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. Author manuscript; available in PMC: 2021 Sep 1.
Published in final edited form as: Curr Opin HIV AIDS. 2020 Sep;15(5):282–289. doi: 10.1097/COH.0000000000000638

Recent insights into Fc-mediated effector responses to HIV-1

Margaret C Carpenter 1, Margaret E Ackerman 1,2
PMCID: PMC7732205  NIHMSID: NIHMS1651343  PMID: 32675573

Abstract

Purpose of Review:

Recent work defining Fc-mediated effector functions for both viral control and protection against infection is summarized and considered along with new strategies to drive robust Fc-mediated responses.

Recent findings:

In new human and nonhuman primate vaccine trials as well as studies of natural infection, Fc-mediated effector responses have sometimes been observed to correlate with decreased risk of infection or with better clinical outcomes, suggesting a potential role for these responses in HIV-1 prevention and therapy. Recent highlights include use of ADCC-sensitizing CD4i mimetic compounds, novel V1V2 immunogens, passive transfer studies, and vaccine regimens that successfully elicited Fc-mediated responses and were reported to decrease risk of infection in challenge studies in NHPs. Lastly, detailed studies of IgG3 forms of HIV-specific antibodies have reported that both neutralizing and Fc-mediated responses can be increased relative to the more prevalent IgG1 subclass.

Summary:

Successful harmonization of neutralizing and Fc-mediated responses may make key contributions to the goal of reducing HIV-1 infection via active and passive vaccination. New studies continue to highlight the importance of Fc-mediated antibody responses as correlates of decreased risk of infection and suggest enhanced phagocytosis is a potential mechanism of reduced risk of infection associated with human IgG3 responses. Results from recent studies may help guide the rational design of therapies and vaccines that aim to specifically leverage antibody effector function.

Keywords: Fc-mediated responses, Antibody dependent cellular cytotoxicity (ADCC), immunogens

Introduction

Recent HIV research continues to define the role of Fc-mediated antibody function in both protection and control of HIV infection. Effective antibody-based interventions against HIV-1 will likely involve both neutralizing antibody (nAbs) responses, which prevent viral entry into cells, and innate immune responses, which can clear viral particles or infected cells mediated through the Fc region of antibodies [1]. The Fc-mediated component of the immune response to vaccination or infection can occur through numerous mechanisms including antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular virus inhibition (ADCVI), antibody-dependent cellular phagocytosis mediated by monocytes (ADCP), neutrophils (ADNP), or other lymphocytes, as well as by antibody-dependent complement-mediated lysis.

This review will focus on work from the past two years in which Fc-mediated effector responses have been found to correlate with and contribute to protection and control of HIV in human vaccine trials, natural infection, and animal models (Figure 1). These studies build upon novel assays [2,3], broadened appreciation of diverse effector cell types and characteristics [4–8], insights into the relevance of gp41 epitopes [9–11], and refinements to understanding of the impact of the conformational state of targeted epitopes and of target cell infection status [12–14]. In the latter portion of the review, we touch on efforts to more effectively recruit Fc-mediated responses with new small molecule CD4 mimetics, by immunogen design efforts, and through antibody Fc modification. Such strategies can elicit robust Fc-mediated responses and may contribute to effective treatments for HIV-1.

Figure 1: Correlates of protection in human and NHP.

Figure 1:

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In recent studies, Fc-Mediated functions have been correlated, along with other biophysical and cellular markers, with protection against HIV-1 infection in humans (black) and NHPs (grey).

Passive Immunity

Recent studies of antibodies targeting viruses other than HIV have increased general appreciation of the role of effector functions in protection from viral infections. For example, two non-neutralizing monoclonal antibodies (mAbs) with phagocytic and NK activating activity that were isolated from a human survivor of Marburg virus mediated FcγR-dependent protection against infection in a mouse model [15]. Similarly, mitigation of clinical indications of infection and clearance of virus were dependent on monocytes and FcγR expression in a study of Chikungunya neutralizing mAbs in mice [16]. Lastly, in vivo antiviral activity of a Hepatitis B Virus neutralizing mAb in a mouse infection model was also found to be dependent on interactions with FcγR [17]. In contrast to these protective roles of effector functions, a study of human Dengue infection risk in infants found that increased maternal afucosylated Fc glycans on anti-Dengue IgGs passively transferred through the placenta were associated with increased risk of symptomatic infection in their infants, attributed to antibody-dependent enhancement (ADE) of infection driven by increased affinity for FcγRIIIa+ human monocytes [18]. Afucosylated antibodies toward other viruses, including SARS-CoV-2, are also beginning to be associated with differences in disease severity (https://doi.org/10.1101/2020.05.18.099507), suggesting the relevance of this Fc glycoform and FcγRIII+ cells to in vivo antibody activity.

The Fc-mediated immune responses studied in the contexts of these diseases provide further general evidence of the importance of antibody Fc effector function in disease progression and also motivation to carefully characterize the mechanistic implications of such interactions. Recent passive immunization studies conducted in the NHP model to monitor the antiviral efficacy of HIV-specific antibodies include comparison of FcγR binding and non-binding forms of the bnAb PGT121. Elimination of binding to FcγR did not reduce protection from challenge, indicating that neutralization was sufficient to protect from infection for this bnAb [19], unlike other bnAbs tested in NHP [20] and unlike PGT121 in studies in a mouse model of infection [21]. In contrast, it was recently reported that polyfunctional cocktails of antibodies restricted infection in an infant NHP model of protection against oral challenge afforded by milk and placentally derived antibodies [22], and that optimal clearance of HIV-1 infected cells in a humanized mouse model mediated by a novel hexavalent glycoengineering bispecific required NK cells [23]. Further, passive transfer of the V2-specific antibody 830A suggested that the human IgG3 subclass may exhibit improved protective capacity relative to IgG1 [24], consistent with its enhanced antiviral activity in vitro and correlates observed in human HIV vaccine efficacy studies, as discussed below. Lastly, in a study of the role of effector function on viral clearance in infected NHP, standard VRC07–523LS exhibited an improved ability to reduce viral loads as compared to a mutated form in which FcγR binding was ablated, suggesting the importance of effector functions to antiviral activities in vivo even in the context of established infection and a potent bnAb [25]. This study also evaluated the antiviral activity of an FcγR-binding enhanced variant, which despite enhanced activity in vitro, paradoxically exhibited reduced antiviral activity in vivo, an effect that was associated with pre-loading of effector cells and alterations in their trafficking and phenotypes, including induction of effector cell necroptosis. In sum, it is becoming clear that across different mAbs, among different individuals, and with different routes of exposure, effector functions are likely to have different degrees of contribution to in vivo anti-HIV activities.

