New paradigms for functional HIV-specific nonneutralizing antibodies

Forthal, Don; Hope, Thomas J.; Alter, Galit

doi: 10.1097/COH.0b013e328363d486
CHANGING ENVIRONMENT IN HIV VACCINE: Edited by Nelson L. Michael and Glenda Gray

Purpose of review: Although a large number of novel broadly neutralizing antibodies has been recently described, the induction of such antibodies via vaccination has proven difficult. By contrast, nonneutralizing antibodies arise early during infection and have been repeatedly associated with both protection from infection and disease progression.

Recent findings: We are beginning to gain new insights into the broader landscape of antiviral mechanisms that nonneutralizing antibodies may harness to fight HIV, providing an unprecedented breadth of approaches by which HIV can be blocked and contained.

Summary: In this review, we summarize the characteristics of nonneutralizing antibodies, their role in HIV infection, and new paradigm-shifting functions that may be exploited by next-generation vaccine approaches aimed at blocking HIV infection.

aUniversity of California, Irvine, California

bDepartment of Cell & Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois

cRagon Institute of MGH, MIT, and Harvard, Cambridge, Massachusetts, USA

Correspondence to Galit Alter, Ragon Institute of MGH, MIT, and Harvard, 400 Technology Square, Cambridge, MA 02139, USA. Tel: +1 857 268 7003; e-mail:

Article Outline
Back to Top | Article Outline


Recent results from the RV144 vaccine trial [1] and Ad26 vaccination in nonhuman primates [2] argue that some degree of protection from infection can be achieved in the absence of neutralizing antibodies or cytotoxic T-cell responses. In RV144, qualitative differences in the vaccine-induced humoral response, associated with low levels of IgA and high levels of antibody-dependent cellular cytotoxicity (ADCC), may have contributed to the limited protection observed [3]. This protection, observed in only 30% of vaccinees, waned rapidly after the final boost. Interestingly, compared with other vaccine trials, RV144 induced lower levels of HIV-specific antibody titers, suggesting that increased titers do not necessarily correlate with better protection, qualitative features of nonneutralizing antibodies may be a more critical measure of protective efficacy, and vaccine strategies able to increase both the titer and functional potency of antibodies may provide enhanced protection from infection. In this review, we will summarize the characteristics of nonneutralizing antibodies, their role in HIV infection, and new paradigm-shifting functions that may be exploited by the next-generation vaccine approaches aimed at blocking HIV infection.

Back to Top | Article Outline


Antibodies consist of two antigen-binding domains (variable domains, Fv) and a constant domain (constant domain, Fc). The double antigen-binding domain structure provides high-avidity tethering of antibodies to the target antigen. Conversely, the Fc domain provides instructions to the immune system on how the target antigen should be destroyed. Although the Fv and Fc domains have largely separable functions, changes in both these ends of the antibody are tightly regulated by a single enzyme, activation-induced cytidine deaminase (AID) [4]. While AID drives somatic hypermutation of the Fv domain, allowing for affinity maturation and diversification of the antibody, AID also drives class switch recombination (CSR) of the Fc domain. Despite its name, the Fc domain varies significantly both in protein sequence, depending on the Ab isotype, and glycosylation, both of which are involved in determining the functional activity of the antibody.

Back to Top | Article Outline


Upon B-cell activation, a naïve B cell can functionally tune its Ab response from the production of IgM to the production of IgG, IgE, or IgA through CSR [5]. As Ab isotypes and subclasses are specialized to have different functional activities and to respond to and eliminate distinct types of pathogens, isotype switching is a highly regulated process largely controlled by cytokines and T helper provided signals [6] received during B-cell priming. For example, IL-4 selectively induces IgG4 and IgE [7,8], whereas IL-10 and IL-21 induce IgG1 and IgG3 [9]. Furthermore, IgG subclass selection varies by infection and is related both to the inflammatory state induced by the pathogen and the location of the pathogen (intracellular vs. extracellular) [10]. Ultimately, differences in functionality are often linked to the Fc affinity for Fcγ receptors (FcγRs) or complement [11,12] (Fig. 1). In general, IgG3 has the highest affinity for FcγRs followed by IgG1 and then IgG2 and IgG4 (Fig. 2a and b). Importantly, specific Ab isotypes have been associated with protective humoral immune responses in various diseases, such as malaria in which IgG3 levels predict parasite control [10].

