Antiretroviral therapy (ART) is an effective treatment for – and prevention against – HIV infection, significantly reducing mortality, morbidity and HIV incidence [1–4]. Despite this, ART alone is not a cure; treatment is lifelong and challenged by the risk of drug toxicities, drug resistance and healthcare constraints [1–4]. As a result, there is a strong commitment from researchers, policy makers and people living with HIV to explore novel approaches for ART-free remission.
HIV-specific neutralizing antibodies occur naturally in around 10–30% of chronically infected untreated individuals, usually years after infection [5–11]. More recently, new laboratory techniques, such as single B cell cloning have facilitated the development of broadly neutralizing antibodies (bNAbs) as therapies to be used for HIV prevention and treatment [12▪]. An exact definition of what classifies an antibody as ‘broadly neutralizing’ is still to be established; however, key general features include being effective against most circulating strains and subtypes and with capacity to neutralize the more resistant ‘tier 2’ and ‘tier 3’ viruses [13,14]. First generation bNAbs were discovered in the early 1990s, where the application of phage display led to the identification and isolation of monoclonal antibodies (mAbs) from humans. This enabled an understanding of the HIV envelope protein structure and conformational epitopes bound by these mAbs . The potency and breadth of these early mAbs were less than ideal, and early neutralizing antibodies only achieved moderate viral suppression with rapid emergence of escape mutants in almost all individuals in clinical trials [16–19]. However, improvements in single cell antibody cloning techniques paved the way for isolation and characterization of newer generation bNAbs with a much higher breadth and neutralization activity . Currently, numerous in-human clinical trials are underway to assess the safety, efficacy and immunogenicity of these bNAbs against HIV infection .
PROPOSED MECHANISMS OF ACTION OF BROADLY NEUTRALIZING ANTIBODIES
Antigen-specific antibodies generated by B-cell clones form a key part of the adaptive immune response, with two key functional components: the antigen binding fragment (Fab) and the crystallizable fragment (Fc). The Fab region is primarily responsible for virus neutralization following binding to a specific antigen – usually a conserved epitope on the HIV-1 envelope protein – thereby preventing virus from attaching to or penetrating the target cell membrane . The Fc region has multiple potential functions, predominantly interacting with other components of the immune system, and serving to complement neutralization [23–25]. bNAbs can opsonize viruses or viral antigens on infected cells via their Fc domains, which enables their recognition by complement and Fc gamma receptors (FcyRs) expressed on innate immune cells, such as natural killer cells (NK) . These FcyRs recognize opsonized viruses and can eliminate infected cells via complement, antibody-dependent cellular phagocytosis (ADCP) and antibody-dependent cellular cytotoxicity (ADCC) [27–33] (Fig. 1).
In addition to complement-mediated pathways, the binding of bNAbs directly to viral antigen expressed on HIV-infected cells results in the formation of immune complexes . These are recognized by FcyR expressed on antigen-presenting cells, such as dendritic cells, which enhances antigen uptake and presentation, and may result in the elicitation of stronger, higher magnitude HIV-specific CD8+ T-cell responses with greater cytotoxic activity . It has been proposed that by harnessing multiple immune-mediated mechanisms, bNAbs can directly clear cell-free virions from the blood and stimulate other components of the antiviral immune responses, the so-called ‘vaccinal effect’ [35–37].
The role of FcyRs in the clearance of HIV-infected cells was demonstrated by Lu et al. in humanized murine models [38,39]. In murine-HIV+ humanized mice that were treated with the bNAbs 3BNC117 and 10-1074, there was a reduction in HIV-1-infected cells compared with animals treated with isotype control antibodies. Furthermore, mice treated with both bNAbs and an FcyR monoclonal antibody had similar levels of HIV-1 infected cells compared with isotype-treated mice, demonstrating that FcyRs are essential for clearance of infected cells during bNAb therapy [38,39]. In addition, the bNab VRC01 was tested in phase I clinical trials in HIV-negative participants to check for immunologic activity. Postinfusion sera exhibited potent neutralizing activity 1 h after infusion; this neutralizing activity was also retained up to 8 weeks postinfusion and trough serum levels were at concentrations sufficient to neutralize a majority of HIV-1 clade B and C strains. Moreover, individuals displayed antibody-dependent cellular phagocytosis and the ability to engage monocyte effector cells . The significance of the Fc region in bNAbs has also been reported in spontaneous HIV controllers who demonstrated enrichment for polyfunctional antibodies in the absence of ART, and an enhanced capacity to drive ADCC , although whether this was the mechanism of viral control is unclear.
