Effective Cytotoxic T Lymphocyte Targeting of Persistent HIV-1 during Antiretroviral Therapy Requires Priming of Naive CD8+ T Cells

Smith, Kellie N.; Mailliard, Robbie B.; Piazza, Paolo A.; Fischer, Will; Korber, Bette T.; Fecek, Ronald J.; Ratner, Deena; Gupta, Phalguni; Mullins, James I.; Rinaldo, Charles R.

doi:10.1128/mbio.00473-16

Title: Effective Cytotoxic T Lymphocyte Targeting of Persistent HIV-1 during Antiretroviral Therapy Requires Priming of Naive CD8⁺ T Cells

Journal Article · 31 May 2016 · mBio (Online)

DOI: https://doi.org/10.1128/mbio.00473-16 · OSTI ID:1626106

Smith, Kellie N. ^[1]; Mailliard, Robbie B. ^[2]; Piazza, Paolo A. ^[2]; Fischer, Will ^[3]; Korber, Bette T. ^[3]; Fecek, Ronald J. ^[2]; Ratner, Deena ^[2]; Gupta, Phalguni ^[2]; Mullins, James I. ^[4]; Rinaldo, Charles R. ^[5]

Univ. of Pittsburgh, PA (United States). Dept. of Microbiology and Molecular Genetics; Univ. of Pittsburgh, PA (United States). Dept. of Infectious Diseases and Microbiology
Univ. of Pittsburgh, PA (United States). Dept. of Infectious Diseases and Microbiology
Los Alamos National Lab. (LANL), Los Alamos, NM (United States). theoretical Biology and Biophysics Group
Univ. of Washington, Seattle, WA (United States). Dept. of Microbiology
Univ. of Pittsburgh, PA (United States). Dept. of Infectious Diseases and Microbiology; Univ. of Pittsburgh School of Medicine, PA (United States). Dept. of Pathology

Curing HIV-1 infection will require elimination of persistent cellular reservoirs that harbor latent virus in the face of combination antiretroviral therapy (cART). Proposed immunotherapeutic strategies to cure HIV-1 infection include enhancing lysis of these infected cells by cytotoxic T lymphocytes (CTL). A major challenge in this strategy is overcoming viral immune escape variants that have evaded host immune control. Here we report that naive CD8⁺ T cells from chronic HIV-1-infected participants on long-term cART can be primed by dendritic cells (DC). These DC must be mature, produce high levels of interleukin 12p70 (IL-12p70), be responsive to CD40 ligand (CD40L), and be loaded with inactivated, autologous HIV-1. These DC-primed CD8⁺ T cell responders produced high levels of gamma interferon (IFN-γ) in response to a broad range of both conserved and variable regions of Gag and effectively killed CD4⁺ T cell targets that were either infected with the autologous latent reservoir-associated virus or loaded with autologous Gag peptides. In contrast, HIV-1-specific memory CD8⁺ T cells stimulated with autologous HIV-1-loaded DC produced IFN-γ in response to a narrow range of conserved and variable Gag peptides compared to the primed T cells and most notably, displayed significantly lower cytolytic function. Our findings highlight the need to selectively induce new HIV-1-specific CTL from naive precursors while avoiding activation of existing, dysfunctional memory T cells in potential curative immunotherapeutic strategies for HIV-1 infection.

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Research Organization:: Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)

Sponsoring Organization:: USDOE Office of Science (SC)

Grant/Contract Number:: AC52-06NA25396

OSTI ID:: 1626106

Journal Information:: mBio (Online), Vol. 7, Issue 3; ISSN 2150-7511

Publisher:: American Society for Microbiology (ASM)Copyright Statement

Country of Publication:: United States

Language:: English

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