Natural Barrier to HIV-1 Entry

RESEARCH HIGHLIGHTS

HIV Natural barrier to HIV-1 entry

DOI: Although it is known that molecules 10.1038/nrd2342 with anti-HIV activity circulate in human blood, their identification has been hampered by difficulties in the purification and characteriza- tion of such compounds. Kirchhoff and colleagues undertook the task of systematically screening a haemofiltrate-derived peptide library of over one million small peptides for natural inhibitors of HIV-1 replication and report the isolation of a novel virus inhibitory peptide (VIRIP) that is active against a wide variety of HIV-1 strains. VIRIP is a 20-residue peptide, corresponding to a fragment of the highly abundant serine protease inhibitor α1-antitrypsin, which strongly inhibits HIV-1 infection and transmission in human peripheral active conformation and to increase What triggers the generation of blood mononuclear cells (PBMCs). the hydrophobic contact area, the VIRIP and its function in the human Chemically synthesized VIRIP authors were able to increase the body remain elusive, but its activity, inhibited PBMC infection by a broad inhibitory potency of VIRIP by two stability and lack of toxicity all range of HIV strains, including orders of magnitude. herald optimized VIRIP derivatives variants that are resistant to current In contrast to enfuvirtide (also as promising candidates for clinical antiretroviral drugs, with similar known as T20), the first HIV-1 entry assessment. This study also highlights potency to isolated VIRIP and inhibitor to be approved by the FDA, a region in gp41 as an attractive drug without causing cytotoxicity. it proved difficult to generate strains target that may pave the way for the Functional and structural data of HIV-1 that were resistant to VIRIP development of a new class of HIV-1 show that VIRIP binds to a hydro- derivatives in vitro. This finding indi- entry inhibitors. phobic region of the HIV-1 envelope cates that VIRIP binds to a highly con- Monica Hoyos Flight

glycoprotein gp41, preventing served region of gp41 and supports ORIGINAL RESEARCH PAPER Münch, J. et al. membrane fusion and virus entry. the use of VIRIP derivatives against Discovery and optimization of a natural HIV-1 Moreover, by substituting a few of HIV-1 variants that are resistant to entry inhibitor targeting the gp41 fusion peptide. Cell 129, 263–275 (2007) VIRIP’s amino acids to stabilize the other entry inhibitor drugs.