Editorial [Hot Topic:Antibody Neutralization (Guest Editor: Kelly Stefano Cole)]

Each year, more than 5 million individuals are newly infected with HIV-1 [1]. To address this, the development of an HIV/AIDS vaccine has remained one of the highest priorities in biomedical research for the last 25 years. During this time, we have witnessed some success with the development of antiretroviral therapies capable of lowering the viral loads and decreasing the severity of disease. While treatment has extended the time course of infection, it has not resulted in a cure and/or prevention of HIV-1 infection. On the other hand, a large number of vaccine candidates have been tested with less than stellar success. Over the last two decades, researchers have focused almost exclusively on vaccines that exploit either cellular or humoral immunity as a goal for AIDS vaccine development. After more than two decades of limited success with vaccines, most researchers now believe that the goal of an AIDS vaccine should be to elicit as robust and broadly active cellular and humoral immunity as possible, thereby maximizing the potential for protection from variant HIV-1 strains by different routes of exposure. Researchers are returning focus back to the importance of antibody-mediated neutralization as a prime determinant in the protection against HIV-1 infection. One of the challenges for the development of an HIV/AIDS vaccine remains the great diversity of sequences present in viral isolates, particularly those in Env. HIV-1 isolates are divided into three different groups based on sequence diversity: Group M, N and O [2]. Isolates of group M (main) comprise the majority of worldwide infections and these viruses are further subdivided into nine different clades A-D, F-H, J, and K. These subtypes are separated by approximately 25-35% amino acid divergence in the surface glycoprotein Env. In addition, there are also circulating recombinant forms (CRFs) which are mosaics of two or more different viral isolates found in at least three epidemiologically independent individuals [2]. Therefore, the elicitation of an antibody response with broad neutralizing activity against primary isolates of multiple HIV-1 subtypes continues to be a desired characteristic of candidate HIV-1 vaccines. Standardized criteria for measuring the immune responses are critical and are being established. The use of new methodologies and testing requirements will provide a stronger environment for the development of broadly protective HIV-1 vaccines. In order to develop a successful AIDS vaccine depends on strategies to overcome the ability of the virus to evade humoral immunity at both the mucosal and systemic sites. This issue of Current HIV Research focuses on several aspects of our present scientific understanding of HIV neutralization. The structure and epitopes of the envelope glycoprotein are reviewed in association with design vaccine immunogens. Hu and Statamatos [3] provide an overview on Env modifications and their limitations vs. successes in vaccine design, while and Lin and Nara [4] discuss the design of core, functional Env modifications using immune dampening and immune refocusing strategies designed to counter immunodominant, decoy responses generated by the virus. Zwick and Burton provide an elegant review of the stoichiometry, kinetic, and thermodynamic parameters involved in neutralization [12]. Pinter describes the roles of Env variable regions important in HIV-1 neutralization that should be considered in vaccine development [5] and Burke and Barnett [13] provide a comparative overview of the described neutralizing epitopes in Env. The HIV-1 envelope is able to assume a variety of structures during binding to various cell receptors during the fusion and entry process, thereby exposing new epitopes to the immune system. DeVico describes the accessibility, antigenicity and immunogenicity of CD4-induced epitopes as possible vaccine immuongens [7]. Two reviews tackle the important issues regarding the diversity of the HIV-1 envelope. McKnight and Aasa-Chapman [6] describe the advantages of clade-specific versus clade-generic vaccines while Gao et al. [8] provide an overview of the use of centralized Env sequences to develop immunogens to elicit broadly reactive antibodies that neutralize isolates from all clades. Two reviews address the critical issue of HIV-1 transmissions across mucosal barriers....