RESUMO
An Amendment to this paper has been published and can be accessed via a link at the top of the paper.
RESUMO
Human immunodeficiency virus (HIV) persists indefinitely in individuals with HIV who receive antiretroviral therapy (ART) owing to a reservoir of latently infected cells that contain replication-competent virus1-4. Here, to better understand the mechanisms responsible for latency persistence and reversal, we used the interleukin-15 superagonist N-803 in conjunction with the depletion of CD8+ lymphocytes in ART-treated macaques infected with simian immunodeficiency virus (SIV). Although N-803 alone did not reactivate virus production, its administration after the depletion of CD8+ lymphocytes in conjunction with ART treatment induced robust and persistent reactivation of the virus in vivo. We found viraemia of more than 60 copies per ml in all macaques (n = 14; 100%) and in 41 out of a total of 56 samples (73.2%) that were collected each week after N-803 administration. Notably, concordant results were obtained in ART-treated HIV-infected humanized mice. In addition, we observed that co-culture with CD8+ T cells blocked the in vitro latency-reversing effect of N-803 on primary human CD4+ T cells that were latently infected with HIV. These results advance our understanding of the mechanisms responsible for latency reversal and lentivirus reactivation during ART-suppressed infection.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Interleucina-15/agonistas , Vírus da Imunodeficiência Símia/fisiologia , Replicação Viral , Animais , Linfócitos T CD4-Positivos/virologia , Infecções por HIV/imunologia , Infecções por HIV/virologia , Humanos , Interleucina-15/imunologia , Depleção Linfocítica , Macaca mulatta , Camundongos , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Latência Viral , Replicação Viral/imunologiaRESUMO
In this article, we summarize the role of CD8+ T cells during natural and antiretroviral therapy (ART)-treated HIV and SIV infections, discuss the mechanisms responsible for their suppressive activity, and review the rationale for CD8+ T cell-based HIV cure strategies. Evidence suggests that CD8+ T cells are involved in the control of virus replication during HIV and SIV infections. During early HIV infection, the cytolytic activity of CD8+ T cells is responsible for control of viremia. However, it has been proposed that CD8+ T cells also use non-cytolytic mechanisms to control SIV infection. More recently, CD8+ T cells were shown to be required to fully suppress virus production in ART-treated SIV-infected macaques, suggesting that CD8+ T cells are involved in the control of virus transcription in latently infected cells that persist under ART. A better understanding of the complex antiviral activities of CD8+ T cells during HIV/SIV infection will pave the way for immune interventions aimed at harnessing these functions to target the HIV reservoir.
