The spreading of HIV-1 infection in the human organism is caused by fractalkine trafficking of the infected lymphocytes—a review, hypothesis and implications for treatment

Abstract

The reviews on HIV-1/AIDS [1-8] highlighted the mechanism by which HIV-1 virions utilize dendritic cells (DCs) for transport from the genitals, the portal of virus infection, to the draining lymph nodes where DCs carry HIV-1 virions and present viral antigens by HLA class I and II to CD4(+) T cells. Interaction of the T cells with viral antigens presented by HLA class II molecules polarizes them to become Th2 cells, the targets of HIV-1 infection and producers of HIV-1 progeny virions. The T cells which interact with viral antigen presented by HLA class I polarize to become Th1 cells, which stimulate the CD8(+) T cell precursors to develop into antiviral cytotoxic T cells. In addition, HIV-1 virions shed gp120 glycoprotein molecules which bind to IgE immunoglobulin molecules bound to FCepsilonRI+ innate system cells (basophils, mast cells and monocytes) and induce them to release large amounts of Th2 cytokines (IL-4, IL-5, IL-10, IL-13), thereby creating an allergy-like condition. The present review attempts to define the role of chemokine receptors like CCR5 and CXCR4, and especially fractalkine receptor CX3CR1 in the trafficking of lymphocytes in healthy individuals and HIV-1/AIDS patients. The role of chemokine receptors as co-receptors for HIV-1 virion gp120 glycoprotein has been defined, but the role of fractalkine and fractalkine receptor has been clarified only recently [9-19]. In healthy individuals fractalkine is expressed by blood vessel endothelial cells and the CX3CR1 receptors are expressed on leukocytes that migrate in the peripheral blood in the direction of increased fractalkine concentration. In HIV-1/AIDS patients the virus-infected CD4(+) Th2 cells migrate to organs that harbor the adaptive immune system cells in the thymus, genitals, gastrointestinal tract, and to the brain. A most significant finding which revealed the importance of the human CX3CR1 gene expression to the progression of the infection to the stage of AIDS was recently reported by Faure and collaborators [20, 21] who showed that the delayed or rapid progression to AIDS was affected in HIV-1-infected individuals who had inherited a fractalkine receptor gene with the polymorphisms V249I or T280M, respectively, located in the sixth and seventh transmembrane domains of CX3CR1 protein. The T280M mutation in the CX3CR1 gene caused a rapid progression to AIDS, while in patients with the V249I mutation progression to AIDS was much slower. These studies led to the idea that it might be possible to slow or prevent HIV-1/AIDS progression in HIV-1 patients by treating them with fractalkine antagonists that will bind to and inhibit the activity of the fractalkine receptor. It is hypothesized that treatment of HIV-1/AIDS patients with a combination of fractalkine antagonists, IL-4 antagonist IL-4delta2 and the adjuvant CpG ODN induced release of type I IFN from PDF, and may inhibit HIV-1 infection, especially in HAART-treated patients infected with drug-resistant HIV-1 mutants due to prevention of the availability of immune cells needed for ...

Increased Levels of Circulating Cytokines with HIV-Related Immunosuppression

“…It had been suggested that fractalkine trafficking of HIV-infected lymphocytes propagates the dissemination of HIV in vivo. 26 Of the 30 cytokines that we evaluated, only fractalkine was associated with viral load, and this association remained significant after adjusting for CD4 count. Similarly, Widney et al found that CXCL13-a B cell stimulatory chemokines-is elevated in HIV infection and correlated with CD4 count and HIV viral load.…”

Fractalkine/CX3CL1 protects striatal neurons from synergistic morphine and HIV-1 Tat-induced dendritic losses and death

“…Functionally, fractalkine is highly pleiotropic [23,27], acting as both an adhesion molecule and chemoattractant for T cells, NK cells, and macrophages [24,29,30]. CX 3 CR1 can also serve as an HIV-1 co-receptor with CD4 [31-33] and is hypothesized to facilitate the spread of HIV-1 infection [34]. Within the nervous system, fractalkine serves a major role as a membrane-tethered neuronal chemokine, while the Cx3cr1 gene is highly expressed by microglia [26,35].…”

“…By contrast, other investigators report reductions in fractalkine and CX 3 CR1 levels and signaling in neuroAIDS [45]. More recently, fractalkine has been proposed as important for trafficking HIV-infected lymphocytes into the brain [34,42]. Soluble fractalkine attenuates gp120 toxicity in hippocampal neuron cultures in the presence or absence of a glial feeder layer suggesting a direct neuroprotective role [46].…”

CB2 Receptor Agonists Protect Human Dopaminergic Neurons against Damage from HIV-1 gp120

“…CCL2, which is up-regulated in activated microglia and constitutively produced by neurons [97], plays a central role in HAND by attracting microglia [98] and monocytes [99-101] into the central nervous system and is considered a marker of poor prognosis [102-105]. CX3CL1 and its receptor CX3CR1 have received increased attention regarding their roles in HIV-1 infection [106-108] and in HAND specifically [106,109,110]. CX3CL1 is expressed by neurons and astrocytes [111], where it induces microglial proliferation [111] and migration [112].…”