Within the human heavy chain locus (IGH@), the IgG3 constant region is the first subtype [13] (Fig. 1), suggesting that it is the first IgG subclass that may be selected during an acute immune response. Moreover, the IGH subclass sequence follows the FcγR binding affinity, and functional potency, of the subclasses (IgG3 > IgG1 > IgG2 > IgG4), suggesting that IgG subclass selection is evolutionarily programmed to allow for the production of the most functional antibodies early in the immune response, followed by less inflammatory Ab subclasses in subsequent waves. Along these lines, HIV-specific IgG3 antibodies have been proposed as markers of early HIV infection because of their enrichment during the first few weeks of infection [14▪▪]. However, IgG3 antibody levels decline rapidly following acute infection and are replaced by a strong IgG1 response in the chronic phase of the disease [15]. Additionally, spontaneous control of HIV infection (Controllers) in the absence of antiretroviral therapy is associated with the induction of high levels of p24-specific and gp120-specific IgG1 and the maintenance of gp120-specific IgG3 antibodies [16], whereas progression to AIDS has been associated with increasing levels HIV-specific IgG4 antibodies [17]. Together, these data suggest that spontaneous control is associated with the induction of functionally enhanced antibody isotypes (IgG1 and IgG3), whereas progression to disease is associated with the selection of poorly functional antibodies [16].

Back to Top | Article Outline


In addition to isotype-associated differences in activity, antibody glycosylation profoundly modulates antibody function. For example, IgG antibodies lacking fucose exhibit increased cytotoxic activity [18–23], as a result of the increased affinity to the activating FcγR3A [18] (Fig. 2c and d). Therapeutic antibodies optimized to contain low levels of fucose residues are more effective in clearing the tumor cells than their fucosylated counterparts [24,25]. Conversely, increased terminal sialylation imbues antibodies with anti-inflammatory properties [26], and the bioactive fraction of intravenous immunoglobulin that is used to treat many inflammatory and autoimmune conditions is thought to be mediated by a fraction of sialylated antibodies within the larger polyclonal pool [27].

In the context of HIV infection, recent data suggest that significant changes occur in both bulk and HIV-specific antibody glycosylation [28▪▪,29]. Specifically, HIV infection is associated with a significant increase in agalactosylated antibodies [29], which are highly inflammatory and typically enriched in patients with inflammatory conditions such as rheumatoid arthritis [27]. Interestingly, the most dramatic enrichment of agalactosylated antibodies was observed among Controllers, suggesting that although these individuals exhibit less overall immune activation [28▪▪], B cells in Controllers continue to receive inflammatory signals that drive the secretion of antibodies with glycan structures associated with chronic inflammation. Intriguingly, the glycosylation of HIV-specific antibodies was further skewed toward a more highly inflammatory glycoform, containing less galactose, fucose, and sialic acid [28▪▪]. The most profound enrichment of afucosylated, agalactosylated antibodies was observed among HIV-specific antibodies in Controllers, who also exhibit enhanced ADCC activity, suggesting that the B cells in these individuals were specifically programmed to make highly functional antibodies that may contribute to persistent viral control. Yet, to date, little information is known about the mechanism by which B cells program antibody glycosylation, even though it may offer new alternatives by which antibody effector functions may be actively recruited through vaccination.

Back to Top | Article Outline


Beyond neutralization, antibodies mediate a broad array of functions including ADCC, antibody-mediated cellular phagocytosis (ADCP), complement-mediated killing (Fig. 3a), and antibody-dependent cell-mediated virus inhibition (ADCVI). On a cellular level, the biological functions of IgG are mediated by interactions between Fc and FcγRs, which are found on all innate immune cells.

Six major FcγRs have been identified in humans: FcγRI, FcγRIIa, FcγRIIb, FcγRIIc, FcγRIIIa, and FcγRIIIb [30] (Fig. 1). With the exception of FcγRIIb, which inhibits activation, all other FcγRs are activating receptors, signaling either directly through immune tyrosine-activating motifs (ITAMs) in their cytoplasmic tail or through interactions with separate ITAM-containing proteins [30–32]. The genes encoding FcγRIIa and FcγRIIIa contain single-nucleotide polymorphisms, which result in receptors that differ in their binding affinities for different IgG subclasses [33]. Natural killer (NK) cells generally express FcγRIIIa and, in some individuals, FcγRIIc. Other cell types likely to be involved in preventing or controlling HIV infection, such as monocytes and macrophages, may express all of the FcγRs with the exception of FcγRIIIb, which is primarily expressed on neutrophils and eosinophils. It should be emphasized that expression of FcγRs on any given cell type may differ according to activation state, cytokine milieu, and location.