Extension of the in-vivo bNAb half-life has been achieved through modification of two amino acids (M428L and N434S) in the Fc region to produce the ‘LS’ variants . These engineered Fc regions have an increased binding affinity to neonatal Fc receptors (FcRn), which have been shown in numerous nonhuman primate (NHP) models and human studies to extend the half-life of serum antibody levels [38,43–45]. Recent clinical trials have shown that the enhanced FcRn binding did not impair Fc-mediated effector functions, such as ADCC [46,47]. In addition, intravenous administration of bNAbs has been reported to distribute systematically, except for crossing the blood–brain barrier where low permeability restricts bNAb transfer into the central nervous system (CNS) . This may be a future cause of concern as data suggests that the CNS may harbour more HIV-1 variants that are resistant to bNAbs than those in the peripheral blood .
The bNAb subclass maybe important to consider when designing novel therapies. Most bNAbs in HIV-1 clinical trials are of the IgG1 isotype; however, studies have reported the potential use of IgG3 instead of IgG1 to dimerize FcyRs and increase their flexibility . Although IgG1 responses have been found to be excellent predictors of neutralization breadth in chronic HIV infection , IgG3 has been shown to have strong effector functions. Reducing serum IgG3 concentrations has been linked to faster disease progression in HIV . Gp120 and Gp140-specific IgG3 antibodies have also been shown to correlate with vaccine efficacy and contributes to disease control in spontaneous controllers of HIV-1 [51,52]. IgG3, however, has a short half-life, which limits its current therapeutic efficiency . Ultimately, these findings provide evidence that the bNab isotype plays an important role in determining and affecting Fc effector functions .
BROADLY NEUTRALIZING ANTIBODIES AS THERAPIES IN HIV INFECTION
Current bNAbs target multiple epitopes on the HIV envelope protein. These relatively conserved and accessible regions become transiently exposed during cell attachment and viral entry, allowing bNAbs to bind to these regions . Some bNAbs target epitopes in the V3 loop (10-1074) whereas others are directed against the highly conserved CD4+-binding site (VRC01 and 3BNC117) . Additional antibodies targeting other epitopes, such as the V1/V2 loop and the membrane proximal external region (MPER) have also entered clinical trials, and recent studies have also evaluated the use of bi-specific and tri-specific antibodies [24,55]. Gp120-Gp41 interface bNAbs have also been described, although these have not yet entered clinical trials . The main targeted epitopes are illustrated in Fig. 2.
In studies administering intravenous bNAbs 3BNC117 and 10-1074 in viraemic individuals not on ART, individuals with antibody sensitive viruses as defined by viral sequencing significantly reduced HIV-1 viral loads for up to 3 months following infusion . Furthermore, combination bNab therapy with 3BNC117 and 10-1074 in participants with preinfusion bNAb sensitive viruses effectively restricted viral escape without development of de novo resistance to either antibody . Another study looking at 3BNC117 monotherapy in viraemic individuals also showed that a single infusion of 3BNC117 reduced viral load with subsequent viral suppression for 28 days . Transient viraemic control has also been observed in other studies using VRC01 and PGT121, although suppression was less durable [44,57]. However, it is worth noting that while combination bNAb therapy was effective in achieving viraemic suppression, full viral suppression of less than 20 copies/ml was only seen in one participant with low prebNab HIV RNA levels (730 copies/ml) [43,58].