Vaccine Trials

In the moderately effective RV144 HIV-1 vaccine trial, which tested an ALVAC-HIV DNA prime followed by and AIDSVAX B/E protein boost, previously described correlates of reduced risk of infection included antibodies that bound directly to the V1V2 loops of HIV Env, envelope-specific IgG3 responses that correlated with ADCP and ADCC responses, complement depositing antibodies, and responses that generated Fc-mediated ADCC in the presence of low serum IgA [26–29]. RV305 was designed to boost RV144 response by re-immunization with either ALVAC-HIV, AIDSVAX B/E, or both ALVAC-HIV + AIDSVAX B/E in the years after original immunization. In this trial, recalled responses were successfully elevated among RV144 trial participants who received a booster vaccination six to eight years after the original immunization series [30]. Results from a follow-up study, RV306, that followed a similar boosting regimen in weeks or months after original immunization, compared additional boosting immunizations and showed that a shorter interval prior to boosting could also result in elevated humoral responses [31,32].

Unfortunately, the past year also saw the HVTN 702 Uhambo trial terminated for futility (NCT02968849). As in RV144, participants in HVTN 702 were immunized with ALVAC-HIV prime, but boosted with subtype C gp120 protein, meant to adapt the regimen to better target the clade C virus common in southern Africa. The outcome of HVTN 702 raises questions about the robustness of the efficacy signal observed in RV144, the role of potential differences in efficacy based on humoral and cellular immune responses related to customization of immunogens for the prevalent strains, the change of adjuvant, and the biology of the epidemic and population in South Africa. To this end, HVTN 097 (ALVAC-HIV + AIDSVAX B/E) and HVTN 100 (ALVAC-HIV + subtype C gp120) served to investigate the immunogenicity of the RV144 vaccine and the adapted regimen in South Africa, respectively [33,34]. Analysis of these trials may offer some insights into discrepant outcomes observed between the RV144 regimen in the Thai population and the HVTN 702 regimen in the South African population. Further, there is some hope that careful case control analysis of HVTN 702 may nonetheless define correlates of risk.

As an example of insights into protection afforded from trials that fail to meet overall efficacy criteria, recent blinded case control analysis of the HVTN 505 vaccine trial, which tested an HIV-1 DNA prime followed by an recombinant adenovirus type 5 boost designed to target T cell responses, determined that IgG3, ADCP, and Env-specific antibody binding to FcγRIIa correlated with decreased risk of infection [35]. Risk of infection was also observed to be modified by a number of different FcγR polymorphisms [36]. In addition, follow-up analysis of the ineffective VAX003 and VAX004 trials (both AIDSVAX vaccinations) showed that responses against variable loop epitopes and ADCC and ADCP functions were observed to decay after the fifth through seventh immunizations [37], suggesting a potential limit to the utility of boosting and challenges in maintaining a highly functional antibody response. Collectively, though all associative in nature, these findings bolster prior observations in human and NHP studies suggesting the importance of Fc-mediated responses in effective humoral responses, highlight the multiple contributions that effector functions may make to protection, and point to the value of evaluating responses among infected and uninfected vaccine recipients regardless of overall vaccine efficacy. Further, hopes for vaccine-mediated protection in the near term remain based on promising immunogenicity data from the APPROACH trial, in which participants were immunized with a mosaic Ad26 prime and gp140 protein boost. This regimen induced robust Env-binding antibodies with ADCP activity [38].

Natural Infection in Humans Shaped by ADCC

Recent studies of early and chronic natural infection also highlight the importance of Fc-mediated response in HIV-1 infection progression and clinical outcomes. It has long been known that in natural infection, nAb responses develop more slowly than non-neutralizing antibodies against HIV-1 [39]. In recent work, Mielke et al. investigated the interplay of neutralizing responses with ADCC in HIV-1 in early infection [40]. In this study, mapping of ADCC and nAb epitopes of HIV-1 clones isolated from a single infected individual identified a single six amino acid deletion in the V4 region of the Env, which imparted resistance to the nAb response but increased the sensitivity of the virus to ADCC mediated by monoclonal antibodies that recognized the CD4 induced (CD4i) conformation of the Env. Next-generation sequencing of the viral repertoire revealed that despite abrogating nAb recognition, this deletion was strongly selected against, indicating that ADCC provides immune pressure that limits nAb escape pathways [40], as has been observed previously in a mouse model [41].

Another recent study of early infection reported that subjects with peptide-specific ADCC activity early in infection exhibited lower set point viral loads than those without ADCC activity, and that these responses were effective in reducing infectivity of primary virus isolates mediated by autologous NK cells [42]. Early ADCC activity associated with lower plasma viral load years to decades later in infection [43], as well as to subsequent development of bnAb responses [44] in recent work. In a study of ADCC activity raised in the context of HIV-1 and HIV-2 dual infection, broader antiviral activity was observed among subjects with HIV-2 infection, providing a potential explanation for the slower disease progression of HIV-1 observed in dually infected individuals [45]. However, in contrast to these associations with improved outcomes, plasma ADCC activity in transmitting versus non-transmitting mothers was evaluated in two recent studies [46,47]; neither observed an association between ADCC and reduced transmission, and one study reported a direct correlation with increased mortality [47].

Several studies of epidemiologically linked transmission investigated the consistency and the consequences of humoral responses to infection. A study of injection drug users reported some consistencies in antibody neutralizing and FcγR binding profiles that were associated with the sequence of the infecting virus [48]. A 15-year longitudinal study of four epidemiologically linked HIV-1 positive Cameroonian individuals reported higher levels of ADCC against Env in the CD4i conformation, higher IgG/IgA ratios, and strong V1V2 loop antibody binding to correlate with better clinical outcomes [49] consistent with correlates observed in RV144. Additionally, another study reported elevated ADCC and high IgG/IgA ratios in serodiscordant couples as compared to known transmitters or comparable HIV-infected control individuals [50]. In contrast, a recent study of superinfection did not find correlative relationships between plasma IgG and IgA responses to HIV in superinfected and non-superinfected women [51]. Although by no means observed universally, the indication that correlates of viral control in natural infection can match those seen in protection after vaccination provides support for both careful vaccine design to include Fc-mediated responses and continued investigation of Fc-mediated responses to infection and vaccination.

NHP studies reveal the route of immunization may affect Fc-mediated responses

Over the past two years, a number of NHP studies have compared the immunogenicity and efficacy of different vaccine strategies and observed that protection against infection was associated with one or more antibody effector functions. For example, Fc-mediated responses were observed to vary with route of immunization, with mucosal administration of an Ad5 vaccine inducing elevated systemic anti-viral IgA, which was correlated with protection from challenge, and intramuscular administration of the same vaccine inducing FcγRIIa-binding IgG antibodies that also correlated with protection. In both arms, phagocytosis correlated with challenge resistance, but was most strongly associated with neutrophil or monocyte activity for mucosal and systemic administration, respectively [52]. Thus, between different routes of administration, both the subtype of the mediating Abs and the effector cell identity most correlated to degree of protection differed. This study suggests the opportunity to leverage immunization route to design vaccines that elicit distinct immune responses.

In another study, oral immunization with either needle-free injectors or with topical administration of the vaccine to the sublingual and buccal tissues was compared to the traditional intradermal/subcutaneous route of injection [53]. The needle-free immunization conferred protection against SHIV challenge whereas oral topical application of the vaccine did not. This immunization developed mucosal, vaccine-specific IgG and IgA responses, but the IgA response waned prior to challenge. Interestingly, the needle-free mucosal immunization also raised immunological responses similar to systemic immunization, including both increased numbers of CD4 and CD8 T cells and increased V1V2-specific IgGs in the blood. These observations suggest that the needle-free delivery method may be uniquely capable of eliciting protective responses in multiple compartments. Because of the low power of the study, animals that received needle-free and intradermal/subcutaneous immunizations were combined to determine correlates of protection. While the immunizations did not raise neutralizing antibodies against SHIV, serum ADCVI activity, serum SHIV-specific IgG, and Env-specific CD4 T cell responses correlated with delayed SHIV infection, suggesting a role for Fc-mediated antibodies in protection.

Lastly, with the goal of stimulating B cell lineages to result in development of bnAbs, Felber et al. immunized NHPs with a series of six sequentially isolated env and gag DNA + envelope proteins from a subject in which a bnAb response was generated [54]. Protection against tier-2 SHIV challenge was only seen in animals immunized with DNA and protein in the same anatomical site, rather than on separate sides of the body. Protected NHPs in this arm of the study had higher Env-specific Ab titers and more Env-specific CD4+ T cells, and the degree of protection was correlated with ADCC activity at early time points but not with neutralizing responses, suggesting that Fc-mediated antibody responses may have driven protection.

These studies provide further support of additional recent reports relating ADCC, ADCP, V1V2 responses, and complement-binding and activating antibodies with resistance to infection in NHP models [55–58]. In sum, across diverse vaccine routes and regimens, and in animal models and human vaccines, there are a wealth of recent observations relating antibody effector functions with resistance to infection (Figure 1).

Strategies to sensitize virus/infected cells to Fc-mediated effector function

Non-neutralizing antibodies that recognize the CD4-bound or -induced (CD4i), open conformation of the Env trimer are readily generated in infection and vaccination and can elicit effective ADCC against Env in this state [59] in a CD4- and time-dependent manner [60,61]. To better leverage these responses toward reduced risk of infection, NHPs immunized with an HIV-1 gp120 immunogen were challenged with SHIV-C5 that was sensitized by a small molecule CD4 receptor mimetic [62], which induces Env to undergo a conformational change to the CD4-bound state susceptible to ADCC mediated by CD4i-specific Abs. NHPs were protected from SHIV infection by addition of the mimetic and exhibited increased ADCC activity toward mimetic-sensitized SHIV. Structural data paired with ADCC experiments suggest that antibodies against the conserved inner domain cluster A of gp120 or the coreceptor binding site (coRBS) mediate the increased ADCC activity seen with mimetic treatment [63]. In a further study of ADCC mediated by combinations of antibodies against either cluster A or coRBS, it was found that both types of antibodies were necessary for successful killing of HIV-1 infected cells in the presence of the mimetic [64]. This strategy of sensitizing virus to Fc-mediated responses has the potential to increase the efficacy of numerous vaccines that elicit antibody responses to CD4i epitopes.

Three additional studies provided further support for how combinations of antibodies might improve Fc-mediated effector functions. The first showed that ADCC activity was proportional to extent of opsonization, and that opsonization sufficient for ADCC was lower than that required for neutralization [65]. The second demonstrated that combinations of antibodies with different epitope specificities can more effectively elicit ADCC [66]. The final showed the unique contribution of the mAb A32 in contributing to the ADCC activity of combinations of nAbs [67]. Collectively, this body work reinforces prior work on how the varying structural states of Env impact antibody neutralizing and effector functions.

Design of Immunogens to Elicit Fc-mediated Responses

Immunogens have been developed with the goal of eliciting focused and protective immune responses toward HIV-1 antigens. In three recent studies, immunogens were designed to present the V1V2 loops to elicit broad, functional antibody responses. SOSIP trimers [68], stabilized multimeric V1V2 scaffolds [69], and V1V2 sequence engineering to reduce the conformational plasticity of the loops [70] successfully elicited cross-clade reactive antibodies in animal models. In particular, V1V2 loops scaffolded on an Fc fragment induced strong and durable ADCC activity in immunized NHPs [69]. V1V2-specific antibody responses have been observed to exhibit broad ADCC activity in humans [71] and have been robustly induced in rabbits and NHP [72].

In contrast to these immunogens, which were designed with the goal of eliciting both neutralizing and Fc-mediated activity, Visciano et al. designed an immunogen comprised of the inner domain of gp120 in its CD4-bound conformation that was designed to elicit Fc-mediated effector function specifically [73]. This immunogen successfully induced cross-clade ADCC responses. While these immunogens have not yet been tested in viral challenge studies, their differing immunogenicity profiles suggest that they could be useful tools for further defining the contribution of neutralizing versus Fc-mediated responses for protection.

IgG3 subclass modulates effector function

Recent work has also sought to explore the potential mechanistic significance of IgG3 responses given their association with reduced risk of infection in both RV144 and HVTN505 [28,35]. Of the human IgG subclasses, IgG3 is structurally and functionally distinct [74]. In a study of variants of the CAP256 bnAb isolated from an HIV-1 infected donor, IgG3 forms showed a 20-fold increase in neutralizing activity against certain viruses as well as broadly increased Fc-mediated functions including ADCP and antibody-dependent cellular trogocytosis relative to IgG1 [75]. In this and studies of other HIV-specific antibodies, the means whereby IgG3 exhibits enhanced ADCP activity was found to be its extended hinge, which when transferred to IgG1 improved phagocytic activity [76]. Together these studies defined unique anti-viral attributes of IgG3. In humans, both IgG3 responses (HVTN 505 and RV144) and ADCP activity (HVTN 505; not reported for RV144) have correlated with vaccine-mediated protection; in NHPs, who do not have an IgG subclass with an extended hinge [77], ADCP has correlated with challenge resistance [52], collectively providing a correlate of protection across species and diverse vaccine regimens (Figure 1).

Conclusion

Over the past several years, many studies have helped to define the role of Fc-mediated responses in protection conferred by vaccines or in control of viral infection. Eliciting these effector responses seems likely to be essential for most effectively preventing and treating HIV-1 infection by active or passive immunization. Retrospective study of natural infections and vaccine trials has further elucidated the responses associated with protection. Recent work to proactively guide Fc-mediated responses reveals new opportunities for innovative vaccine and treatment regimens. Taken together these new insights will guide HIV prevention and treatment in the future.

Main points.

  • Passive immunity studies for HIV and other diseases suggest different roles for effector functions across Abs and individuals.

  • Fc-mediated responses correlate with and may contribute to resistance to HIV infection in recent human vaccine trials and NHP vaccine studies.

  • Longitudinal studies of natural HIV infection suggest Fc-mediated responses to infection may shape the evolution of HIV virus and improve clinical outcomes.

  • New developments in HIV vaccine design including vaccine delivery method, inclusion of CD4 mimetic compounds, and novel immunogen designs that may leverage Fc-mediated responses for effective HIV treatment.