Over the last three decades, significant work has pointed toward a role for Fc–FcγR interactions in both infection and vaccine-mediated control of HIV/SIV in vitro and in vivo. Although several studies have explored the potential role of FcγR-mediated antibody functions in preventing HIV infection [34–37], only one study directly implicated these functions in prevention [38]. In this study, infusion of IgG1 b12, a monoclonal antibody (mAb) that engages FcγRs, protected macaques from vaginal exposure to simian/human immunodeficiency virus (SHIV)162p3, and this protection was partially lost when the mAb was mutated to abrogate FcγR binding. Although this study directly demonstrated the importance of Fc–FcγR interactions in augmenting protection, the precise antibody function(s) responsible remain unknown. Thus, although Fc–FcγR interactions have been directly identified as a mechanism of protection in a rhesus macaque model of vaginal SHIV infection, the contribution of any single FcγR-mediated antibody function to protective immunity remains unknown.

Back to Top | Article Outline


Although passive transfer strategies using nonneutralizing, functional antibodies alone have failed to definitively demonstrate protection from HIV/SIV infection [35–37,39], the biology underlying the protective activity of neutralizing and nonneutralizing antibodies is likely different. Therefore, comparisons of passively administered single mAbs may not be informative. Unlike neutralizing antibodies that block a limited number of viral epitopes on the surface of a virus [40], nonneutralizing antibodies must form avid immune complexes that are able to recruit the low-affinity receptors or innate immune proteins necessary for their function [12]. Because of the limited amount of envelope on the surface of HIV [41], nonneutralizing antibodies may have a limited impact on the virus itself; however, because HIV assembles in lipid rafts [42], the concentration of HIV antigens on the surface of cells may allow nonneutralizing antibodies to bind and cluster Fc receptors on effector cells. However, polyclonal nonneutralizing antibodies simultaneously targeting several epitopes on a single envelope may have a better opportunity to form large avid immune complexes than mAbs. Therefore, although previous passive transfer efforts of single, nonneutralizing antibodies exhibited limited success [34], it is likely that cocktails of high-affinity, Fc-enhanced nonneutralizing antibodies that could simultaneously decorate the surface of HIV envelope could mediate sterilizing protection from infection.

Back to Top | Article Outline


Antibodies are able to recruit a spectrum of different antiviral functions.

Back to Top | Article Outline

Antibody-dependent cellular cytotoxicity

ADCC occurs when an antibody forms a bridge between antigen-expressing target cells and FcγR-expressing effector cells; the cross-linking of FcγRs on the effector cells results in target cell death. Although several studies have explored the role of vaccine-elicited ADCC-inducing antibodies in preventing HIV, SIV, or SHIV infection, there has been no direct demonstration of a protective effect. However, as mentioned above, in the secondary analyses of the RV144 data, the combination of low vaccine-elicited plasma antigp120 IgA levels and high ADCC antibody activity was associated with a lower infection rate [3]. Furthermore, in macaques, vaccine-induced ADCC activity has been correlated with infection outcomes [37,39,43▪]. For example, a very strong trend toward protection from infection was observed following heterologous prime-boost vaccinated macaques exposed to repetitive SIVmac251 intrarectal challenge [2]. Likewise, ADCC-inducing responses elicited by live, attenuated SIVδnef correlated with protection from intravenous or vaginal challenge with SIVmac251 [43▪]. Additionally, ADCC-mediating IgG in cervicovaginal secretions has been elicited by vaccination of macaques, and it is possible that such ADCC activity plays a role in protection against SHIV162p3 vaginal challenge [44]. Other studies have found either an inverse correlation between ADCC activity prior to challenge and acute or chronic viremia levels or a direct correlation between ADCC activity and the number of challenges required for infection [35,37,45], suggesting that these responses may have postacquisition antiviral effects.

However, no study to date has directly demonstrated that an ADCC-mediating antibody is responsible for preventing HIV/SIV infection. Moreover, ADCC-inducing responses following modified vaccinia Ankara vaccination were not associated with the risk of SIVsmE660 infection after rectal challenge [46]. Furthermore, a recent mAb passive infusion study has now called into question whether NK-cell-mediated ADCC activity is involved in protection against mucosal SHIV challenge [47▪▪]. In this study, animals were infused with either IgG1 b12 or a nonfucosylated version of the mAb, designed to increase FcγRIIIa binding and NK-cell-mediated ADCC activity. Although a small number of animals were studied, there was no difference in the protection against repeated low-dose vaginal SHIV challenge for the two forms of the mAb, suggesting that other FcγR interactions could be more critical in driving antiviral control and clearance, particularly at mucosal surfaces.