In individuals interrupting ART after being treated in chronic HIV infection, 3BNC117 delayed viral rebound by up to 19 weeks, compared with an average of 2.6 weeks for historical ART-only treated controls . Among the nine HIV+ participants interrupting therapy with antibody-sensitive HIV viruses, the combination of bNabs 3BNC117 and 10-1074 maintained viral suppression for between 15 and more than 30 weeks, . Overall, these findings show that combination bNab therapy is more effective in achieving viral suppression than monotherapy, and that factors, such as antibody sensitivity, the maintenance of therapeutic levels and the optimization of epitope targets can affect the therapeutic efficacy of bNAbs against HIV-1 infection . Multiple combined bNAb trials are ongoing including the RIO trial; a blinded placebo-controlled RCT amongst participants treated since acute HIV infection with nonbNAb-resistant HIV envelope sequences.
HIV-1 ENVELOPE BROADLY NEUTRALIZING ANTIBODY SENSITIVITY
One crucial aspect determining the effectiveness of bNAbs is their neutralization breadth . Having a high neutralization breadth in bNAbs is important for viral control as it allows them to target a diverse range of genetically distinct variants of HIV-1, and preferably induce viral escape mutations associated with a high fitness cost . The neutralization sensitivity profiles of different bNAb classes – based on their binding site on the envelope protein – vary slightly, which is possibly because of amino acid mutations or potential N-linked glycosylation sites on or around bNAb contact residues . For instance, V3 glycan binding bNAbs are highly potent against some clade B and C viruses but poorly neutralize CRF 01_AE strains, whereas some bNAbs, such as CD4bs and MPER have a high neutralization breadth against highly conserved epitopes but at a slightly lower potency . The clinical significance of antibody sensitivity is difficult to confirm, and which assay best predicts true sensitivity remains uncertain . A recent study demonstrated that when 3BNC117 was administered to HIV+ participants at 24 and 12 weeks and 2 days before ATI and 3 weeks after ATI, without preselection for 3BNC117 sensitivity, the time to rebound was strongly influenced by the neutralization sensitivity of the pretreatment viruses as measured by TZM.bl neutralization assays (3.6 vs. 9.2 weeks in those with resistant vs. sensitive viruses, respectively) .
THE VACCINAL HYPOTHESIS
That bNAb–HIV-envelope immune complexes might enhance innate or HIV-specific T- cell immunity by stimulating antigen processing, presentation and immune cell proliferation has been recently proposed as the ‘vaccinal effect’ (Fig. 3). In line with evidence that sustained undetectable viraemia in ‘elite controllers’ is sustained by T-cell immunity  and that postbNAb viral suppression in rhesus macaques can be transiently reversed with anti-CD8 monoclonals , the vaccinal effect may confer long-term viral remission but this remains unproven as yet in humans and hence controversial.
EVIDENCE TO SUPPORT A ‘VACCINAL EFFECT’ OF MONOCLONAL ANTIBODIES
Studies of retroviral infection in humanized mice demonstrated that the formation of immune complexes between mAbs and infected cells was a potent driver of the Fc-dependent immune response by dendritic cells. These studies suggest that mAb-based immunotherapy strategies should consider more than simply blunting viral propagation  as recognition of immune complexes by dendritic cells leads to stronger antigen-specific cytotoxic T-lymphocyte immunity . The role of immune complexes in stimulating antiviral responses, however, seems to depend on multiple parameters. Firstly, the IgG isotype of the bNab that binds to the HIV immune complex has been shown to affect effector functions. In a recent study, the IgG3 version of 15 tested bNabs showed similar or increased neutralization potencies compared with the IgG1 isotype, as well as significantly improved binding to FcyRIIa, which correlated with phagocytosis of trimeric Env antigens . Further studies should focus on whether these antibody-mediated immune mechanisms also apply to other HIV-1 bNab-based immunotherapies ; early evidence shows that the bNAbs 3BNC117 and 10-1074, when given during treatment interruption, induce an increase in Gag-specific, polyfunctional T cell responses [71▪] which lends support to this argument.
