Gene therapy approaches to HIV infection.

The HIV pandemic represents a new challenge to biomedical research. What began as a handful of recognized cases among homosexual men in the US has become a global pandemic of such proportions that it clearly ranks as one of the most destructive viral scourges in history. In the past few years new treatments and drugs have been developed and tested, but the development of a new generation of therapies remains a major priority, because of the lack of chemotherapeutic drugs or vaccines that show long-term efficacy in vivo. Recently, gene therapeutic strategies for the treatment of patients with HIV infection have received increased attention because they are able to offer the possibility of simultaneously targeting multiple sites in the HIV genome, thereby minimizing the production of resistant virus. Recombinant genes for gene therapy can be classified as expressing interfering proteins (intracellular antibodies, dominant negative proteins) or interfering RNAs (antisense RNAs, ribozymes, RNA decoys). The latter group offers the advantage of avoiding the stimulation of host immune response which might progressively decrease the efficacy of proteins. The stumbling block to achieving lasting antiviral effects is still represented by the lack of efficient gene transfer techniques capable of generating persistent transgene expression and a high number of transduced cells relative to untransduced cells. Novel delivery vectors, such as lentiviruses, might overcome some of these shortcomings. The use of recombinant genes to generate immunity is a very promising concept that is rapidly expanding. Since the immune system can significantly amplify the response to tiny amounts of antigen, DNA vaccines can indeed be delivered by exploiting traditional gene therapy approaches without the need of high transduction efficiency.

Macrophage-stimulating protein is produced by tubular cells and activates mesangial cells.

Until now, hepatocytes have been the only known cell source of macrophage-stimulating protein (MSP), and tissue macrophages have been the cells on which the biologic effects of MSP have been proved. To extend the understanding of the biologic meaning of MSP, it was investigated whether MSP operates in the kidney. MSP protein was evaluated by Western blot in supernatant of cultured human tubular cells (HK2) and human mesangial cells (HMC). MSP mRNA was investigated in HK2 by reverse transcription-polymerase chain reaction (RT-PCR). The expression of the MSP receptor, RON, was evaluated in HMC and HK2 by Western blot. RON mRNA was investigated in HMC by RT-PCR. The expression of MSP and RON in normal human renal tissue was studied by immunohistochemistry. HMC were stimulated with recombinant MSP (rMSP) and HK2 supernatant to study cell growth, migration, and the capacity to invade an artificial collagen matrix and synthesize interleukin-6 (IL-6). HK2 produced MSP and expressed RON in a form that was phosphorylated by rMSP. HMC expressed RON but did not produce MSP. MSP in HK2 supernatant and rMSP induced in HMC phosphorylation of RON, growth, migration, invasion, and IL-6 synthesis. In normal human kidney, tubules expressed MSP and RON. These results indicate a novel field of operation for MSP and suggest a pathogenic role of the MSP/RON system in renal disease. In fact, MSP released by tubular cells may recruit monocytes/macrophages in inflammatory tubulointerstitial disorders. In addition, MSP either circulating or as paracrine product may sustain glomerular mesangioproliferative disease.