Lipopolysaccharide-induced HIV-1 expression in transgenic mice is mediated by tumor necrosis factor-alpha and interleukin-1, but not by interferon-gamma nor interleukin-6.
BACKGROUND
As serum HIV-1 load correlates well with the prognosis of the disease, it is suggested that the viral load is one of the major determinants of the disease progression of AIDS. Accordingly, HIV-1 activation mechanisms were extensively studied in vitro, and involvement of cytokines including tumor necrosis factor (TNF)-alpha, interleukin (IL)-1, IL-6 and interferon (IFN)-gamma has been suggested in this process. However, so far the roles of these cytokines in the HIV-1 expression in vivo have not been well elucidated because of the lack of appropriate animal disease models.


OBJECTIVE
To elucidate the roles of cytokines in HIV-1 activation in vivo.


METHODS
Transgenic mice carrying a defective HIV-1 genome were used as a model for HIV-1 carriers. In order to examine the possible involvement of cytokines in HIV-1 expression, TNF-alpha-, IL-1-, IL-6- and IFN-gamma-deficient HIV-1 transgenic mice, were produced and HIV-1 expression was analyzed after activation with bacterial lipopolysaccharides (LPS).


RESULTS
HIV-1 expression in the transgenic mouse spleen was activated 10- to 20-fold by LPS, and the serum p24 Gag protein levels reached 400 pg/ml, which is nearly equal to the levels that occur in AIDS patients. However, this augmentation was suppressed by 60% in TNF-alpha-deficient mice and by 40% in IL-1alpha/beta-deficient mice. In contrast, no suppression was observed in either IL-6-, IFN-gamma-, IL-1alpha, or IL-1beta-deficient mice.


CONCLUSIONS
Results suggest that TNF-alpha and IL-1 play important roles in HIV-1 gene activation and selective suppression of these cytokines could improve clinical prognosis and potentially slow progression of the disease.
Tanaka
J
J
Center for Experimental Medicine, Institute of Medical Science, University of Tokyo, Japan.
Ozaki
H
H
Yasuda
J
J
Horai
R
R
Tagawa
Y
Y
Asano
M
M
Saijo
S
S
Imai
M
M
Sekikawa
K
K
Kopf
M
M
Iwakura
Y
Y
D000818:Animals; D016207:Cytokines / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D004195:Disease Models, Animal; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D015658:HIV Infections / Q000276:immunology / Q000821:virology; D015497:HIV-1 / Q000235:genetics* / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D007375:Interleukin-1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D015850:Interleukin-6 / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D007700:Kinetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D008822:Mice, Transgenic; D013154:Spleen / Q000276:immunology / Q000821:virology; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D014766:Viremia / Q000276:immunology / Q000821:virology
D016207:Cytokines; D007375:Interleukin-1; D015850:Interleukin-6; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma