Date Published: September 12, 2017
Publisher: BioMed Central
Author(s): Yousuf Ahmed, Meijuan Tian, Yong Gao.
The extreme HIV diversity posts a great challenge on development of an effective anti-HIV vaccine. To solve this problem, it is crucial to discover an appropriate immunogens and strategies that are able to prevent the transmission of the diverse viruses that are circulating in the world. Even though there have been a number of broadly neutralizing anti-HIV antibodies (bNAbs) been discovered in recent years, induction of such antibodies to date has only been observed in HIV-1 infection. Here, in this mini review, we review the progress in development of HIV vaccine in eliciting broad immune response, especially production of bNAbs, discuss possible strategies, such as polyvalent sequential vaccination, that facilitates B cell maturation leading to bNAb response.
According to the WHO, there were ~36.7 million people worldwide living with HIV/AIDS by the end of 2015 and 2.1 million new HIV infections in 2015. In Canada, there were estimated 75,500 people living with HIV infection or AIDS at the end of 2014, a 9.7% increase from 2011, with more than 2500 people are newly infected each year. Unfortunately, even after over 30 years of intensive research, there is still no effective anti-HIV vaccine. This mini review will focus on the development of anti-HIV vaccine targeting elicitation of broadly neutralizing antibodies (bNAbs) against extremely diverse HIV strains.
The extreme genetic diversity of HIV, as a result of high baseline rates of viral mutation and replication, has been a great challenge for HIV vaccine development [1, 2]. There are two types of HIV: HIV-1, predominant throughout the world, and HIV-2, found primarily in West/Central Africa. HIV-1 contains four groups: M (main), O (outlier), N (non-M/non-O), and P (pending). Group M is further subdivided into 9 distinct subtypes  and numerous additional circulating recombinant forms (CRF) . Viruses within the same subtype differ by up to 20%, within the highly variable env region by up to 38%. Furthermore, the virus continuously diversifies in infected individuals, resulting in the virus quasispecies varying up to 5% genetic difference in the same patient at different time points. These quasispecies compose of a unique and highly complex mixture of variants in infected individuals, and ultimately give rise to a highly diverse global virus population.
It is widely thought that an effective strategy to prevent HIV infection will likely come from T cell and B-cell mediated immunity, especially a broadly neutralizing antibody (bNAb) response against the Envelope (Env) protein. The power of bNAbs comes from their ability to recognize epitopes from a variety of viruses, i.e. tackling the extreme viral diversity, and their ability to protect in vivo at low plasma levels . A safe vaccine eliciting bNAbs against HIV could be used to attenuate its spread.
Anti-HIV bNAbs were discovered in the early 1990s when researchers found antibodies capable of neutralizing different virus subtypes . Characterization of these responses has shown the bNAbs target sites include the conserved regions near the CD4 binding site (CD4bs) , the membrane-proximal external region (MPER) , and the base of the V3 and V1/V2 loops  of which some bNAbs are glycan-dependent [16–18]. Despite the early discovery of broadly neutralizing anti-HIV antibodies (bNAbs), including 447-52D (V3 loop), b12 (CD4 binding site), 17b (co-receptor binding site), 2G12 (viral glycan), 4E10 and 2F5 (gp41 MPER), enthusiasm for an Ab-based vaccine was limited based on the unusual characteristics of these bNAbs: 2G12 has three antigen combining sites, instead of the usual two ; 2F5 and 4E10 are self-reactive [20, 21]; and b12 is a phage-derived Ab generated by random pairing of heavy and light chains that may have never existed in nature . However, recent development of single-cell antibody cloning techniques applied to plasma B cells of HIV infected patients uncovered variety of new bNAbs (Table 1), and detailed analyses of these antibodies indicated they are approximately 10- to 100-fold more potent and have an increased breadth compared with the original 4 isolates [23, 24]. To date, there have been a few clinical trials with anti-HIV bNAbs that are successful in reducing viral loads, most notably with 3BNC117 (a CD4bs-specific antibody) currently in phase 2 clinical trials [3–5]. Other studies also showed that passive infusion of NAbs could effectively protect macaques from vaginal SHIV challenge [25, 26]. These results suggest a role of Abs in HIV protection and control, but HIV has a tendency to accumulate mutations, making it a difficult target in vaccination strategies. Epitope mapping of the new, potent antibodies has invigorated the vaccine field by providing precise regions to target when designing new protein or subunit vaccine antigens to induce bNAbs . However, even with this new wealth of information at hand, generating bNAbs with improved, redesigned antigens still prove to be problematic, and there are no appropriate immunogens/vaccination strategies that have been discovered to elicit an effectively protective Ab response.Table 1Characteristics of anti-HIV bNAbsEnv siteAntibody designationNeutralization breadth, %Neutralization potency, μg/mlLength of CDR H3, a.a.Somatic mutations %Year of generationCD4bsb12a35–752.821817.31991HJ16368.012136.72010VRC0188–930.091438.82010VRC0290–910.131434.92010VRC0351–590.081634.92010PGV0477–880.141638.22011CH3184–910.021531.92011CH33900.241531.92011NIH45-4684–860.08184420113BNC11786–920.061236.9201112A1292–960.0715342011VRC2365–800.582013V1/V2 loopPG977–830.083015.42009PG1673–790.023016.82009PG145780.293322.82011CH01463.752423.32011V1/V2 loop2G12a28–391.451633.61994PGT121700.032621.22011PGT128720.022127.92011CD4i/V33BC1766412.81929.42012gp41 MPER2F5a55–671.442415.219924E10a85–1001.622015.61994Z1335401921200110E898–990.252222.12012gp120/gp41PGT151-15564–660.008–0.012282014InterfaceInterface670.8792011aFirst generation of bNAb
It has been reported that, during chronic infection, potent and cross-reactive bNAbs that are capable of neutralizing heterologous viruses of diverse subtypes develop in a small portion of HIV-1 infected individuals [28–31]. The effective humoral responses are slow, with NAbs to the initial viral strain appearing after ~12 weeks, and broad NAbs (in 10–30% of individuals) after 2–4 years [30, 32–34]. The development of bNAbs was shown to correlate with high plasma viremia and could result from evolving antigen exposure over many years that has allowed sufficient somatic hypermutation in the B-cell receptors (BCRs) and focuses the B-cell response to the conserved neutralization sites on Env . Therefore, delayed bNAb response might be attributed to the slow, antigen-dependent affinity maturation process. Abs typically accumulate mutations in the complementarity determining region (CDR) loops, i.e. the typical antigen contact region . Whereas most human Abs that have undergone affinity maturation carry 15–20 somatic mutations, potent anti-HIV bNAbs carry 40–110 mutations. Reversion of these mutations to the germline sequence drastically reduces their neutralizing potency and breadth [36–40]. These findings suggest that bNAb-producing B cells are the products of clonal evolution which coined the term “B cell maturation”. Thus, selecting the right combination of immunogens and vaccination strategy is crucial for induction of these bNAb-producing B cells via continual increase in affinity-driven selection in the germinal centers (GCs).
A major obstacle for HIV vaccine development is the extreme virus diversity. Although a number of bNAbs have been isolated from HIV patients, the vaccine and procedures capable to elicit such a response remain a mystery. The sequential vaccination with multiple immunogen variants might favor B cell re-circulation within GCs for additional rounds of affinity maturation. This may promote the B cell response to focus on the most conserved regions of immunogens through positive selection, resulting in more potent and broader antibody responses.