Acknowledgements

The authors thank Chanc Van Winkle Orzell for copyediting.

Financial support and sponsorship

This work was supported by NIGMS and NIAID R01 AI131975, and NIAID P01 AI120756.

Footnotes

Conflicts of interest

The authors report no conflicts of interest.

References

  • 1.Parsons MS, Chung AW, Kent SJ: Importance of Fc-mediated functions of anti-HIV-1 broadly neutralizing antibodies. Retrovirology 2018, 15:58. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Alrubayyi A, Schuetz A, Lal KG, Jongrakthaitae S, Paolino KM, Ake JA, Robb ML, de Souza MS, Michael NL, Paquin-Proulx D, et al. : A flow cytometry based assay that simultaneously measures cytotoxicity and monocyte mediated antibody dependent effector activity. J Immunol Methods 2018, 462:74–82. [DOI] [PubMed] [Google Scholar]
  • 3.Richardson SI, Crowther C, Mkhize NN, Morris L: Measuring the ability of HIV-specific antibodies to mediate trogocytosis. J Immunol Methods 2018, 463:71–83. [DOI] [PubMed] [Google Scholar]
  • 4.Fisher L, Zinter M, Stanfield-Oakley S, Carpp LN, Edwards RW, Denny T, Moodie Z, Laher F, Bekker LG, McElrath MJ, et al. : Vaccine-Induced Antibodies Mediate Higher Antibody-Dependent Cellular Cytotoxicity After Interleukin-15 Pretreatment of Natural Killer Effector Cells. Front Immunol 2019, 10:2741. [DOI] [PMC free article] [PubMed] [Google Scholar]; *Detection of HIV-1 vaccine-induced ADCC was improved using NK cells treated with IL-15, which mimics cytokine stimulation in natural infection.
  • 5.Lisovsky I, Kant S, Tremblay-McLean A, Isitman G, Kiani Z, Dupuy FP, Gilbert L, Bruneau J, Shoukry NH, Lebouche B, et al. : Differential contribution of education through KIR2DL1, KIR2DL3, and KIR3DL1 to antibody-dependent (AD) NK cell activation and ADCC. J Leukoc Biol 2019, 105:551–563. [DOI] [PMC free article] [PubMed] [Google Scholar]; *Study of the role of inhibitory NK receptors in NK cell education leading to ADCC activity.
  • 6.Worley MJ, Fei K, Lopez-Denman AJ, Kelleher AD, Kent SJ, Chung AW: Neutrophils mediate HIV-specific antibody-dependent phagocytosis and ADCC. J Immunol Methods 2018, 457:41–52. [DOI] [PubMed] [Google Scholar]
  • 7.Naluyima P, Lal KG, Costanzo MC, Kijak GH, Gonzalez VD, Blom K, Eller LA, Creegan M, Hong T, Kim D, et al. : Terminal Effector CD8 T Cells Defined by an IKZF2(+)IL-7R(−) Transcriptional Signature Express FcgammaRIIIA, Expand in HIV Infection, and Mediate Potent HIV-Specific Antibody-Dependent Cellular Cytotoxicity. J Immunol 2019, 203:2210–2221. [DOI] [PMC free article] [PubMed] [Google Scholar]; **In the context of long-term, uncontrolled HIV-1 infection, CD8 T cells functionally diversify by expressing FcγRIIIA and mediating ADCC.
  • 8.Powell RLR, Fox A, Itri V, Zolla-Pazner S: Primary Human Neutrophils Exhibit a Unique HIV-Directed Antibody-Dependent Phagocytosis Profile. J Innate Immun 2019, 11:181–190. [DOI] [PMC free article] [PubMed] [Google Scholar]; *Comparison of phagocytic activity mediated by HIV-1 Ab and primary human neutrophils or THP-1 cell line finds variation across donors and between primary cells and a cell line.
  • 9.Duchemin M, Khamassi M, Xu L, Tudor D, Bomsel M: IgA Targeting Human Immunodeficiency Virus-1 Envelope gp41 Triggers Antibody-Dependent Cellular Cytotoxicity Cross-Clade and Cooperates with gp41-Specific IgG to Increase Cell Lysis. Front Immunol 2018, 9:244. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Williams KL, Stumpf M, Naiman NE, Ding S, Garrett M, Gobillot T, Vezina D, Dusenbury K, Ramadoss NS, Basom R, et al. : Identification of HIV gp41-specific antibodies that mediate killing of infected cells. PLoS Pathog 2019, 15:e1007572. [DOI] [PMC free article] [PubMed] [Google Scholar]; *Four anti-gp41 mAbs isolated from a HIV-1+ individual mediate ADCC of HIV-1 infected cells and highlight effective targeting of relatively conserved HIV-1 epitope.
  • 11.Sojar H, Baron S, Sullivan JT, Garrett M, van Haaren MM, Hoffman J, Overbaugh J, Doranz BJ, Hicar MD: Monoclonal Antibody 2C6 Targets a Cross-Clade Conformational Epitope in gp41 with Highly Active Antibody-Dependent Cell Cytotoxicity. J Virol 2019, 93. [DOI] [PMC free article] [PubMed] [Google Scholar]; *mAb cloned from long-term nonprogressor targets well-defined epitope between gp41 oligomers and elicits strong ADCC across HIV clades.
  • 12.Dupuy FP, Kant S, Barbe A, Routy JP, Bruneau J, Lebouche B, Tremblay C, Pazgier M, Finzi A, Bernard NF: Antibody-Dependent Cellular Cytotoxicity-Competent Antibodies against HIV-1-Infected Cells in Plasma from HIV-Infected Subjects. mBio 2019, 10. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Richard J, Prevost J, Baxter AE, von Bredow B, Ding S, Medjahed H, Delgado GG, Brassard N, Sturzel CM, Kirchhoff F, et al. : Uninfected Bystander Cells Impact the Measurement of HIV-Specific Antibody-Dependent Cellular Cytotoxicity Responses. mBio 2018, 9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Tolbert WD, Sherburn RT, Van V, Pazgier M: Structural Basis for Epitopes in the gp120 Cluster A Region that Invokes Potent Effector Cell Activity. Viruses 2019, 11. [DOI] [PMC free article] [PubMed] [Google Scholar]; *Review of structural work to define gp120 epitopes exposed mainly in the open Env conformation and targeted by non-neutralizing antibodies.
  • 15.Ilinykh PA, Huang K, Santos RI, Gilchuk P, Gunn BM, Karim MM, Liang J, Fouch ME, Davidson E, Parekh DV, et al. : Non-neutralizing Antibodies from a Marburg Infection Survivor Mediate Protection by Fc-Effector Functions and by Enhancing Efficacy of Other Antibodies. Cell Host Microbe 2020. [DOI] [PMC free article] [PubMed] [Google Scholar]; *Characterization of acitivity of two mAbs that mediate protection from Marburg infection through two distinct mechanisms.
  • 16.Fox JM, Roy V, Gunn BM, Huang L, Edeling MA, Mack M, Fremont DH, Doranz BJ, Johnson S, Alter G, et al. : Optimal therapeutic activity of monoclonal antibodies against chikungunya virus requires Fc-FcgammaR interaction on monocytes. Sci Immunol 2019, 4. [DOI] [PMC free article] [PubMed] [Google Scholar]; *Study defines essential role of Fc-mediated monocyte activity in clinical outcomes of chikungunya treatment with neutralizing antibodies in mouse model.
