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1.
J Gen Virol ; 88(Pt 2): 641-651, 2007 Feb.
Article in English | MEDLINE | ID: mdl-17251583

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-gamma) 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-gamma production predominantly by the CD3(-) CD8(+) subset of NK cells, and addition of anti-IL-15 to the system decreased IFN-gamma production. Moreover, in vitro stimulation with recombinant IL-15 (rIL-15) augmented IFN-gamma 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-gamma, and that IL-15 elicits IFN-gamma production in this subpopulation of NK cells in HIV-1-infected chimpanzees.


Subject(s)
CD8 Antigens/metabolism , HIV Infections/immunology , HIV-1/pathogenicity , Interleukin-15/pharmacology , Killer Cells, Natural/drug effects , Animals , Chronic Disease , HIV Infections/physiopathology , HIV Infections/virology , Humans , Interferon-gamma/metabolism , Interleukin-15/blood , Interleukin-15/immunology , Killer Cells, Natural/immunology , Killer Cells, Natural/metabolism , Pan troglodytes , RNA, Viral/blood , Viral Load
2.
DNA Cell Biol ; 24(2): 63-72, 2005 Feb.
Article in English | MEDLINE | ID: mdl-15699627

ABSTRACT

CpG-C are a novel class of CpG motif-containing immunostimulatory sequences (ISS) that includes both a 5'-TCG element and a CpG-containing palindrome. CpG-C drive all known ISS activities and, in particular, are potent enhancers of IFN-alpha from plasmacytoid dendritic cells (PDCs). In our examination of CpG-C sequence requirements, we determined that optimal IFN-alpha-inducing activity could be achieved with longer palindromes. Longer palindromes also correlated with maintenance of the double-stranded (ds) form despite concentration and pH changes, indicating a preference for ds oligodeoxynucleotides (ODNs) by the ISS-induced signaling mechanism for IFN-alpha synthesis. This correlation did not hold for all arms of the ISS-induced immune response, since we did not observe increased B cell activity with the longer palindrome CpG-C ODNs. We further demonstrated that CpG-C retained activity in an in vitro primate system and induced the expression of several cytokines and IFN-alpha-inducible genes when CpG-C were administered in vivo to mice and primates. In conclusion, we have shown CpG-C to exert several types of immune functions across multiple species, and this novel class is thus an attractive candidate for ISS-based therapeutic strategies.


Subject(s)
Adjuvants, Immunologic/pharmacology , B-Lymphocytes/drug effects , Cytokines/biosynthesis , Gene Expression/drug effects , Oligodeoxyribonucleotides/pharmacology , Adjuvants, Immunologic/genetics , Animals , Apoptosis Regulatory Proteins , B-Lymphocytes/immunology , Cell Proliferation , CpG Islands/genetics , Female , GTP-Binding Proteins/biosynthesis , GTP-Binding Proteins/genetics , Gene Expression/physiology , Gene Expression Regulation/physiology , Humans , Interferon-alpha/metabolism , Interferon-gamma/metabolism , Interleukin-12/metabolism , Interleukin-6/metabolism , Lymph Nodes/chemistry , Lymph Nodes/metabolism , Mice , Myxovirus Resistance Proteins , Oligodeoxyribonucleotides/genetics , Papio , RNA, Messenger/analysis , RNA, Messenger/metabolism , RNA-Binding Proteins , Transcription Factors/biosynthesis , Transcription Factors/genetics
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