In spite of 25 years of effort, a vaccine against human immunodeficiency virus type 1 (HIV-1) is not available. However, there are several appropriate vaccine targets that are exposed on the viral surface and play an important role in infection. Infection of the target cell by HIV-1 is mediated by two envelope proteins (Env): surface gp120 and membrane-anchored gp41. Initially, Env is produced as a highly glycosylated gp160 precursor, which is processed by a host protease into the two subunits (96
). These two proteins remain associated by noncovalent interactions and form heterotrimeric spikes on the viral surface (65
); Env is the only viral protein expressed in the viral membrane as well as in the membranes of infected cells. The infection process is initiated when gp120 binds to the primary CD4 receptor on the target cell (52
). This interaction induces conformational changes to gp120 that expose and/or form the coreceptor binding site that is specific for the chemokine receptors CCR5 and CXCR4 (14
). Coreceptor binding triggers several conformational changes in gp41, which leads to the fusion of viral and host membranes, pore formation, and, ultimately, the release of the viral nucleocapsid core into the cell (39
A vaccine that targets Env could potentially block the infection process by eliciting neutralizing (Nt) antibodies (Abs) against HIV-1. However, producing a vaccine that targets an immune response against HIV-1 has been extremely challenging for several reasons. First, HIV-1 mutates easily, thus creating a large number of quasispecies that act as a decoy for the immune response. In addition, the virus evades immune recognition by expressing a small number of viral spikes, shedding gp120, and masking Nt epitopes. The immunogenicity of Env is decreased by the trimeric structure of the spike, which occludes important epitopes, and by surface glycosylation. Moreover, HIV-1 infects T cells, which are critical for orchestrating the immune response to viral infection. Taken together, these viral characteristics complicate approaches to HIV-1-targeting vaccines.
Due to their exposure on the viral surface, both gp120 and gp41 are the targets of Ab-mediated viral neutralization (178
). These proteins are immunogenic, as shown by the large amount of Ab that is produced during the course of natural infection; however, Nt Ab levels are generally low and/or isolate specific (156
). This low level of Nt Ab is perpetuated by the persistent nature of HIV-1 infection since high viral replication and mutation rates lead to the appearance of viral escape mutants against which the immune system responds with new Abs. This constant interplay between the virus and the host immune response results in the inability of the immune system to clear an established infection (192
). Nevertheless, broadly Nt (bNt) Abs are sometimes generated. So far, only six bNt monoclonal Abs (MAbs) have been isolated from HIV-1-infected donors; they are all directed against Env. bNt MAbs b12, 447-52D, and 2G12 bind to gp120 (32
), whereas, 2F5, Z13, and 4E10 recognize the membrane-proximal external region (MPER) of gp41 (162
). These bNt MAbs inhibit infection by multiple genetic HIV-1 clades in vitro and prevent experimental infections in animal models with viruses bearing the envelope proteins from primary HIV-1 isolates (18
The discovery of bNt MAbs and their characterization have introduced the possibility of targeting their production in vivo by active immunization. This has proven difficult due to a number of factors including the structural complexities of the sites targeted by these Abs. For example, MAb b12 is directed against a complex discontinuous epitope that overlaps the CD4 binding site of gp120, whereas 2G12 recognizes the termini of several oligosaccharide chains on the highly glycosylated face of gp120. MAbs 2F5 and 4E10 bind adjacent linear epitopes located on the MPER; however, it is thought that those linear regions do not completely represent their full immunogenic epitopes. In addition to the complexities of their epitopes, bNt MAbs share several uncommon structural features, including a long hypervariable loop comprising the third complementarity-determining region of the heavy chain (CDR-H3) (b12, 2F5, 447-52D, Z13, and 4E10) (38
) as well as VH domain swapping (2G12) (35
). In spite of these complex features, the goal of eliciting bNt Abs continues to be crucial for the development of an HIV-1 vaccine.
Of the six known bNt MAbs, three are directed to the MPER, thus defining this region as major target for vaccine efforts. This review focuses on the MPER as a target for HIV-1 vaccine design and describes (i) the current understanding of the structure and function of gp41 and in particular the MPER, (ii) the structure and function of bNt MAbs against the MPER, (iii) challenges in producing bNt Abs against the MPER, and (iv) potential approaches that could be used to make an MPER-targeting vaccine. It is generally accepted that an efficient anti-HIV-1 vaccine should involve both the cellular and humoral arms of the host immune response; however, our discussion will be limited to approaches that target the production of Nt Abs.