  • 17.Li D, He W, Liu X, Zheng S, Qi Y, Li H, Mao F, Liu J, Sun Y, Pan L, et al. : A potent human neutralizing antibody Fc-dependently reduces established HBV infections. Elife 2017, 6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Thulin NK, Brewer RC, Sherwood R, Bournazos S, Edwards KG, Ramadoss NS, Taubenberger JK, Memoli M, Gentles AJ, Jagannathan P, et al. : Maternal Anti-Dengue IgG Fucosylation Predicts Susceptibility to Dengue Disease in Infants. Cell Rep 2020, 31:107642. [DOI] [PMC free article] [PubMed] [Google Scholar]; *Increased placentally transferred afucosylated anti-Dengue IgGs with increased ADCC activity in infants correlates with increased risk of symptomatic Dengue infection.
  • 19.Parsons MS, Lee WS, Kristensen AB, Amarasena T, Khoury G, Wheatley AK, Reynaldi A, Wines BD, Hogarth PM, Davenport MP, et al. : Fc-dependent functions are redundant to efficacy of anti-HIV antibody PGT121 in macaques. J Clin Invest 2019, 129:182–191. [DOI] [PMC free article] [PubMed] [Google Scholar]; **Evidence that reducing Fc-mediated effector functions does not reduce the protection of PGT121 in an NHP model.
  • 20.Hessell AJ, Hangartner L, Hunter M, Havenith CE, Beurskens FJ, Bakker JM, Lanigan CM, Landucci G, Forthal DN, Parren PW, et al. : Fc receptor but not complement binding is important in antibody protection against HIV. Nature 2007, 449:101–104. [DOI] [PubMed] [Google Scholar]
  • 21.Bournazos S, Klein F, Pietzsch J, Seaman MS, Nussenzweig MC, Ravetch JV: Broadly neutralizing anti-HIV-1 antibodies require Fc effector functions for in vivo activity. Cell 2014, 158:1243–1253. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Himes JE, Goswami R, Mangan RJ, Kumar A, Jeffries TL Jr., Eudailey JA, Heimsath H, Nguyen QN, Pollara J, LaBranche C, et al. : Polyclonal HIV envelope-specific breast milk antibodies limit founder SHIV acquisition and cell-associated virus loads in infant rhesus monkeys. Mucosal Immunol 2018, 11:1716–1726. [DOI] [PMC free article] [PubMed] [Google Scholar]; **Infusion and oral treatment of infant rhesus monkeys with tri-mAb cocktail of weakly neutralizing and ADCC mediating Abs limited acquisition of SHIV over treatment with weakly neutralizing mAb alone.
  • 23.Bardhi A, Wu Y, Chen W, Li W, Zhu Z, Zheng JH, Wong H, Jeng E, Jones J, Ochsenbauer C, et al. : Potent In Vivo NK Cell-Mediated Elimination of HIV-1-Infected Cells Mobilized by a gp120-Bispecific and Hexavalent Broadly Neutralizing Fusion Protein. J Virol 2017, 91. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Hessell AJ, Shapiro MB, Powell R, Malherbe DC, McBurney SP, Pandey S, Cheever T, Sutton WF, Kahl C, Park B, et al. : Reduced Cell-Associated DNA and Improved Viral Control in Macaques following Passive Transfer of a Single Anti-V2 Monoclonal Antibody and Repeated Simian/Human Immunodeficiency Virus Challenges. J Virol 2018, 92. [DOI] [PMC free article] [PubMed] [Google Scholar]; **To our knowledge, this is the first study reporting passive transfer of a human IgG3 in the NHP model. Though not powered to detect a difference, activity appeared to be at least similar to IgG1, and potentially better given similar protection at lower plasma concentrations.
  • 25.Asokan M, Dias J, Liu C, Maximova A, Ernste K, Pegu A, McKee K, Shi W, Chen X, Almasri C, et al. : Fc-mediated effector function contributes to the in vivo antiviral effect of an HIV neutralizing antibody. Proc Natl Acad Sci 2020, in press. [DOI] [PMC free article] [PubMed] [Google Scholar]; **Study comparing the ability of FcR binding enhanced and reduced variants to reduce viral loads in established infection in an NHP model. Effector functions were found to contribute to the antiviral activity of VRC07–523LS. Enhanced receptor binding mAb bound blood effector cells and changed their biodistirubtion, phenotypes, and drove necroptosis. This study points to unintended consequences of modification of FcR binding affinities.
  • 26.Haynes BF, Gilbert PB, McElrath MJ, Zolla-Pazner S, Tomaras GD, Alam SM, Evans DT, Montefiori DC, Karnasuta C, Sutthent R, et al. : Immune-correlates analysis of an HIV-1 vaccine efficacy trial. N Engl J Med 2012, 366:1275–1286. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Perez LG, Martinez DR, deCamp AC, Pinter A, Berman PW, Francis D, Sinangil F, Lee C, Greene K, Gao H, et al. : V1V2-specific complement activating serum IgG as a correlate of reduced HIV-1 infection risk in RV144. PLoS One 2017, 12:e0180720. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Yates NL, Liao HX, Fong Y, deCamp A, Vandergrift NA, Williams WT, Alam SM, Ferrari G, Yang ZY, Seaton KE, et al. : Vaccine-induced Env V1-V2 IgG3 correlates with lower HIV-1 infection risk and declines soon after vaccination. Sci Transl Med 2014, 6:228ra239. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Chung AW, Ghebremichael M, Robinson H, Brown E, Choi I, Lane S, Dugast AS, Schoen MK, Rolland M, Suscovich TJ, et al. : Polyfunctional Fc-effector profiles mediated by IgG subclass selection distinguish RV144 and VAX003 vaccines. Sci Transl Med 2014, 6:228ra238. [DOI] [PubMed] [Google Scholar]
  • 30.Rerks-Ngarm S, Pitisuttithum P, Excler JL, Nitayaphan S, Kaewkungwal J, Premsri N, Kunasol P, Karasavvas N, Schuetz A, Ngauy V, et al. : Randomized, Double-Blind Evaluation of Late Boost Strategies for HIV-Uninfected Vaccine Recipients in the RV144 HIV Vaccine Efficacy Trial. J Infect Dis 2017, 215:1255–1263. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Pitisuttithum P, Nitayaphan S, Chariyalertsak S, Kaewkungwal J, Dawson P, Dhitavat J, Phonrat B, Akapirat S, Karasavvas N, Wieczorek L, et al. : Late boosting of the RV144 regimen with AIDSVAX B/E and ALVAC-HIV in HIV-uninfected Thai volunteers: a double-blind, randomised controlled trial. Lancet HIV 2020, 7:e238–e248. [DOI] [PMC free article] [PubMed] [Google Scholar]; *Boost of RV144 regimen at longer time interval from primary vaccination series improved immune responses that correlated with protection in initial series.