Back to Top | Article Outline


Phagocytes, such as monocytes, macrophages, and dendritic cells, can internalize antibody-coated virus or antibody-coated infected cells. Like ADCC-inducing antibodies, it is likely that phagocytosis of HIV-1 immune complexes augments the antiviral activity of neutralizing or nonneutralizing antibodies. However, interestingly, depending on the inflammatory state, phagocytes, and not CD16+ NK cells, are more abundant at mucosal membranes where the large majority of infections occurs [48,49]. Therefore, it is possible that antibodies able to mediate the rapid clearance of the virus or virally infected cells could have a beneficial role in preventing the HIV infection [50–53]. Recently, antibodies elicited in healthy human volunteers by an Ad26 vaccine expressing clade A HIV-1 Env were shown to mediate phagocytosis of gp120-coated beads [54].

As with other FcγR-mediated antibody functions, IgG subclass is a determinant of phagocytosis, and it is likely that FcγRIIa or FcγRIIIa genotypes and differential binding to different FcγRs impact phagocytosis in vivo[55,56]. Individuals possessing the FcγRIIa RR genotype demonstrated reduced internalization of HIV-1 immune complexes than individuals with the RH or HH genotypes, and this reduced phagocytic activity was linked to more a rapid decline in CD4 cells, suggesting that phagocytic clearance of virus and virally infected cells plays a role in postacquisition disease control [57]. Similarly, quantitative differences in the capacity of antibodies to drive phagocytosis were recently associated with qualitative differences in FcγR binding profiles. Specifically, antibodies from Controllers exhibited increased phagocytic activity that was associated with the enhanced capacity of both bulk plasma and HIV-specific IgG to engage FcγRIIa and not FcγR2IIb [56], this altered FcγR binding profile was associated with changes in antibody glycosylation, potentially pointing to new antibody glycoforms that may allow antibodies to prevent infection more robustly at mucosal membranes, where phagocytic cells are more abundant. Moreover, as mentioned above, although the nonfucosylated b12 did not exhibit enhanced protection from infection, it is plausible that modifications, such as those elicited by Controllers that enhance phagocytosis, may offer an alternate mechanism by which passively transferred mAbs may mediate enhanced protection from infection via the utilization of the phagocytic cells that abundantly line mucosal membranes.

Back to Top | Article Outline

Antibody-dependent cell-mediated virus inhibition

ADCVI is not an antibody function itself; rather, it is a measure of net antiviral activity provided by antibody in combination with FcγR-bearing effector cells. The components contributing to the antiviral effect measured in ADCVI assays include ADCC, the production of β chemokines, and phagocytosis [58]. ADCVI antibody activity has been shown to rise early and to correlate with the fall in viremia observed during acute infection [58]. Moreover, ADCVI activity is enriched in Controllers and is associated with the preferential accumulation of agalactosylated antibodies [28▪▪]. As with ADCC, ADCVI-inducing antibodies elicited by vaccination or present in passively infused reagents correlate with protection or reductions in viral load in monkeys after various types of challenge with SIV or SHIV [35–38,59,60]. In humans, increased ADCVI activity elicited by a recombinant gp120 vaccine in the Vax004 trial was associated with lower infection rates [61]. However, the ADCVI response to primary infection with HIV-1 did not correlate with the risk of superinfection in a cohort of women in Kenya [62].

Back to Top | Article Outline


Antibodies are present at the majority of the mucosal surfaces exposed to HIV during sexual transmission. In addition to the presence of antibodies within the fluids associated with these barriers, the antibodies may also be able to interact with the mucosal and mucus components themselves (Fig. 3b). The first barrier encountered by HIV at mucosal epithelial barriers is composed of secreted mucins, which coat the mucosal surfaces of the colorectal tract and the female reproductive tract. Because most HIV infections are caused by a single transmitted founder virus [63], the majority of viruses must get stuck or cleared at the mucosal surface. Therefore, recent efforts have been focused on dissecting the potential properties of antibodies that promote more effective interactions with mucins to trap the virus, a mechanism that would effectively neutralize the virus by preventing it from reaching the potential target cells.

Although the interaction of antibodies and mucus has not been well defined, there have been a number of recent studies that suggest that antibodies and mucus can function together to reduce the pathogenic consequences of microbes. For example, mucus in combination with secretory IgA provided optimal protection from toxin-induced injury in a tissue culture model [64]. These results echo the studies published a decade ago, suggesting that the secretory component of IgA mediates the protective effects of mucus-bound IgA [65]. Similarly, the deletion of MyD88 in mice decreased mucin 2 and secretory IgA production, leading to compromised antibacterial immunity [66]. IgG may also interact comparably with mucus. For example, the presence of IgG antibodies to Helicobacter pylori in cervical mucus has been associated with infertility [67].

