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

ABSTRACT: UNLABELLED: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-?) 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-? 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. IMPORTANCE:Current immunotherapeutic approaches aim to enhance antiviral immunity against the HIV-1 reservoir; however, it has yet to be shown whether T cells from persons on cART can recognize and eliminate virus-infected cells. We show that in persons on cART a personalized medicine approach using their dendritic cells to stimulate their naive T cells induces potent effector CTL in vitro that recognize and eradicate HIV-1-infected CD4(+) T cells. Additionally, we show that the same stimulation of existing memory T cells results in cytokine secretion but limited effector function. Our study demonstrates that the naive T cell repertoire can recognize persistent HIV-1 during cART and supports immunotherapy strategies for an HIV-1 cure that targets naive T cells, rather than existing, dysfunctional, memory T cells.

SUBMITTER: Smith KN

PROVIDER: S-EPMC4895106 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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

Smith Kellie N KN Mailliard Robbie B RB Piazza Paolo A PA Fischer Will W Korber Bette T BT Fecek Ronald J RJ Ratner Deena D Gupta Phalguni P Mullins James I JI Rinaldo Charles R CR

mBio 20160531 3

<h4>Unlabelled</h4>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 HI ...[more]

PMID: 27247230

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Project description:CD8+ lymphocytes play an important role in suppressing in vivo viral replication in HIV infection. However, both the extent to which and the mechanisms by which CD8+ lymphocytes contribute to viral control are not completely understood. A recent experiment depleted CD8+ lymphocytes in simian immunodeficiency virus (SIV)-infected rhesus macaques (RMs) on antiretroviral treatment (ART) to study the role of CD8+ lymphocytes. CD8+ lymphocytes depletion resulted in temporary plasma viremia in all studied RMs. Viral control was restored when CD8+ lymphocytes repopulated. We developed a viral dynamic model to fit the viral load (VL) data from the CD8 depletion experiment. We explicitly modeled the dynamics of the latent reservoir and the SIV-specific effector cell population including their exhaustion and their potential cytolytic and noncytolytic functions. We found that the latent reservoir significantly contributes to the size of the peak VL after CD8 depletion, while drug efficacy plays a lesser role. Our model suggests that the overall CD8+ lymphocyte cytolytic killing rate is dynamically changing depending on the levels of antigen-induced effector cell activation and exhaustion. Based on estimated parameters, our model suggests that before ART or without ART the overall CD8 cytolytic killing rate is small due to exhaustion. However, after the start of ART, the overall CD8 cytolytic killing rate increases due to an expansion of SIV-specific CD8 effector cells. Further, we estimate that the cytolytic killing rate can be significantly larger than the cytopathic death rate in some animals during the second phase of ART-induced viral decay. Lastly, our model provides a new explanation for the puzzling findings by Klatt et al. and Wong et al. that CD8 depletion done immediately before ART has no noticeable effect on the first phase viral decay slope seen after ART initiation Overall, by incorporating effector cells and their exhaustion, our model can explain the effects of CD8 depletion on VL during ART, reveals a detailed dynamic role of CD8+ lymphocytes in controlling viral infection, and provides a unified explanation for CD8 depletion experimental data.

Dataset Information

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

Publications

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

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