HIV-1 induces complement factor C3 synthesis in astrocytes and neurons by modulation of promoter activity.

Virus-induced complement expression and activation in the brain is hypothesized to contribute to the process of neurodegeneration in AIDS-associated neurological disorders. Previous experiments have shown that the human immunodeficiency virus (HIV) upregulates the low basal production of complement factor C3 in astrocytes and neurons. Since inhibition of complement synthesis and activation in the brain may represent a putative therapeutic goal to prevent virus-induced damage, we analysed the mechanism of the HIV-induced modulation of C3 expression.

Complement in different stages of HIV infection and pathogenesis.

The complement system is one of the most important weapons of innate immunity and is involved in all infectious processes. It is not only a mechanism for direct protection against an invading pathogen but it also interacts with the adaptive immunity to optimize the pathogen-specific humoral and cellular defence cascade in the body. One of the greatest challenges for the complement system is infection by HIV with its chronic course and sequential destruction of immune cells and immune organs.

Neuroinvasion by pathogens: a key role of the complement system.

Complement (C) is one of the most critical defence mechanisms of the innate immunity against cerebral infection by viruses, bacteria and fungi, with different molecular pathways contributing to the clearance of the invading pathogens. There is now compelling evidence that C proteins can be synthesized by brain cells in response to the infectious challenge and leading to cytotoxic and cytolytic activities against the harmful intruders. However, since there is also emerging evidence that uncontrolled C biosynthesis/activation can lead to brain inflammation with loss of neurons and oligodendrocytes, it is important to highlight that C may have adverse effects in infectious diseases of the CNS and induce profound tissue damage.

HIV-1 envelope protein gp41 modulates expression of interleukin-10 and chemokine receptors on monocytes, astrocytes and neurones.

Objective: To analyse the effect of HIV-1 transmembrane protein gp41 on cytokine production and chemokine receptor expression in blood and brain.

Design: Because previous results had demonstrated that recombinant gp41 contributes to HIV-induced dysfunction of blood immune cells we investigated its effect on interleukin (IL)-10 synthesis and expression of the HIV coreceptors CCR5 and CXCR4 in different human brain cells.

Methods: Astrocytic, microglial and neuronal cell lines were incubated with the extracellular domain of gp41 (aa565-647).

gp41 envelope protein of human immunodeficiency virus induces interleukin (IL)-10 in monocytes, but not in B, T, or NK cells, leading to reduced IL-2 and interferon-gamma production.

The effect of extracellular domain of human immunodeficiency virus (HIV-1) transmembrane glycoprotein gp41 on interleukin (IL)-10, IL-2, interferon (IFN)-y, IL-4, and tumor necrosis factor-alpha production by human peripheral blood mononuclear cells (PBMC) was assessed by ELISA. Rapid gp41-induced increase of IL-10 production was detected in resting PBMC and isolated monocytes but not in B, T, or NK cells. Furthermore, gp41 also enhanced IL-10 production in staphylococcal enterotoxin B-stimulated PBMC, while synthesis of IL-2, IFN-gamma, and IL-4 in these cells was down-modulated.