oa Editorial [Hot topic:Sealing the Envelope-the HIV-1 Envelope Glycoproteins as Targets for Therapeutics and Vaccines (Executive Editors: Rogier W. Sanders, Ben Berkhout)]

HIV-1 is an enveloped virus that derives its lipid envelope from the virus producing cell. The envelope glycoprotein complex (Env) mediates viral attachment to and entry in susceptible target cells and is therefore an attractive target for therapeutic intervention. The T20 peptide (Fuzeon, enfuvirtide), targeting the Env fusion machinery, was approved for clinical use in 2003 and served as salvage therapy for many HIV-1 infected individuals for whom no other effective inhibitors were available because of the development of viral resistance. The approval in 2007 of the small molecule inhibitor maraviroc (Selzentry, Celsentri), targeting the coreceptor CCR5, marked a new era for entry inhibitors, which now occupy a mature position in the repertoire of antiviral drugs available to clinicians. Very recently a major breakthrough finding in the HIV-1 microbicide field was reported. A tenofovir containing gel offered (partial) protection against infection [1]. This success illuminates the possibilities of HIV prevention by antiviral drugs. Entry inhibitors may be particularly valuable for microbicide action because they act outside the cell by preventing viral infection and thus block the virus at the portal of entry. Entry inhibitors have already shown promise as active microbicides in monkey models [2,3]. In addition, therapeutic antibodies can also be used in the microbicide setting. Since Env is the only viral protein on the outside of the HIV-1 virion, it is also the only viral component to which neutralizing antibodies can be raised and as such Env is of vital importance for vaccine research. Despite massive efforts, an Env vaccine that induces broadly neutralizing antibodies has remained elusive. The recent RV144 trial in Thailand appeared to show some protection (31%) by combining two vaccines that individually did not provide any protection [4]. The results of this trial suggest two things. 1. It is possible to generate (partial) protection against HIV acquisition by vaccination. 2. The current vaccines need to be improved considerably before they can have any significant impact on stemming of the HIV epidemic. In fact, the antibody component of the RV144 vaccine was an old-fashioned monomeric gp120 protein. Better alternatives are currently available, most notably trimeric Env immunogens, but there is a need for further improvement. This issue of Current Pharmaceutical Design contains 5 reviews in the field of Env therapeutics and vaccines. These manuscripts address diverse new findings that have recently been reported and collectively describe the exciting progress made in recent years in these fields. Pollakis and Paxton [5] introduce the cellular receptors that are involved in Env biology and that can all be targets for therapeutic intervention. The focus is on the coreceptors CCR5 and CXCR4 as well as the viral inhibitors that target these membrane proteins, of which maraviroc is the prototype. The review by Eggink et al. [6] discusses the past and the future of HIV-1 inhibitors that target the Env fusion machinery, including the T20 peptide and improved variants thereof. The article by Pantophlet [7] describes the different Env protein domains that can be targeted by antibodies and sets the stage for the next two articles. Pejchal and Wilson [8] review Env-based vaccine design from the angle of structural biology. Finally, the review by Abele et al. [9] combines the two topics of this issue - vaccines/antibodies and therapeutics - by describing the development of therapeutic antibodies. The HIV-1 Env field is exciting and fast moving, yielding valuable products for therapeutic use, yet the translation of the accumulating knowledge into an effective and safe HIV vaccine remains a daunting challenge.