  • 32.Crowley AR, Ackerman ME: Vaccine boosts: balancing response magnitude and character. Lancet HIV 2020, 7:e217–e219. [DOI] [PubMed] [Google Scholar]
  • 33.Gray GE, Huang Y, Grunenberg N, Laher F, Roux S, Andersen-Nissen E, De Rosa SC, Flach B, Randhawa AK, Jensen R, et al. : Immune correlates of the Thai RV144 HIV vaccine regimen in South Africa. Sci Transl Med 2019, 11. [DOI] [PMC free article] [PubMed] [Google Scholar]; *HVTN 097 evaluated RV144 vaccine regimen in South Africa. Correlates of protection induced in RV144 also elicited in HVTN 097 trial suggesting applicability of regimen across diverse populations.
  • 34.Laher F, Moodie Z, Cohen KW, Grunenberg N, Bekker LG, Allen M, Frahm N, Yates NL, Morris L, Malahleha M, et al. : Safety and immune responses after a 12-month booster in healthy HIV-uninfected adults in HVTN 100 in South Africa: A randomized double-blind placebo-controlled trial of ALVAC-HIV (vCP2438) and bivalent subtype C gp120/MF59 vaccines. PLoS Med 2020, 17:e1003038. [DOI] [PMC free article] [PubMed] [Google Scholar]; *Study found adding boost to RV144 trial at 12 months improved durability of vaccine-induced immune responses.
  • 35.Neidich SD, Fong Y, Li SS, Geraghty DE, Williamson BD, Young WC, Goodman D, Seaton KE, Shen X, Sawant S, et al. : Antibody Fc effector functions and IgG3 associate with decreased HIV-1 risk. J Clin Invest 2019, 129:4838–4849. [DOI] [PMC free article] [PubMed] [Google Scholar]; **Study indentifies correlates of protection in HVTN505 trial finding that high anti-Env IgG3, FcR-binding Abs, and phagocytosis decrease infection risk.
  • 36.Li SS, Gilbert PB, Carpp LN, Pyo CW, Janes H, Fong Y, Shen X, Neidich SD, Goodman D, deCamp A, et al. : Fc Gamma Receptor Polymorphisms Modulated the Vaccine Effect on HIV-1 Risk in the HVTN 505 HIV Vaccine Trial. J Virol 2019, 93. [DOI] [PMC free article] [PubMed] [Google Scholar]; *Host genetic variation in FcγR influenced protectective outcome of HVTN 505 vaccine regimen.
  • 37.Balasubramanian P, Williams C, Shapiro MB, Sinangil F, Higgins K, Nadas A, Totrov M, Kong XP, Fiore-Gartland AJ, Haigwood NL, et al. : Functional Antibody Response Against V1V2 and V3 of HIV gp120 in the VAX003 and VAX004 Vaccine Trials. Sci Rep 2018, 8:542. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Barouch DH, Tomaka FL, Wegmann F, Stieh DJ, Alter G, Robb ML, Michael NL, Peter L, Nkolola JP, Borducchi EN, et al. : Evaluation of a mosaic HIV-1 vaccine in a multicentre, randomised, double-blind, placebo-controlled, phase 1/2a clinical trial (APPROACH) and in rhesus monkeys (NHP 13–19). Lancet 2018, 392:232–243. [DOI] [PMC free article] [PubMed] [Google Scholar]; **Immunogenicity data of large human vaccine trial. Shows robust induction of Env-specific antibodies with ADCP activity. In NHP, vaccine protection is correlated with antibody titers, which in turn correlate with with ADCP.
  • 39.Pilgrim AK, Pantaleo G, Cohen OJ, Fink LM, Zhou JY, Zhou JT, Bolognesi DP, Fauci AS, Montefiori DC: Neutralizing antibody responses to human immunodeficiency virus type 1 in primary infection and long-term-nonprogressive infection. J Infect Dis 1997, 176:924–932. [DOI] [PubMed] [Google Scholar]
  • 40.Mielke D, Bandawe G, Pollara J, Abrahams MR, Nyanhete T, Moore PL, Thebus R, Yates NL, Kappes JC, Ochsenbauer C, et al. : Antibody-Dependent Cellular Cytotoxicity (ADCC)-Mediating Antibodies Constrain Neutralizing Antibody Escape Pathway. Front Immunol 2019, 10:2875. [DOI] [PMC free article] [PubMed] [Google Scholar]; **Study combines in vitro functional testing of serum antibodies and next generation sequencing of viruses to define effect of Fc-mediated antibody responses on viral escape mechanisms in early infection.
  • 41.Horwitz JA, Bar-On Y, Lu CL, Fera D, Lockhart AAK, Lorenzi JCC, Nogueira L, Golijanin J, Scheid JF, Seaman MS, et al. : Non-neutralizing Antibodies Alter the Course of HIV-1 Infection In Vivo. Cell 2017, 170:637–648 e610. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Chen X, Lin M, Qian S, Zhang Z, Fu Y, Xu J, Han X, Ding H, Dong T, Shang H, et al. : The Early Antibody-Dependent Cell-Mediated Cytotoxicity Response Is Associated With Lower Viral Set Point in Individuals With Primary HIV Infection. Front Immunol 2018, 9:2322. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43.Talathi S, Bagul R, Ghate M, Kulkarni S, Thakar M: Higher Baseline ADCC Responses in Chronic Nonprogressive HIV Infection Are Associated with Reduced HIV Burden in Later Course of Disease. Viral Immunol 2020, 33:77–85. [DOI] [PubMed] [Google Scholar]; *In comparison to individual with progressive HIV infection, individuals with slow-progressive HIV had high early ADCC responses to infection and these early ADCC responses increased over time. Suggesting role for ADCC in long term control of HIV infection.
  • 44.Richardson SI, Chung AW, Natarajan H, Mabvakure B, Mkhize NN, Garrett N, Abdool Karim S, Moore PL, Ackerman ME, Alter G, et al. : HIV-specific Fc effector function early in infection predicts the development of broadly neutralizing antibodies. PLoS Pathog 2018, 14:e1006987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45.Karlsson I, Tingstedt JL, Sahin GO, Hansen M, Szojka Z, Buggert M, Biague A, Da Silva Z, Mansson F, Esbjornsson J, et al. : Cross-Reactive Antibodies With the Capacity to Mediate HIV-1 Envelope Glycoprotein-Targeted Antibody-Dependent Cellular Cytotoxicity Identified in HIV-2-Infected Individuals. J Infect Dis 2019, 219:1749–1754. [DOI] [PMC free article] [PubMed] [Google Scholar]; *Study identified cross-reactive ADCC mediating antibodies raised in response to HIV-2 infection. The cross-reactivity of this response may limit HIV-1 infection progression in dual infection.
