Vaccine Protection Against Functional CTL Abnormalities in Simian Human Immunodeficiency Virus-Infected Rhesus Monkeys

Abstract

Accumulating evidence suggests that HIV-specific CD8+ CTL are dysfunctional in HIV-infected individuals with progressive clinical disease. In the present studies, cytokine production by virus-specific CTL was assessed in the rhesus monkey model for AIDS to determine its contribution to the functional impairment of CTL. CTL from monkeys infected with nonpathogenic isolates of simian and simian-human immunodeficiency virus expressed high levels of IFN-γ, TNF-α, and IL-2 after in vitro exposure to a nonspecific mitogen or the optimal peptide representing a dominant virus-specific CTL epitope. However, similarly performed studies assessing these capabilities in CTL from monkeys infected with pathogenic immunodeficiency virus isolates demonstrated a significant dysfunction in the ability of the CTL to produce IL-2 and TNF-α. Importantly, CTL from vaccinated monkeys that effectively controlled the replication of a highly pathogenic simian-human immunodeficiency virus isolate following challenge demonstrated a preserved capacity to produce these cytokines. These experiments suggest that defects in cytokine production may contribute to CTL dysfunction in chronic HIV or SIV infection. Moreover, an AIDS vaccine that confers protection against clinical disease evolution in this experimental model also preserves the functional capacity of these CTL to produce both IL-2 and TNF-α.

A Novel Functional CTL Avidity/Activity Compartmentalization to the Site of Mucosal Immunization Contributes to Protection of Macaques against Simian/Human Immunodeficiency Viral Depletion of Mucosal CD4+ T Cells

“…It has been recently reported that dysfunction of IL-2 and TNF-␣ production might be observed even earlier than the loss of IFN-␥ production by HIV-specific CD8 ϩ CTL (66). It was demonstrated that i.m.…”

SIV-specific CD8+ T cells express high levels of PD1 and cytokines but have impaired proliferative capacity in acute and chronic SIVmac251 infection

“…17 As in human infection with HIV, functional defects in SIV-specific CD8 ϩ T cells have been reported, potentially explaining why virtually all SIV-infected rhesus macaques progress to simian AIDS and death despite a readily measurable CD8 ϩ T-cell response. [17][18][19][20] Therefore, understanding factors that regulate the function(s) of SIV-and HIV-specific CD8 ϩ T cells is critical in the fight against AIDS.…”

“…17 As in human infection with HIV, functional defects in SIV-specific CD8 ϩ T cells have been reported, potentially explaining why virtually all SIV-infected rhesus macaques progress to simian AIDS and death despite a readily measurable CD8 ϩ T-cell response. [17][18][19][20] Therefore, understanding factors that regulate the function(s) of SIV-and HIV-specific CD8 ϩ T cells is critical in the fight against AIDS.Chronic viral infection with ongoing antigenic stimulation often results in exhaustion of virus-specific CD8 ϩ T cells. 21,22 Chronically stimulated virus-specific CD8 ϩ T cells express only low levels of receptors for IL-7 and IL-15 23 and lose the ability to maintain homeostatic proliferation.…”

HIV-189.6 Gag expressed from a replication competent HSV-1 vector elicits persistent cellular immune responses in mice

“…HIV-specific CTL responses can recognize and kill HIV infected cells and are effective in controlling HIV-1 replication during the course of natural infection [7][8][9]. Vaccines which elicit these types of responses can also control the replication of pathogenic retroviruses and protect against the development of immunodeficiency and death in nonhuman primate (NHP) models [10][11][12][13][14][15][16][17][18][19]. The current mechanisms for induction of potent CTL mediated immunity include immunogen delivery by attenuated viral vectors, bacterial vectors, direct plasmid DNA injection, and co-delivery of vaccine adjuvants (reviewed in [20][21][22]).…”