In search of an HIV vaccination: failures, successes, and innovations in eliciting humoral and cellular immunity against HIV

Forty years ago, the human immunodeficiency virus (HIV) pandemic began. It has since claimed the lives of at least 39 million people. In this time, incredible progress has been made in the prevention, diagnosis, and treatment of HIV. However, an effective, economically viable vaccination remains elusive. Most viral vaccinations prompt the creation of neutralising antibodies, which bind surface antigens and prevent the infection of host cells. In the case of HIV-1, there exists only one envelope protein – the trimeric envelope spike. This spike consists of three gp120-gp41 heterodimers. Together, gp120 and gp41 are responsible for attachment and entry into CD4+ T-cells and macrophages. Unfortunately, the trimeric spike is not an ideal target. Neutralisation-sensitive epitopes are recessed and surrounded by host glycans, against which the host will not produce antibodies. The env sequence is highly variable between HIV strains, and undergoes extremely high rates of mutation. Researchers would ideally like to prompt the creation of broadly neutralising antibodies (bNAbs), which bind to, and neutralise, epitopes from different HIV strains. However, an immunogen that stimulates bNAb production to a significant degree has not yet been discovered. Many human trials have explored potential immunogens. For instance, recombinant gp120 with alum adjuvant, HIV-1 gag/pol/nef expressed by an adenovirus vector, and HIV-1 gp120-gp41 expressed by a canarypox vector have all been tested in at-risk populations. Only one – the RV144 vaccination – has been modestly successful in preventing infection. Recently, innovations in the HIV-1 vaccination field have shown great promise. Researchers are attempting to target germline B-cells, which are capable of somatic hypermutation in order to keep pace with the rapid rate of mutation of HIV. They are synthesising ever-improving immunogens that closely resemble the quaternary structure of the envelope protein, exploring the possibility of passive immunisation, and probing the field of gene therapy, in which a viral vector delivers DNA to be incorporated into host cell genomes. All in all, it would seem that a safe and effective HIV vaccination is a challenging yet attainable goal – one that would prevent countless HIV infections worldwide and save the lives of millions.