  • 46.Hompe ED, Jacobson DL, Eudailey JA, Butler K, Edwards W, Pollara J, Brummel SS, Fouda GG, Chinula L, Kamanga M, et al. : Maternal Humoral Immune Responses Do Not Predict Postnatal HIV-1 Transmission Risk in Antiretroviral-Treated Mothers from the IMPAACT PROMISE Study. mSphere 2019, 4. [DOI] [PMC free article] [PubMed] [Google Scholar]; *Study of postnatal HIV-1 transmission risk found that materal plasma Ab ADCC activity did not correlate with decreased transmission risk. Increased transmission was associated with high Env-specfic IgA in breast milk.
  • 47.Naiman NE, Slyker J, Richardson BA, John-Stewart G, Nduati R, Overbaugh JM: Antibody-dependent cellular cytotoxicity targeting CD4-inducible epitopes predicts mortality in HIV-infected infants. EBioMedicine 2019, 47:257–268. [DOI] [PMC free article] [PubMed] [Google Scholar]; *Study measured epitope-specific ADCC activity of plasma Abs from transmitting and non-transmitting mothers, finding that presence CD4i targeting Abs that mediate ADCC correlated with infant mortality.
  • 48.Redd AD, Doria-Rose NA, Weiner JA, Nason M, Seivers M, Schmidt SD, Laeyendecker O, Martens C, Bruno D, Keele BF, et al. : Longitudinal Antibody Responses in People Who Inject Drugs Infected With Similar Human Immunodeficiency Virus Strains. J Infect Dis 2020, 221:756–765. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49.Tuen M, Bimela JS, Banin AN, Ding S, Harkins GW, Weiss S, Itri V, Durham AR, Porcella SF, Soni S, et al. : Immune Correlates of Disease Progression in Linked HIV-1 Infection. Front Immunol 2019, 10:1062. [DOI] [PMC free article] [PubMed] [Google Scholar]; *15 year longitudinal study of three individuals with epidemiologically linked HIV-1 infections links high titers of ADCC active antibodies to better clinical outcomes.
  • 50.Ruiz MJ, Salido J, Abusamra L, Ghiglione Y, Cevallos C, Damilano G, Rodriguez AM, Trifone C, Laufer N, Giavedoni LD, et al. : Evaluation of Different Parameters of Humoral and Cellular Immune Responses in HIV Serodiscordant Heterosexual Couples: Humoral Response Potentially Implicated in Modulating Transmission Rates. EBioMedicine 2017, 26:25–37. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 51.Ronen K, Dingens AS, Graham SM, Jaoko W, Mandaliya K, McClelland RS, Overbaugh J: Comprehensive Characterization of Humoral Correlates of Human Immunodeficiency Virus 1 Superinfection Acquisition in High-risk Kenyan Women. EBioMedicine 2017, 18:216–224. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 52.Ackerman ME, Das J, Pittala S, Broge T, Linde C, Suscovich TJ, Brown EP, Bradley T, Natarajan H, Lin S, et al. : Route of immunization defines multiple mechanisms of vaccine-mediated protection against SIV. Nat Med 2018, 24:1590–1598. [DOI] [PMC free article] [PubMed] [Google Scholar]; *Study that demonstrates route of immunization affects antibody features and functions. Phagocytic antibodies correlated strongly with protection.
  • 53.Jones AT, Shen X, Walter KL, LaBranche CC, Wyatt LS, Tomaras GD, Montefiori DC, Moss B, Barouch DH, Clements JD, et al. : HIV-1 vaccination by needle-free oral injection induces strong mucosal immunity and protects against SHIV challenge. Nat Commun 2019, 10:798. [DOI] [PMC free article] [PubMed] [Google Scholar]; **Vaccine delivered to NHPs by needle-free oral injection elicits strong, protective mucosal and systemic response in comparison to subdermal immunization of the same vaccine.
  • 54.Felber BK, Lu Z, Hu X, Valentin A, Rosati M, Remmel CAL, Weiner JA, Carpenter MC, Faircloth K, Stanfield-Oakley S, et al. : Co-immunization of DNA and Protein in the Same Anatomical Sites Induces Superior Protective Immune Responses against SHIV Challenge. Cell Rep 2020, 31:107624. [DOI] [PMC free article] [PubMed] [Google Scholar]; *DNA prime and protein immunization given to NHPs either in the same or different anatomical sites. Only animals vaccinated in the same site were protected against SHIV infection.
  • 55.Miller-Novak LK, Das J, Musich TA, Demberg T, Weiner JA, Venzon DJ, Mohanram V, Vargas-Inchaustegui DA, Tuero I, Ackerman ME, et al. : Analysis of Complement-Mediated Lysis of Simian Immunodeficiency Virus (SIV) and SIV-Infected Cells Reveals Sex Differences in Vaccine-Induced Immune Responses in Rhesus Macaques. J Virol 2018, 92. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56.Pittala S, Bagley K, Schwartz JA, Brown EP, Weiner JA, Prado IJ, Zhang W, Xu R, Ota-Setlik A, Pal R, et al. : Antibody Fab-Fc properties outperform titer in predictive models of SIV vaccine-induced protection. Mol Syst Biol 2019, 15:e8747. [DOI] [PMC free article] [PubMed] [Google Scholar]; *Shows that qualitative antibody features predict challenge resistance more accurately than response magnitude. Complement protein-binding antibodies support accurate predictions of risk of infection.
  • 57.Bradley T, Pollara J, Santra S, Vandergrift N, Pittala S, Bailey-Kellogg C, Shen X, Parks R, Goodman D, Eaton A, et al. : Pentavalent HIV-1 vaccine protects against simian-human immunodeficiency virus challenge. Nat Commun 2017, 8:15711. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 58.Vaccari M, Gordon SN, Fourati S, Schifanella L, Liyanage NP, Cameron M, Keele BF, Shen X, Tomaras GD, Billings E, et al. : Adjuvant-dependent innate and adaptive immune signatures of risk of SIVmac251 acquisition. Nat Med 2016, 22:762–770. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 59.Richard J, Prevost J, Alsahafi N, Ding S, Finzi A: Impact of HIV-1 Envelope Conformation on ADCC Responses. Trends Microbiol 2018, 26:253–265. [DOI] [PubMed] [Google Scholar]
  • 60.Lee WS, Prevost J, Richard J, van der Sluis RM, Lewin SR, Pazgier M, Finzi A, Parsons MS, Kent SJ: CD4- and Time-Dependent Susceptibility of HIV-1-Infected Cells to Antibody-Dependent Cellular Cytotoxicity. J Virol 2019, 93. [DOI] [PMC free article] [PubMed] [Google Scholar]; *Plasma Abs from HIV-1 infected individuals mediate ADCC of HIV-1 infected cells at multiple stages of CD4 downregulation.
