IFN-γ

T and NK cells represent the cellular source of IFN-γ. In HIV individuals, levels of IFN-γ have been found elevated both in the peripheral blood compartment and in the germinal centers of lymph nodes (LN) [28].

IFN-γ can mediate either suppressive [29] or upregulatory effects on HIV replication as a function of whether cells are acutely or chronically infected by HIV and whether other stimuli are present. In chronically HIV infected promonocytic U1 cells IFN-γ has been reported to induced viral expression [30], either by itself or with TNF-α [31]. Similar findings have also been reported in primary cells, demonstrating reduced viral replication in IL-2 stimulated PBMC infected in vitro in which IFN-γ has been neutralized [32]. On the other side, IFN-γ stimulation of infected monocytic cells may lead to the redirection of the primary site of virion budding from the plasma membrane to Golgi-derived intracytoplasmic vacuoles [30], today recognized belonging to multivesicular bodies (MVB), and resembling morphological features typical of brain macrophages of individuals with HIV encephalitis [33,34]. Of interest is the fact that signaling generated by IFN-γ unrelated molecules, including CCL2/MCP-1 [35], and urokinase/urokinase receptor [36], may induce similar features in infected and differentiated monocytic cells. These observation suggest the existence of a common target of diverse signaling pathways that can influence the “choice” of the virion assembly machinery to target either the plasma membrane or endosomal membranes [37]. Of interest, this seems to be restricted to mononuclear phagocytes, although inactivation of VpU results in similar features in T lymphocytes [38].

IFN-γ, as well as IL-10, production increased during the interaction of infected DC and T cells leading to HIV spreading [39]. In particular, the HIV matrix protein p17 Gag upregulated the secretion of IFN-γ and TNF-α in human NK cells stimulated with IL-12 and IL-15 [40].

Concerning the interaction between the cytokine network and the virus in animal models, it has been shown that IFN-γ mRNA expression in PBMC, LN, bronchoalveolar mononuclear cells [41-43], and in intestinal lamina propria lymphocytes [44] is increased during primary SIV infection of macaques. At later time points, IFN-γexpression decreased in SIV infected macaques receiving IL-12 vs. controls [45] as also observed in SIV-infected PBMC stimulated [44]. During primary SIV infection of macaques, upregulation of IFN- γmRNA expression in PBMC, LN, bronchoalveolar mononuclear cells [41-43], and intestinal lamina propria lymphocytes [44] has been associated with the containment of viral replication.