racivir and Viremia

The programmed cell death-1 (PD-1)/programmed cell death ligand-1 pathway has been shown to limit cell-mediated effector functions during chronic viral infections impeding clearance of pathogens. As a strategy to reverse this exhaustion and increase T cell polyfunctionality, PD-1 ligands were blocked in vivo using a recombinant macaque PD-1 fused to a macaque Ig-Fc (rPD-1-Fc) in SIVmac239-infected rhesus macaques during the early chronic phase of infection, either alone or in combination with antiretroviral therapy. In vitro blockade showed improvement of Ag-specific CD4(+) and CD8(+) T cells from monkeys chronically infected with SIV. Of note, a prolonged 5-d blockade in culture was beneficial for both gag-specific CD4(+) and CD8(+) T cells based on proliferation and dual cytokine production. Although the in vivo administration of rPD-1-Fc induced enhanced SIV-specific CD4 and CD8 T cell proliferation both in the blood and gut, it failed to alter plasma viremia. However, rPD-1-Fc administration in the context of antiretroviral therapy interruption induced a significant delay of viral load rebound. In addition, rPD-1-Fc administration in MamuA*001(+) monkeys led to both an increase in the frequencies and Ki67 expression of GagCM9(+) CD8(+) T cells in the blood and rectal mucosa and polyfunctionality of GagCM9(+) CD8(+) T cells in blood. In conclusion, however, our data suggest that PD-1/programmed cell death ligand-1 blockade using soluble rPD-1-Fc instead of anti-PD-1 mAb, although effective in rescuing the effector function of SIV-specific CD4(+) and CD8(+) T cells during the early chronic phase of infection, has limited clinical benefit.

Topics: Adenine; Animals; Anti-Retroviral Agents; Antibodies, Monoclonal; Apoptosis; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Combined Modality Therapy; Drug Evaluation, Preclinical; Emtricitabine; Histocompatibility Antigens Class I; Immunity, Cellular; Immunoglobulin Fc Fragments; Immunotherapy; Lymphokines; Macaca mulatta; Organophosphonates; Programmed Cell Death 1 Receptor; Recombinant Proteins; RNA, Viral; Simian Acquired Immunodeficiency Syndrome; Simian Immunodeficiency Virus; Solubility; Tenofovir; Viremia; Zalcitabine

There is currently no SIV macaque model in which the effects of combination antiretroviral therapy on tissue immune responses and latent reservoirs have been measured. This study was performed to define the impact of combination therapy on the specificity and distribution of the T lymphocyte response in multiple tissue compartments. Pigtailed macaques (Macaca nemestrina) were infected with SIV/17E-Fr and treated with combination antiretroviral therapy consisting of 9-R-(2-phosphonomethoxypropyl)adenine (PMPA) and beta-2',3'-dideoxy-3'-thia-5-fluorocytidine (FTC). The SIV-specific T lymphocyte response was measured in peripheral blood, spleen and several lymph nodes at necropsy by IFN-gamma Elispot analysis. Two animals (one treated, one untreated) had high acute peak viremia, which was associated with lower SIV-specific T lymphocyte responses in the peripheral blood and lymphoid tissues. In the treated animal, viremia was controlled to low or undetectable for the study duration, and virus-specific responses remained low. The untreated animal remained viremic throughout the study and developed clinical symptoms of AIDS. In contrast, the two animals that had lower acute peak viremia (one treated, one untreated) had more robust T lymphocyte responses, and controlled viral replication. Virus-specific responses were detected in the treated animal despite 6 months of suppressive therapy. These data suggest that in this model, in the context of acute peak viremia and weak T cell responses, combination therapy may be essential to control virus replication and disease progression. Conversely, in the setting of low initial viremia and robust T lymphocyte responses, treatment does not have a detrimental effect on the immune response.

Topics: Adenine; Animals; Anti-Retroviral Agents; Drug Therapy, Combination; Emtricitabine; Immunity, Cellular; Interferon-gamma; Linear Models; Macaca nemestrina; Organophosphonates; Primate Diseases; Simian Acquired Immunodeficiency Syndrome; Simian Immunodeficiency Virus; T-Lymphocytes; Tenofovir; Viremia; Zalcitabine