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Enfuvirtide (T20) is the first and only HIV-1 fusion inhibitor approved for clinical use, but it can easily induce drug resistance limiting its practical application. A novel anti-HIV peptide, termed sifuvirtide, was designed based on the three-dimensional structure of the HIV-1 gp41 fusogenic core conformation. Here we report its in vitro anti-HIV potency, its mechanism of action, as well as the results from Phase Ia clinical studies. We demonstrated that sifuvirtide inhibited HIV-1-mediated cell-cell fusion in a dose-dependent manner and exhibited high potency against infections by a wide range of primary and laboratory-adapted HIV-1 isolates from multiple genotypes with R5 or X4 phenotypes. Notably, sifuvirtide was also highly effective against T20-resistant strains. Unlike T20, sifuvirtide could efficiently block six-helix bundle formation in a dominant negative fashion. These results suggest that sifuvirtide has a different mechanism of action from that of T20. Phase Ia clinical studies of sifuvirtide (FS0101) in 60 healthy individuals demonstrated good safety, tolerability, and pharmacokinetic profiles. A single dose regimen (5, 10, 20, 30, and 40 mg) by subcutaneous injection once daily at abdominal sites was well tolerated without serious adverse events. Pharmacokinetic studies of single and multiple administration of sifuvirtide showed that its decay half-lives were 20.0 +/- 8.6 h and 26.0 +/- 7.9 h, respectively. In summary, sifuvirtide has potential to become an ideal fusion inhibitor for treatment of HIV/AIDS patients, including those with HIV-1 strains resistant to T20.

Undifferentiated nasopharyngeal carcinoma is very common among Southern Chinese. While most patients have the disease detected and treated early, those who are diagnosed with advanced stages face a poor prognosis. Nasopharyngeal carcinoma is associated with latent Epstein-Barr virus (EBV); it was suggested previously that a cytotoxic T-lymphocyte (CTL)-based therapy targeting EBV proteins may offer a possible new form of treatment for this disease. The most likely target of this treatment is latent membrane protein 2 (LMP2). To define further the preexisting level of anti-EBV immunity in Chinese subjects, the frequency of peripheral blood mononuclear cells (PBMCs) responding to peptide epitopes was determined using an ELISPOT assay in 50 healthy control blood donors and in 26 patients newly diagnosed with nasopharyngeal carcinoma. A total of 7 LMP2, 2 LMP1, 1 EBNA3A, and 1 EBNA3B epitopes were used in a HLA-restricted manner. As reported previously for healthy virus carriers in western countries, it was found that in both groups the strongest responses were to epitopes in the EBNA proteins with weaker responses to the LMP epitopes. It was found that LMP2 epitopes were recognized in a greater percentage of both groups than previously reported, due most likely to the greater sensitivity of the ELISPOT method. However, patients with nasopharyngeal carcinoma demonstrated a weaker response than that displayed by healthy control subjects to several epitopes. The results demonstrate that LMP2 epitopes are recognized widely in an HLA-restricted manner in patients with nasopharyngeal carcinoma and that immunotherapy to boost preexisting immunity to these epitopes may offer a viable method to treat such patients or to protect against recurrence., (Copyright 2002 Wiley-Liss, Inc.)

A Phase 1, double-blind, placebo controlled trial was conducted in Longchuan County, China, to evaluate the safety and immunogenicity of a prototype HIV-1 synthetic peptide vaccine in a target population at risk for HIV infection, and to establish the infrastructure for future large-scale HIV vaccine efficacy trials. Subjects were randomly assigned to receive 100 microg or 500 microg of vaccine or alum placebo, and were given three injections at an accelerated 0, 1, and 2 month schedule. The vaccine was well tolerated with no significant local or systemic reactions observed in any subjects. Fifty-five percent (100 microg dose) and 64% (500 microg dose) of subjects who received the vaccine produced binding antibody to the immunogen as determined by ELISA. However, HIV-1 (MN) neutralizing antibody was detected in only 23% (3/13) of subjects with detectable HIV-1 specific binding antibody. It was concluded that this prototype HIV-1 synthetic peptide vaccine was well tolerated, safe and immunogenic, and that a 0, 1, 2 month schedule was not as effective in stimulating HIV-1 specific neutralizing antibodies compared with previous trials utilizing a 0, 1, 6 month schedule. Finally, this trial demonstrated that well-designed HIV vaccine trials can be performed at this clinical trials site in Yunnan, China, and that this site should be considered for conducting larger safety, immunogenicity and efficacy trials of candidate HIV vaccines.