Antibodies may also interact with the mucosal surfaces, potentially retaining HIV at the interface of the mucosal epithelium and the lumen. Trapped at the surface, HIV would not be able to penetrate the mucosal epithelial barrier. These interactions could take place between cell-associated mucins (e.g., MUC1, MUC4, and MUC16) and the Fc portions of antibodies. Antibodies have also been observed to accumulate in the superficial aspects of the squamous epithelium of the ectocervix [68,69]. However, although these observations suggest another level of potential protection provided by nonneutralizing antibodies at the mucosal epithelium, these interactions need to be better defined.

Back to Top | Article Outline


Although a large number of novel broadly neutralizing antibodies have been recently described [70–72], the induction of such antibodies via vaccination has proven difficult [73]. By contrast, nonneutralizing antibodies arise early during infection and have been repeatedly associated with both protection from infection and disease progression. Moreover, we are beginning to gain new insights into the broader landscape of antiviral mechanisms that nonneutralizing antibodies may harness to fight HIV, providing an unprecedented breadth of approaches by which HIV can be blocked and contained. Together with new insights into the biophysical properties that allow antibodies to recruit specific innate effector functions, significant progress is being made in our understanding of the humoral parameters that might be manipulated via vaccination to improve the antiviral control of HIV.

Back to Top | Article Outline



Back to Top | Article Outline

Conflicts of interest

The authors do not have any conflicts of interest.

Back to Top | Article Outline


Papers of particular interest, published within the annual period of review, have been highlighted as:

▪ of special interest

▪▪ of outstanding interest

Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 513).

Back to Top | Article Outline


1. Rerks-Ngarm S, Pitisuttithum P, Nitayaphan S, et al. Vaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand. N Engl J Med 2009; 361:2209–2220.
2. Barouch DH, Liu J, Li H, et al. Vaccine protection against acquisition of neutralization-resistant SIV challenges in rhesus monkeys. Nature 2012; 482:89–93.
3. Haynes BF, Gilbert PB, McElrath MJ, et al. Immune-correlates analysis of an HIV-1 vaccine efficacy trial. N Engl J Med 2012; 366:1275–1286.
4. Keim C, Kazadi D, Rothschild G, et al. Regulation of AID, the B-cell genome mutator. Genes Dev 2013; 27:1–17.
5. Kinoshita K, Lee CG, Tashiro J, et al. Molecular mechanism of immunoglobulin class switch recombination. Cold Spring Harb Symp Quant Biol 1999; 64:217–226.
6. Banchereau J, Blanchard D, Briere F, et al. Role of cytokines in human B lymphocyte growth and differentiation. Nouv Rev Fr Hematol 1993; 35:61–66.
7. Lundgren M, Persson U, Larsson P, et al. Interleukin 4 induces synthesis of IgE and IgG4 in human B cells. Eur J Immunol 1989; 19:1311–1315.
8. Pene J, Rousset F, Briere F, et al. IgE production by normal human lymphocytes is induced by interleukin 4 and suppressed by interferons gamma and alpha and prostaglandin E2. Proc Natl Acad Sci USA 1988; 85:6880–6884.
9. Pene J, Gauchat JF, Lecart S, et al. Cutting edge: IL-21 is a switch factor for the production of IgG1 and IgG3 by human B cells. J Immunol 2004; 172:5154–5157.
10. Garraud O, Perraut R, Riveau G, et al. Class and subclass selection in parasite-specific antibody responses. Trends Parasitol 2003; 19:300–304.
11. Jefferis R. Glycosylation of antibody therapeutics: optimisation for purpose. Methods Mol Biol 2009; 483:223–238.
12. Nimmerjahn F, Ravetch JV. FcgammaRs in health and disease. Curr Top Microbiol Immunol 2011; 350:105–125.
13. Murphy K, Travers P, Walport M, et al. Janeway's Immunobiology. 8th ed.2012; New York:Garland Science, xix, 868 pp.
14▪▪. Yates NL, Lucas JT, Nolen TL, et al. Multiple HIV-1-specific IgG3 responses decline during acute HIV-1: implications for detection of incident HIV infection. AIDS 2011; 25:2089–2097.

This study points to an early selection of the IgG3 subclass following acute HIV infection, that precipitously declines following infection, potentially useful as a marker of early disease.