The most convincing evidence to date comes from SHIV-infected rhesus macaques studies, which have demonstrated the ability of bNAbs to enhance HIV-specific T-cell responses . For example, cocktails of the HIV-1-specific monoclonal antibodies PGT121, 3BNC117 and b12, given to rhesus macaques with chronic SHIV infection were able to reduce viraemia to undetectable levels, increase host virus-specific neutralizing antibody activity. More importantly, monoclonal antibody administration improved the functionality of host Gag-specific T lymphocyte responses, and these responses had an increased functional capacity to suppress viral replication as measured by CD8 T-lymphocyte-dependent virus suppression assays . Macaques infected with different strains of SHIV (chimeric viruses that combine simian immune deficiency virus with HIV-1 Env, making them susceptible to neutralization by anti-HIV-1 antibodies [73–75]), were treated with mAbs or polyclonal immunoglobulins, and displayed enhanced SHIV-specific antibody responses with potent neutralizing activity [33,76–78].
In another study, SHIV-infected monkeys that were given a single 2-week course of bNAbs 3BNC117 and 10-1074 alone were associated with very low levels of persistent HIV viraemia and maintenance of CD4 cell counts. In contrast, untreated SHIV-infected monkeys that only received 15 weeks of ART experienced sustained viral rebound when treatment was interrupted. More importantly, the bNAb-treated monkeys had lower frequencies of reservoir cells harbouring replication-competent virus. However, when the bNAb-treated monkeys received a T-cell-depleting monoclonal antibody, there was a specific decline in CD8 T-cell levels and a rapid reappearance of plasma viremia, suggesting that CD8 T cells were mediating the sustained viral suppression . In an extension of this study, six of the controller macaques that received combination bNAb immunotherapy were able to maintain long-term viral remission for up to 4 years postinfection, with evidence of induction of CD8 T-cell immunity [79▪]. The effect of bNAbs on the latent viral reservoir has also been observed in other studies involving passive antibody administration in animals infected with SHIVSF162.P3 while remaining virally suppressed on ART . The animals were treated with ART 7 days after infection and were subsequently given a course of combination PGT121 and a toll-like receptor 7 agonist (TLR-7) beginning 2 years after infection. Combining bNAb administration with innate immune stimulation delayed viral rebound following the discontinuation of ART, and activation of CD4+ T and NK cells by TLR-7 therapy correlated with this delayed viral rebound. In contrast to Nishimura et al., bNab administration did not result in a ‘vaccinal’ effect of increased autologous antigen-specific CD8 T-cell responses. However, the amount of SHIVSF162.P3 DNA in these animals was more than three orders less than that seen in human HIV-1 infection, which may account for the observed attenuated T-cell responses, which have not been similarly observed in humans . The TITAN trial in humans, has currently completed recruitment and tests the impact of dual bNAbs 10-1074 and 3BNC-117LS with or without TLR-9 agonist on measures of the HIV reservoir and post-ART viral control, and results are awaited [80▪].
The potential vaccinal effect in humans of bNAbs on the adaptive immune response has been reported by some studies and is being investigated by numerous clinical trials . More importantly, evidence also shows that 3BNC117 and 10-1074 can enhance T-cell immunity by increasing the frequency and polyfunctionality of Gag-specific T cells in HIV-infected, bNAb-treated individuals during treatment interruption [71▪]. The increased T-cell responses associated with bNab treatment have been observed in previous clinical trials [23,36,81,82]; however, these increased HIV-specific T-cell responses occurred during plasma viral rebound with increased viral replication. Arguably, it is uncertain whether this enhanced T-cell immunity is because of a possible vaccinal effect or because of low-grade viral replication that exceeds assay detection limits. Also, it is unclear without CD8 depletion, whether these antibody-enhanced T-cell responses correlate with prolonged control of viral replication in the absence of ART. Although polyfunctional HIV-specific CD8 T cells have been associated in previous studies with better viral control, further studies of a higher statistical power should be performed to tease out ‘cause’ versus ‘effect’ here. Furthermore, clinical data is currently limited to phase I and II trials. Future data from larger trials will allow us to better understand their potential clinical role in treating HIV infection.
