection is characterized by a progressive depletion of memory CD4+ T cells which mostly express CD127, the α chain of the IL-7 receptor (IL-7R). Depletion results from both direct infection and bystander loss of memory CD4+ T cells in part attributed to dysregulated IL-7/IL-7R signaling. While IL-7/IL7R signaling is not essential for the generation of effector CD4+ T cells from naïve cells, it is essential for the further transition of effectors to memory CD4+ T cells and their subsequent homeostatic maintenance. HIV-1 infection therefore limits the transition of CD4+ T cells from an effector to long-lived memory state. With the onset of ART, virus load (VL) levels rapidly decrease and the frequency of CD127+ CD4+ memory T cells increases, indicating restoration of effector to memory transition in CD4+ T cells. Collectively these data suggest that following ART initiation, HIV-1 infected effector CD4+ T cells transition to long-lived, CD127+ CD4+ T cells forming the majority of the stable HIV-1 reservoir. We propose that combining ART initiation with inhibition of IL-7/IL-7R signaling to block CD4+ T cell memory formation will limit the generation of long-lived HIV-infected CD4+ T cells and reduce the overall size of the stable HIV-1 reservoir. © 2019 Goonetilleke, Clutton, Swanstrom and Joseph.
Date of publication
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Journal title
  • Frontiers in Immunology
Journal volume
  • 10
Journal issue
  • AUG
Language
  • English
ISSN
  • 1664-3224
Publisher
  • Frontiers Media S.A.

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