15. Tomaras GD, Yates NL, Liu P, et al. Initial B-cell responses to transmitted human immunodeficiency virus type 1: virion-binding immunoglobulin M (IgM) and IgG antibodies followed by plasma antigp41 antibodies with ineffective control of initial viremia. J Virol 2008; 82:12449–12463.
16. Banerjee K, Klasse PJ, Sanders RW, et al. IgG subclass profiles in infected HIV type 1 controllers and chronic progressors and in uninfected recipients of Env vaccines. AIDS Res Hum Retroviruses 2010; 26:445–458.
17. Ljunggren K, Broliden PA, Morfeldt-Manson L, et al. IgG subclass response to HIV in relation to antibody-dependent cellular cytotoxicity at different clinical stages. Clin Exp Immunol 1988; 73:343–347.
18. Shields RL, Lai J, Keck R, et al. Lack of fucose on human IgG1 N-linked oligosaccharide improves binding to human Fcgamma RIII and antibody-dependent cellular toxicity. J Biol Chem 2002; 277:26733–26740.
19. Shinkawa T, Nakamura K, Yamane N, et al. The absence of fucose but not the presence of galactose or bisecting N-acetylglucosamine of human IgG1 complex-type oligosaccharides shows the critical role of enhancing antibody-dependent cellular cytotoxicity. J Biol Chem 2003; 278:3466–3473.
20. Yamane-Ohnuki N, Kinoshita S, Inoue-Urakubo M, et al. Establishment of FUT8 knockout Chinese hamster ovary cells: an ideal host cell line for producing completely defucosylated antibodies with enhanced antibody-dependent cellular cytotoxicity. Biotechnol Bioeng 2004; 87:614–622.
21. Mori K, Iida S, Yamane-Ohnuki N, et al. Nonfucosylated therapeutic antibodies: the next generation of therapeutic antibodies. Cytotechnology 2007; 55:109–114.
22. Matsumiya S, Yamaguchi Y, Saito J, et al. Structural comparison of fucosylated and nonfucosylated Fc fragments of human immunoglobulin G1. J Mol Biol 2007; 368:767–779.
23. Peipp M, Lammerts van Bueren JJ, Schneider-Merck T, et al. Antibody fucosylation differentially impacts cytotoxicity mediated by NK and PMN effector cells. Blood 2008; 112:2390–2399.
24. Junttila TT, Parsons K, Olsson C, et al. Superior in vivo efficacy of afucosylated trastuzumab in the treatment of HER2-amplified breast cancer. Cancer Res 2010; 70:4481–4489.
25. Niwa R, Natsume A, Uehara A, et al. IgG subclass-independent improvement of antibody-dependent cellular cytotoxicity by fucose removal from Asn297-linked oligosaccharides. J Immunol Methods 2005; 306:151–160.
26. Anthony RM, Nimmerjahn F, Ashline DJ, et al. Recapitulation of IVIG anti-inflammatory activity with a recombinant IgG Fc. Science 2008; 320:373–376.
27. Kaneko Y, Nimmerjahn F, Ravetch JV. Anti-inflammatory activity of immunoglobulin G resulting from Fc sialylation. Science 2006; 313:670–673.
28▪▪. Ackerman ME, Crispin M, Yu X, et al. Natural variation in Fc glycosylation of HIV-specific antibodies impacts antiviral activity. J Clin Invest 2013; 123:2183–2192.

This study demonstrates the unusual accumulation of inflammatory antibody glycans among HIV-infected patients, which are agalactosylated and asialated. However, beyond these changes, spontaneous HIV controllers elicited more inflammatory glycoforms associated with higher ADCVI functionality, which were additionally afucosylated.