  • 61.Davis-Gardner ME, Gardner MR, Alfant B, Farzan M: eCD4-Ig promotes ADCC activity of sera from HIV-1-infected patients. PLoS Pathog 2017, 13:e1006786. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 62.Madani N, Princiotto AM, Mach L, Ding S, Prevost J, Richard J, Hora B, Sutherland L, Zhao CA, Conn BP, et al. : A CD4-mimetic compound enhances vaccine efficacy against stringent immunodeficiency virus challenge. Nat Commun 2018, 9:2363. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 63.Alsahafi N, Bakouche N, Kazemi M, Richard J, Ding S, Bhattacharyya S, Das D, Anand SP, Prevost J, Tolbert WD, et al. : An Asymmetric Opening of HIV-1 Envelope Mediates Antibody-Dependent Cellular Cytotoxicity. Cell Host Microbe 2019, 25:578–587 e575. [DOI] [PMC free article] [PubMed] [Google Scholar]; *Structural study of Env with CD4 mimetic compound establishes asymmetric conformation that is stabilized by cluster A and coreceptor binding site antibodies from HIV-1 infected individual.
  • 64.Beaudoin-Bussieres G, Prevost J, Gendron-Lepage G, Melillo B, Chen J, Smith Iii AB, Pazgier M, Finzi A: Elicitation of Cluster A and Co-Receptor Binding Site Antibodies are Required to Eliminate HIV-1 Infected Cells. Microorganisms 2020, 8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 65.von Bredow B, Andrabi R, Grunst M, Grandea AG 3rd, Le K, Song G, Berndsen ZT, Porter K, Pallesen J, Ward AB, et al. : Differences in the Binding Affinity of an HIV-1 V2 Apex-Specific Antibody for the SIVsmm/mac Envelope Glycoprotein Uncouple Antibody-Dependent Cellular Cytotoxicity from Neutralization. mBio 2019, 10. [DOI] [PMC free article] [PubMed] [Google Scholar]; **Study examines activity of HIV bnAb PGT145 against SIV infection, finding that ADCC of SIV-infected cells is highly correlated to the extent of opsonization. ADCC was induced at lower levels of bound antibody than neutralization.
  • 66.Anand SP, Prevost J, Baril S, Richard J, Medjahed H, Chapleau JP, Tolbert WD, Kirk S, Smith AB 3rd, Wines BD, et al. : Two Families of Env Antibodies Efficiently Engage Fc-Gamma Receptors and Eliminate HIV-1-Infected Cells. J Virol 2019, 93. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 67.Tuyishime M, Garrido C, Jha S, Moeser M, Mielke D, LaBranche C, Montefiori D, Haynes BF, Joseph S, Margolis DM, et al. : Improved Killing of HIV-infected Cells Using Three Neutralizing and Non-neutralizing Antibodies. J Clin Invest 2020, in press. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 68.Fisher BS, Dambrauskas N, Trakhimets O, Andrade DV, Smedley J, Sodora DL, Sather DN: Oral Immunization with HIV-1 Envelope SOSIP trimers elicits systemic immune responses and cross-reactive anti-V1V2 antibodies in non-human primates. PLoS One 2020, 15:e0233577. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 69.Hessell AJ, Powell R, Jiang X, Luo C, Weiss S, Dussupt V, Itri V, Fox A, Shapiro MB, Pandey S, et al. : Multimeric Epitope-Scaffold HIV Vaccines Target V1V2 and Differentially Tune Polyfunctional Antibody Responses. Cell Rep 2019, 28:877–895 e876. [DOI] [PMC free article] [PubMed] [Google Scholar]; *Comparison of the responses elicited in NHPs immunized with differentially scaffolded V1V2 immunogens. Cocktail of the immunogens generated polyfunctional, durable, and protective immune responses.
  • 70.Lai JI, Eszterhas SK, Brooks SA, Guo C, Zolla-Pazner S, Seaman MS, Bailey-Kellogg C, Griswold KE, Ackerman ME: Induction of cross-reactive HIV-1 specific antibody responses by engineered V1V2 immunogens with reduced conformational plasticity. Vaccine 2020, 38:3436–3446. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 71.van Eeden C, Wibmer CK, Scheepers C, Richardson SI, Nonyane M, Lambson B, Mkhize NN, Vijayakumar B, Sheng Z, Stanfield-Oakley S, et al. : V2-Directed Vaccine-like Antibodies from HIV-1 Infection Identify an Additional K169-Binding Light Chain Motif with Broad ADCC Activity. Cell Rep 2018, 25:3123–3135 e3126. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 72.Jones AT, Chamcha V, Kesavardhana S, Shen X, Beaumont D, Das R, Wyatt LS, LaBranche CC, Stanfield-Oakley S, Ferrari G, et al. : A Trimeric HIV-1 Envelope gp120 Immunogen Induces Potent and Broad Anti-V1V2 Loop Antibodies against HIV-1 in Rabbits and Rhesus Macaques. J Virol 2018, 92. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 73.Visciano ML, Gohain N, Sherburn R, Orlandi C, Flinko R, Dashti A, Lewis GK, Tolbert WD, Pazgier M: Induction of Fc-Mediated Effector Functions Against a Stabilized Inner Domain of HIV-1 gp120 Designed to Selectively Harbor the A32 Epitope Region. Front Immunol 2019, 10:677. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 74.Damelang T, Rogerson SJ, Kent SJ, Chung AW: Role of IgG3 in Infectious Diseases. Trends Immunol 2019, 40:197–211. [DOI] [PubMed] [Google Scholar]; **Review of IgG3 activity across diseases. Paper explores the physiochemical characteristics of IgG3 that lead to immunomodulatory effects and approaches to overcome limitations of IgG3 treatment.
  • 75.Richardson SI, Lambson BE, Crowley AR, Bashirova A, Scheepers C, Garrett N, Abdool Karim S, Mkhize NN, Carrington M, Ackerman ME, et al. : IgG3 enhances neutralization potency and Fc effector function of an HIV V2-specific broadly neutralizing antibody. PLoS Pathog 2019, 15:e1008064. [DOI] [PMC free article] [PubMed] [Google Scholar]; *IgG3 variant of broadly neutralizing antibody isolated from an HIV-1-infected individual has stronger neutralizing and Fc-mediated activity than IgG1 variant. Reports a novel IgG3 allotype.
  • 76.Chu TH, Crowley AR, Backes I, Chang C, Tay M, Broge T, Tuyishime M, Ferrari G, Seaman MS, Richardson SI, et al. : Hinge length contributes to the phagocytic activity of HIV-specific IgG1 and IgG3 antibodies. PLoS Pathog 2020, 16:e1008083. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 77.Crowley AR, Ackerman ME: Mind the Gap: How Interspecies Variability in IgG and Its Receptors May Complicate Comparisons of Human and Non-human Primate Effector Function. Front Immunol 2019, 10:697. [DOI] [PMC free article] [PubMed] [Google Scholar]; *Review examining differences in IgG and Fc receptor sequences, expression patterns, and allelic variation in humans and NHPs, as well as Fc-Fc receptor affinity differences that may complicate translation from NHP model results to human treatment design.

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