THE EFFECTS OF BROADLY NEUTRALIZING ANTIBODIES ON THE LATENT RESERVOIR AND HIV REMISSION
The concept that bNAbs may be able to limit or eliminate the latent HIV reservoir in humans is currently unproven but is of high clinical importance. Targeting the intact portion of the latent viral reservoir is crucial to achieve a HIV cure as this contains the replication-competent proviruses that can contribute to viral replication and rebound . As such, specifically quantifying this intact reservoir is important for assessing the impact of HIV cure interventions. Several assays aim to achieve this, with varying limitations. Quantitative viral outgrowth assays (QVOA), for example, directly measure replication-competent virus using reporter cells that are infected by reactivated viruses in culture; however, they have limited scalability with slow turnaround times, and may underestimate the true reservoir size . The intact proviral DNA (IPDA) assay relies on sequence conservation within two regions of the provirus to infer replication competence and is capable of separately quantifying intact and defective proviruses via use of droplet digital PCR ; this provides a more useful estimate of the replication competent reservoir. The Q4PCR assay extends the IPDA further by targeting four proviral regions and including viral sequence analysis .
Some studies have suggested that bNAbs can reduce proviral SHIV DNA and cell-associated HIV DNA in animal models, although more data are needed [72,87]. HIV-specific bNAbs may contribute to the elimination of HIV reservoirs by binding to reactivated HIV-infected cells and targeting them for antibody-dependent cell-mediated cytotoxicity (ADCC). Studies in both humanized mice and rhesus macaques have shown that bNAbs are able to block viral entry into cells and achieve reductions in cell-associated viral DNA in peripheral blood mononuclear cells (PBMCs) and tissues [72,87–91]. bNAbs have also been found to significantly reduce cell-associated SHIV DNA in the gut and lymph node tissues of SHIV-infected macaques . These findings have also been confirmed by other adoptive transfer experiments, where bNAbs given to humanized mice shortened the half-life and accelerated the clearance of HIV-infected cells in vivo, predominantly via Fc-mediated mechanisms . Trials with VRC01 or 3BNC117 given with ART did not impact the size or composition of the HIV reservoir as measured using quantitative and qualitative viral outgrowth assay (Q2VOA) at entry and after 6 months of therapy [57,65]. Recent data (in press reference to follow once available) has demonstrated a significant impact in human studies on measures of IPDA in peripheral blood samples from individuals who interrupt ART following treatment with bNAbs 3BNC-117 and 10-1074. Combination treatment with bNAbs 3BNC117 and 10-1074 in individuals with antibody-sensitive viral reservoirs had lower frequencies of HIV-infected cells after 12 weeks as measured via quantitative and qualitative viral outgrowth assays . Interestingly, Scheid et al. previously showed that in antibody-sensitive, ART-treated individuals who underwent treatment interruption, 3BNC117 restricted the outgrowth of viral genotypes from the reservoir, and emerging viruses in almost all individuals showed no apparent resistance to 3BNC117, suggesting that pretherapy bNAb sensitivity may impact outcomes.
Early clinical trial data using combination HIV-specific bNAbs in virally suppressed ART treated PLWH who stop ART, demonstrate significant extension of post-ART viral control compared with placebo or ART-alone controls. The mechanism of posttreatment viral control may be two-fold: an initial antiviral effect combined with an immunomodulatory, or ‘vaccinal’, effect. In the latter, bNAbs have been shown to increase the magnitude and breadth of HIV-specific T-cell responses, NK T-cell function, immune complex formation, ADCC and ADCP. Further elucidation of the immune mechanisms abrogating viral rebound in patients stopping ART after receiving bNAb therapy is warranted. Overall, the success of bNAbs in eliminating the latent HIV reservoir may depend on numerous factors, including a comprehensive analysis of bNAb susceptibility, the prevalence of bNAb-resistant viruses, co-administration of bNAbs with ART to reduce viral burden and the role of Fc-dependent ‘vaccinal’ enhanced HIV-specific immunity.
Financial support and sponsorship
This article is a discussion document, and therefore, represents the views of the co-authors. JF. and S.F. acknowledge funding from Oxford and Imperial College NIHR BRC, respectively, which support their salaries through their university. We also acknowledge funding from the Bill and Melinda Gates Foundation (funder reference number OPP1210792).
Conflicts of interest
There are no conflicts of interest.
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