29. Moore JS, Wu X, Kulhavy R, et al. Increased levels of galactose-deficient IgG in sera of HIV-1-infected individuals. AIDS 2005; 19:381–389.
30. Takai T. Roles of Fc receptors in autoimmunity. Nat Rev Immunol 2002; 2:580–592.
31. Dijstelbloem HM, van de Winkel JG, Kallenberg CG. Inflammation in autoimmunity: receptors for IgG revisited. Trends Immunol 2001; 22:510–516.
32. Budde P, Bewarder N, Weinrich V, et al. Tyrosine-containing sequence motifs of the human immunoglobulin G receptors FcRIIb1 and FcRIIb2 essential for endocytosis and regulation of calcium flux in B cells. J Biol Chem 1994; 269:30636–30644.
33. Bruhns P, Iannascoli B, England P, et al. Specificity and affinity of human Fcgamma receptors and their polymorphic variants for human IgG subclasses. Blood 2009; 113:3716–3725.
34. Burton DR, Hessell AJ, Keele BF, et al. Limited or no protection by weakly or nonneutralizing antibodies against vaginal SHIV challenge of macaques compared with a strongly neutralizing antibody. Proc Natl Acad Sci USA 2011; 108:11181–11186.
35. Xiao P, Zhao J, Patterson LJ, et al. Multiple vaccine-elicited nonneutralizing antienvelope antibody activities contribute to protective efficacy by reducing both acute and chronic viremia following simian/human immunodeficiency virus SHIV89.6P challenge in rhesus macaques. J Virol 2010; 84:7161–7173.
36. Florese RH, Demberg T, Xiao P, et al. Contribution of nonneutralizing vaccine-elicited antibody activities to improved protective efficacy in rhesus macaques immunized with Tat/Env compared with multigenic vaccines. J Immunol 2009; 182:3718–3727.
37. Hidajat R, Xiao P, Zhou Q, et al. Correlation of vaccine-elicited systemic and mucosal nonneutralizing antibody activities with reduced acute viremia following intrarectal simian immunodeficiency virus SIVmac251 challenge of rhesus macaques. J Virol 2009; 83:791–801.
38. Hessell AJ, Hangartner L, Hunter M, et al. Fc receptor but not complement binding is important in antibody protection against HIV. Nature 2007; 449:101–104.
39. Gomez-Roman VR, Patterson LJ, Venzon D, et al. Vaccine-elicited antibodies mediate antibody-dependent cellular cytotoxicity correlated with significantly reduced acute viremia in rhesus macaques challenged with SIVmac251. J Immunol 2005; 174:2185–2189.
40. Koff WC. HIV vaccine development: challenges and opportunities towards solving the HIV vaccine-neutralizing antibody problem. Vaccine 2012; 30:4310–4315.
41. Klasse PJ. Modeling how many envelope glycoprotein trimers per virion participate in human immunodeficiency virus infectivity and its neutralization by antibody. Virology 2007; 369:245–262.
42. Campbell SM, Crowe SM, Mak J. Lipid rafts and HIV-1: from viral entry to assembly of progeny virions. J Clin Virol 2001; 22:217–227.
43▪. Alpert MD, Harvey JD, Lauer WA, et al. ADCC develops over time during persistent infection with live-attenuated SIV and is associated with complete protection against SIV(mac)251 challenge. PLoS Pathog 2012; 8:e1002890.

This study points to a potential protective role for ADCC-inducing antibodies, induced by vaccination with the live-attenuated SIV, against infection, pointing to a prophylactic.

44. Bomsel M, Tudor D, Drillet AS, et al. Immunization with HIV-1 gp41 subunit virosomes induces mucosal antibodies protecting nonhuman primates against vaginal SHIV challenges. Immunity 2011; 34:269–280.
45. Xiao P, Patterson LJ, Kuate S, et al. Replicating adenovirus-simian immunodeficiency virus (SIV) recombinant priming and envelope protein boosting elicits localized, mucosal IgA immunity in rhesus macaques correlated with delayed acquisition following a repeated low-dose rectal SIV(mac251) challenge. J Virol 2012; 86:4644–4657.
46. Lai L, Kwa SF, Kozlowski PA, et al. SIVmac239 MVA vaccine with and without a DNA prime, similar prevention of infection by a repeated dose SIVsmE660 challenge despite different immune responses. Vaccine 2012; 30:1737–1745.
47▪▪. Moldt B, Shibata-Koyama M, Rakasz EG, et al. A nonfucosylated variant of the anti-HIV-1 monoclonal antibody b12 has enhanced FcgammaRIIIa-mediated antiviral activity in vitro but does not improve protection against mucosal SHIV challenge in macaques. J Virol 2012; 86:6189–6196.

This study shows a lack of an enhanced protective effect against HIV acquisition following administration of an ADCC-enhanced (afucosylated) variant of B12, suggesting that the Fc-mediated protective role of B12 may be mediated through other effector mechanisms than ADCC.

