Cytokine and Chemokine Based Control of HIV Infection and Replication

Abstract

HIV infects and propagates into CD4+ T lymphocytes and macrophages, although many other cell types play an important role in virus spreading and pathogenesis. In addition to regulatory viral proteins, the cytokine network has early been implicated as a major controller of the plastic capacity of HIV to spread productively or rather remain silently integrated in the chromosomes of infected cells. The recent discovery of CCR5 and CXCR4 as essential entry co-receptors together with CD4 has highlighted a novel and potentially important step in the pharmacological hunt for more effective antiviral agents. In addition to regulate HIV expression and replication, several cytokines have demonstrated the capacity of up- or down-modulating chemokine receptors including CCR5 and CXCR4 with the consequence of influencing the susceptibility of T cells and macrophages to HIV infection. Pharmacological agents such as pertussis toxin B-oligomer have demonstrated HIV suppressive effects via non competitive binding of CCR5, whereas interferons or interleukin-16 (IL-16) can prevent post-entry steps in HIV expression. At the clinical level, several cytokines or their receptors are useful markers for monitoring disease progression and its consequence on the immune system. Cytokine-based therapy represents a realistic complementary approach to traditional antiretroviral therapy potentially capable of restoring important adaptive or innate immune functions ultimately curtailing HIV spreading and its consequences on the immune system, as exemplified by the experimental clinical use of IL-2.

Pertussis Toxin B-Oligomer Suppresses IL-6 Induced HIV-1 and Chemokine Expression in Chronically Infected U1 Cells via Inhibition of Activator Protein 1

“…Indeed, transfection of a Tat-expressing plasmid (10,22,24) or incubation of U1 cells with exogenous Tat protein (25,26) rescues viral production. Minimal to undetectable levels of HIV are produced by unstimulated U1 cells, although robust virion release can be promptly induced in these cells upon stimulation with phorbol esters, such as PMA (27), and several proinflammatory cytokines (28,29). For this reason, this cell line has served as a useful model to identify cytokines and other factors capable of modulating HIV expression and replication in primary cells in vitro and ex vivo (28,30,31).…”

“…Minimal to undetectable levels of HIV are produced by unstimulated U1 cells, although robust virion release can be promptly induced in these cells upon stimulation with phorbol esters, such as PMA (27), and several proinflammatory cytokines (28,29). For this reason, this cell line has served as a useful model to identify cytokines and other factors capable of modulating HIV expression and replication in primary cells in vitro and ex vivo (28,30,31). At the molecular level, in addition to Tat (32), several cellular transcription factors with binding sites in the HIV-1 long-terminal repeats (LTR) or present in the HIV genome (33) can be activated by chemical agents such as ionomycin (34) and PMA (35), superinfection by other viruses (36,37), or cytokine stimulation (28,29).…”

“…For this reason, this cell line has served as a useful model to identify cytokines and other factors capable of modulating HIV expression and replication in primary cells in vitro and ex vivo (28,30,31). At the molecular level, in addition to Tat (32), several cellular transcription factors with binding sites in the HIV-1 long-terminal repeats (LTR) or present in the HIV genome (33) can be activated by chemical agents such as ionomycin (34) and PMA (35), superinfection by other viruses (36,37), or cytokine stimulation (28,29). Among these latter, IL-6 was early identified as a potent HIV-inductive cytokine acting by a mechanism different from that triggered by TNF-␣ or PMA (i.e., activation of NF-B and consequent HIV-1 LTRdriven transcription) (12).…”

Inhibition of intra‐ and extra‐cellular Tat function and HIV expression by pertussis toxin B‐oligomer

“…Among the latter, cell surface expression of CD4 and chemokine receptors CCR5 (R5) and/or CXCR4 (X4) are required for HIV infection [4]. In addition, several cytokines favor HIV replication and HIV-associated diseases, and their expression is profoundly altered in the course of HIV infection towards a pro-inflammatory state [5].…”

Relationship among MIF, MCP-1, viral loads, and HBs Ag levelsin chronic hepatitis B patients

“…However, as we did not collect data on the ANA values of the patients, we cannot draw any definite conclusions. In other studies, researchers observed that when the viral load increased, numerous viral proteins antagonized chemokines by competitively binding their receptors, such as CCR5 and CXCR4 (35)(36)(37)(38). They suggested that levels of chemokines might be correspondingly downregulated (39).…”