Influence of interleukin-15 on CD8+ natural killer cells in human immunodeficiency virus type 1-infected chimpanzees

Abstract

Chimpanzees are susceptible to human immunodeficiency virus type-1 (HIV-1) and develop persistent infection but generally do not progress to full-blown AIDS. Several host and immunological factors have been implicated in mediating resistance to disease progression. Chimpanzees have a higher prevalence of circulating natural killer (NK) cells than humans; however, their role in mediating resistance to disease progression is not well understood. Furthermore, NK cell survival and activity have been shown to be dependent on interleukin-15 (IL-15). Accordingly, the influence of IL-15 on NK cell activity and gamma interferon (IFN-γ) production was evaluated in naive and HIV-1-infected chimpanzees. In vitro stimulation of whole-blood cultures with recombinant gp120 (rgp120) resulted in enhanced IFN-γ production predominantly by the CD3− CD8+ subset of NK cells, and addition of anti-IL-15 to the system decreased IFN-γ production. Moreover, in vitro stimulation with recombinant IL-15 (rIL-15) augmented IFN-γ production from this subset of NK cells and increased NK cell cytotoxic activity. Stimulation with rgp120 also resulted in a 2- to 7-fold increase in IL-15 production. These findings suggest that chimpanzee CD3− CD8+ NK cells play a vital role in controlling HIV-1 infection by producing high levels of IFN-γ, and that IL-15 elicits IFN-γ production in this subpopulation of NK cells in HIV-1-infected chimpanzees.

High Frequencies of Polyfunctional CD8+NK Cells in Chronic HIV-1 Infection Are Associated with Slower Disease Progression

“…This could be an indication that CD8 Ϫ and CD8 ϩ NK cells assume different roles in chimpanzees than in humans. Several studies addressed the role of CD8 ϩ NK cells during HIV-1 infection in chimpanzees and found no decline of these cells (53,55,56). One likely explanation is arguably the observation that the immune pathologies caused by HIV-1 infection in humans vary substantially from those caused by HIV-1 infection in chimpanzees, since HIV-1-infected chimpanzees do not progress to AIDS, although a seminal study demonstrated the development of AIDS in wild chimpanzees infected with naturally occurring chimpanzee simian immunodeficiency virus (SIV cpz ) (57).…”

Higher Type 1 Interferon Levels in Plasma of Asymptomatic HIV-2 than in HIV-1 Individuals

“…The maturation of NK cells is then mainly facilitated by IL-15 [7]- [9] which together with other cytokines such as IL-12 and IL-18, enhances NK cytotoxicity [10] and increases the production of IFN-γ [11] [12]. The subsequent secretion of IFN-α and γ by both NK and T cells represents the key effector functions in the control of viral infection [13] [14].…”

New players in cytokine control of HIV infection

“…In addition, IL-15 is more potent than IL-2 in stimulating NK cell function, including secretion of IFN-and of CCR5-binding chemokines [15]. IL-15 has been shown to stimulate the function of immune cells of individuals who are HIV positive, particularly CD8 + memory T cells and NK cell survival and activity [15]. In addition, IL-15 induced increasing antibody-dependent cellular cytotoxicity and complement-dependent lysis of HIV-1 Env-expressing target cells through augmentation of specific IgG levels in immunized mice [16•].…”

“…In addition, IL-15 is more potent than IL-2 in stimulating NK cell function, including secretion of IFN-and of CCR5-binding chemokines [15]. IL-15 has been shown to stimulate the function of immune cells of individuals who are HIV positive, particularly CD8 + memory T cells and NK cell survival and activity [15].…”