48. Sips M, Sciaranghella G, Diefenbach T, et al. Altered distribution of mucosal NK cells during HIV infection. Mucosal Immunol 2012; 5:30–40.
49. Smith PD, Meng G, Salazar-Gonzalez JF, et al. Macrophage HIV-1 infection and the gastrointestinal tract reservoir. J Leukoc Biol 2003; 74:642–649.
50. Holl V, Hemmerter S, Burrer R, et al. Involvement of Fc gamma RI (CD64) in the mechanism of HIV-1 inhibition by polyclonal IgG purified from infected patients in cultured monocyte-derived macrophages. J Immunol 2004; 173:6274–6283.
51. Holl V, Peressin M, Decoville T, et al. Nonneutralizing antibodies are able to inhibit human immunodeficiency virus type 1 replication in macrophages and immature dendritic cells. J Virol 2006; 80:6177–6181.
52. Holl V, Peressin M, Schmidt S, et al. Efficient inhibition of HIV-1 replication in human immature monocyte-derived dendritic cells by purified anti-HIV-1 IgG without induction of maturation. Blood 2006; 107:4466–4474.
53. Forthal DN, Moog C. Fc receptor-mediated antiviral antibodies. Curr Opin HIV AIDS 2009; 4:388–393.
54. Barouch DH, Liu J, Peter L, et al. Characterization of humoral and cellular immune responses elicited by a recombinant adenovirus serotype 26 HIV-1 Env vaccine in healthy adults (IPCAVD 001). J Infect Dis 2013; 207:248–256.
55. Forthal DN, Landucci G, Ding H, et al. IgG2 inhibits HIV-1 internalization by monocytes, and IgG subclass binding is affected by gp120 glycosylation. AIDS 2011; 25:2099–2104.
56. Ackerman ME, Dugast AS, McAndrew EG, et al. Enhanced phagocytic activity of HIV-specific antibodies correlates with natural production of immunoglobulins with skewed affinity for FcgammaR2a and FcgammaR2b. J Virol 2013; 87:5468–5476.
57. Forthal DN, Landucci G, Bream J, et al. FcgammaRIIa genotype predicts progression of HIV infection. J Immunol 2007; 179:7916–7923.
58. Forthal DN, Landucci G, Daar ES. Antibody from patients with acute human immunodeficiency virus (HIV) infection inhibits primary strains of HIV type 1 in the presence of natural-killer effector cells. J Virol 2001; 75:6953–6961.
59. Forthal DN, Landucci G, Cole KS, et al. Rhesus macaque polyclonal and monoclonal antibodies inhibit simian immunodeficiency virus in the presence of human or autologous rhesus effector cells. J Virol 2006; 80:9217–9225.
60. Bialuk I, Whitney S, Andresen V, et al. Vaccine induced antibodies to the first variable loop of human immunodeficiency virus type 1 gp120, mediate antibody-dependent virus inhibition in macaques. Vaccine 2011; 30:78–94.
61. Forthal DN, Gilbert PB, Landucci G, et al. Recombinant gp120 vaccine-induced antibodies inhibit clinical strains of HIV-1 in the presence of Fc receptor-bearing effector cells and correlate inversely with HIV infection rate. J Immunol 2007; 178:6596–6603.
62. Forthal DN, Landucci G, Chohan B, et al. Antibody-dependent cell-mediated virus inhibition (ADCVI) antibody activity does not correlate with risk of HIV-1 superinfection. J Acquir Immune Defic Syndr 2013; 63:31–33.
63. Boeras DI, Hraber PT, Hurlston M, et al. Role of donor genital tract HIV-1 diversity in the transmission bottleneck. Proc Natl Acad Sci USA 2011; 108:E1156–E1163.
64. Olson A, Diebel LN, Liberati DM. Effect of host defenses on Clostridium difficile toxin-induced intestinal barrier injury. J Trauma Acute Care Surg 2013; 74:983–989.discussion 989–990..
65. Phalipon A, Cardona A, Kraehenbuhl JP, et al. Secretory component: a new role in secretory IgA-mediated immune exclusion in vivo. Immunity 2002; 17:107–115.
66. Frantz AL, Rogier EW, Weber CR, et al. Targeted deletion of MyD88 in intestinal epithelial cells results in compromised antibacterial immunity associated with downregulation of polymeric immunoglobulin receptor, mucin-2, and antibacterial peptides. Mucosal Immunol 2012; 5:501–512.
67. Ambrosini G, Andrisani A, Fiore C, et al. Anti-Helicobacter pylori antibodies in cervical mucus: a new cause of infertility. Eur J Obstet Gynecol Reprod Biol 2011; 155:157–160.
68. Blaskewicz CD, Pudney J, Anderson DJ. Structure and function of intercellular junctions in human cervical and vaginal mucosal epithelia. Biol Reprod 2011; 85:97–104.
69. Fahrbach KM, Barry SM, Anderson MR, et al. Enhanced cellular responses and environmental sampling within inner foreskin explants: implications for the foreskin's role in HIV transmission. Mucosal Immunol 2010; 3:410–418.
70. Huang J, Ofek G, Laub L, et al. Broad and potent neutralization of HIV-1 by a gp41-specific human antibody. Nature 2012; 491:406–412.
71. Walker LM, Huber M, Doores KJ, et al. Broad neutralization coverage of HIV by multiple highly potent antibodies. Nature 2011; 477:466–470.
72. Wu X, Yang ZY, Li Y, et al. Rational design of envelope identifies broadly neutralizing human monoclonal antibodies to HIV-1. Science 2010; 329:856–861.
73. Mascola JR, Montefiori DC. The role of antibodies in HIV vaccines. Annu Rev Immunol 2010; 28:413–444.

ADCC; antibodies; HIV

Copyright © 2013 Wolters Kluwer Health, Inc. All rights reserved.