The hydrophobic patches on these antibodies are difficult to maintain because they are often polyreactive, which may lead to clonal deletion [100]. One of the challenges facing structure-based design is how to elicit antibodies with the high degree of somatic mutation found in the bNAbs that guide rational design. HIV-1 vaccines. Immunologic basis for preventive HIV-1 vaccines The rationale for antibody vaccines Effective HIV-1 vaccines will likely elicit both humoral and cellular immune responses (Fig. 1) [20,21]. Several observations have provided the rationale for pursuing antibody-based vaccination. Antibodies that can bind to the HIV-1 Env and prevent virus Enecadin entry would Enecadin provide the best chance for sterilizing protective immunity because the virus would not be able to enter target cells. Passive transfer of neutralizing antibodies into nonhuman primates (NHP) suggests that potent neutralizing antibodies are sufficient to protect against chimeric SIV/HIV (SHIV) contamination [22,23], providing a proof of concept for sterilizing immunity. Also, antibodies could potentially inhibit HIV-1 through Fc-mediated effector functions such as antibody-dependent cellular cytotoxicity and antibody-dependent cellular virus inhibition (Fig. 1). However, the contribution of these responses to protection is still unclear [21]. Open in a separate window Fig. 1. Immune mechanisms of HIV-1 inhibition.(a) Antibody neutralization of Enecadin HIV-1. Antibodies (light red) directed against the HIV-1 envelope (Env) trimer (blue and brown) prevent contamination by blocking HIV-1 entry into target cells. (b) Antibody-dependent cellular cytotoxicity (ADCC) is usually mediated by antibodies that recognize envelope on the surface of infected cells. The Fc portion of these antibodies engages Fc receptors on certain innate immune cells such as natural killer (NK) cells. The engagement of activating Fc receptors on NK cells leads to secretion of granzymes and perforin, which causes the death of infected cells [20]. (c) Antibody-dependent HSF cellular virus inhibition includes both ADCC and other Fc-mediated modes of viral inhibition. For example, Fc receptor binding to antibody attached to Env around the virion surface can mediate phagocytosis of the virus (top left of panel). Additionally, activated NK cells can secrete effector molecules, such as beta-chemokines, that interfere with viral entry of new target cells (bottom left of panel) [20]. (d) The CD8+ T-cell antiviral response is usually mediated by major histocompatibility complex class I (MHC-1) proteins that present short processed viral peptides on the surface of HIV-infected cells. CD8+ T cells are activated upon recognition of MHC-1-peptide complexes and begin to produce granzymes and perforin that kill the infected cell. Also, other antiviral cytokines are secreted Enecadin from CD8+ T cells that inhibit replication of HIV-1. Adapted from [21]. bNAbs emerge late in natural contamination in 10C30% of HIV-infected individuals [24,25,26,27]. Antibody-based vaccines aim to elicit these types of bNAbs. A variety of vaccines have been utilized to elicit such responses, including [28,29] (Fig. 2). Nef-deleted lentiviruses were among the first experimental vaccines to confer protection against simian immunodeficiency virus contamination in rhesus macaques [30]; however, the high mutation rate of retroviruses [28] can lead to reversion of the vaccine strain to a pathogenic virus [31]. This possibility raises a serious safety concern for this class of vaccines in humans. Virus-like lentiviral particles (VLPs) represent a safer alternative to live-attenuated virus vaccines because these particles lack a viral genome [28]. Although VLPs have proven to be immunogenic, antibody responses seem to be directed to nonfunctional Env variants on the surface of the VLP [32]. The low density of viral spike around the virus surface is suboptimal.