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Natural killer ( NK) cells are essential components of the immune system, and due to their rapid response potential, can have a great impact during early anti-viral immune responses. We have previously shown that interleukin-2-dependent NK and CD4+ T-cell co-operative immune responses exist in long-term simian immunodeficiency virus ( SIV) -infected controlling macaques and can be rescued in SIV-infected non-controlling macaques by a short course of antiretroviral therapy ( ART). Given that co-operative responses may play an important role in disease prevention and therapeutic treatment, in the present study we sought to determine if these responses can be enhanced in chronically SIV-infected macaques by vaccination with a single-dose of envelope protein given during ART. To this end, we treated 14 chronically SIV-infected macaques with ART for 11 weeks and gave 10 of these macaques a single intramuscular dose of SIV gp120 at week 9 of treatment. ART significantly decreased plasma and mucosal viral loads, increased the numbers of circulating CD4+ T cells in all macaques, and increased T-cell-dependent envelope- and gag-specific interferon- γ and tumour necrosis factor- α production by circulatory CD56+ NK cells. The therapeutic envelope immunization resulted in higher envelope-specific responses compared with those in macaques that received ART only. Functional T-cell responses restored by ART and therapeutic Env immunization were correlated with transiently reduced plasma viraemia levels following ART release. Collectively our results indicate that SIV-specific T-cell-dependent NK cell responses can be efficiently rescued by ART in chronically SIV-infected macaques and that therapeutic immunization may be beneficial in previously vaccinated individuals. [ABSTRACT FROM AUTHOR]

Summary Natural killer (NK) cells are important components of the innate immune system that mediate effector and regulatory functions. As effector cells, NK cells help control virus-infected cells through cell-mediated antibody-dependent mechanisms such as antibody-dependent cellular cytotoxicity (ADCC). Although macaques are an important and reliable animal model for the study of retrovirus-induced human diseases, and despite the crucial role played by NK cells in innate and adaptive immune responses against simian immunodeficiency virus (SIV), only a few studies have attempted to characterize different macaque NK cell subpopulations. In the present study, we identified a subpopulation of circulatory CD8α− macaque NK cells that express NK lineage markers and exhibit cytotoxic potential. CD8α− NK cells were phenotypically characterized as CD3− CD14− CD20− CD8α− cells that express NK cell markers including CD16, CD56, granzyme B, perforin, NKG2D and KIR2D. Based on their CD56/CD16 expression patterns, cells within the CD8α− gate can be divided into four subpopulations: CD56dim CD16bright, CD56dim CD16−, CD56bright CD16−, and CD56− CD16− cells. In contrast, CD8α+ NK cells are 95% CD56dim CD16bright, which correlates with their high cytotoxic potential. Upon interleukin-15 activation, CD8α− cells up-regulated CD69 expression and produced low levels of interferon-γ and tumour necrosis factor-α. Sorted CD8α− NK cells were capable of killing MHC-I-devoid target cells and mediated ADCC responses against SIV gp120-coated target cells in the presence of macaque anti-gp120 antibodies. Taking into account CD8α− myeloid dendritic cells, we show that about 35% of macaque CD8α− cells represent a novel, functional population of circulatory NK cells that possesses cytotoxic potential and is capable of mediating anti-viral immune responses. [ABSTRACT FROM AUTHOR]