Abstract
Since the brain is separated from the blood immune system by a tight barrier, the brain-resident complement system may represent a central player in the immune defense of this compartment against human immunodeficiency virus (HIV). Chronic complement activation, however, may participate in HIV-associated neurodegeneration. Since the level of complement factors in the cerebrospinal fluid is known to be elevated in AIDS-associated neurological disorders, we evaluated the effect of HIV type 1 (HIV-1) on the complement synthesis of brain astrocytes. Incubation of different astrocytic cell lines and primary astrocytes with HIV-1 induced a marked upregulation of the expression of the complement factors C2 and C3. The synthesis of other secreted or membrane-bound complement proteins was not found to be altered. The enhancement of C3 production was measured both on the mRNA level and as secreted protein in the culture supernatants. HIV-1 laboratory strains as well as primary isolates were capable of inducing C3 production with varied effectiveness. The usage of viral coreceptors by HIV-1 was proved to be a prerequisite for the upregulation of C3 synthesis, which was modulated by the simultaneous addition of cytokines. The C3 protein which is secreted after incubation of the cells with HIV was shown to be biologically active as it can participate in the complement cascade.
Highlights
The human immunodeficiency virus type 1 (HIV-1) is detected in more than 80% of the brains of patients with AIDS [12, 17, 29] and induces neurological manifestations in 20 to 30% of HIV type 1 (HIV-1)-infected individuals
Since the level of complement factors in the cerebrospinal fluid is known to be elevated in AIDSassociated neurological disorders, we evaluated the effect of HIV type 1 (HIV-1) on the complement synthesis of brain astrocytes
U373 astrocytes were incubated with HIV-1 strain IIIB, and the production of several complement factors of classical, alternative, and terminal pathways was measured on the mRNA level at different time points
Summary
The human immunodeficiency virus type 1 (HIV-1) is detected in more than 80% of the brains of patients with AIDS [12, 17, 29] and induces neurological manifestations in 20 to 30% of HIV-1-infected individuals. The complement factor C3 is a central protein of the cascade, and its degradation products, like C3b, iC3b, C3d, and C3a, harbor a variety of biological functions, including cell activation, initiation of phagocytosis, and transport of immune complexes on erythrocytes [31]. Besides the lysis of pathogens, the complement activation products and anaphylatoxins C3a and C5a can exert important functional effects on brain cells like the modulation of cytokine expression [27], the induction of nerve growth factor synthesis [15], and the activation of signal transduction pathways [19, 22]. There is increasing evidence that complement biosynthesis occurs in the CNS and that all components of the cascade can be synthesized locally in the brain by the major cell types including astrocytes, microglia, neurons, and oligodendrocytes [21]. The HIV-induced secreted C3 was proven to be biologically active, indicating a variety of possible interactions between the complement system and HIV in the brain
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