Fc receptor-mediated phagocytosis in tissues as a potent mechanism for preventive and therapeutic HIV vaccine strategies

Sips, Magdalena; Krykbaeva, Marina; Diefenbach, Thomas; Ghebremichael, Musie; Bowman, Brittany A.; Dugast, Anne‐Sophie; Boesch, Austin W.; Streeck, Hendrik; Kwon, Douglas S.; Ackerman, Margaret E.; Suscovich, Todd J.; Brouckaert, Peter; Schacker, Timothy W.; Alter, Galit

doi:10.1038/mi.2016.12

Cited by 86 publications

(89 citation statements)

References 59 publications

(83 reference statements)

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“…It has been suggested that nonneutralizing mechanisms, such as phagocytosis, neutrophil activation, and ADCC, are likely to play a role in both HIV prevention and reservoir-eliminating therapeutic approaches (77,78). This is supported by the RV144 clinical trial where a correlate of reduced infection was found with various Fc-mediated activities but not with neutralization (9-18).…”

Section: Discussionmentioning

confidence: 50%

Rationally Designed Vaccines Targeting the V2 Region of HIV-1 gp120 Induce a Focused, Cross-Clade-Reactive, Biologically Functional Antibody Response

Zolla‐Pazner

Powell

Yahyaei

et al. 2016

J Virol

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Strong antibody (Ab) responses against V1V2 epitopes of the human immunodeficiency virus type 1 (HIV-1) gp120 envelope (Env) correlated with reduced infection rates in studies of HIV, simian-human immunodeficiency virus (SHIV), and simian immunodeficiency virus (SIV). In order to focus the Ab response on V1V2, we used six V1V2 sequences and nine scaffold proteins to construct immunogens which were tested using various immunization regimens for their ability to induce cross-reactive and biologically active V2 Abs in rabbits. A prime/boost immunization strategy was employed using gp120 DNA and various V1V2-scaffold proteins. The rabbit polyclonal Ab responses (i) were successfully focused on the V1V2 region, with weak or only transient responses to other Env epitopes, (ii) displayed broad cross-reactive binding activity with gp120s and the V1V2 regions of diverse strains from clades B, C, and E, (iii) included V2 Abs with specificities similar to those found in HIV-infected individuals, and (iv) remained detectable >1 year after the last boosting dose. Importantly, sera from rabbits receiving V1V2-scaffold immunogens displayed Ab-dependent cellular phagocytosis whereas sera from rabbits receiving only gp120 did not. The results represent the first fully successful example of reverse vaccinology in the HIV vaccine field with rationally designed epitope scaffold immunogens inducing Abs that recapitulate the epitope specificity and biologic activity of the human monoclonal Abs from which the immunogens were designed. Moreover, this is the first immunogenicity study using epitope-targeting, rationally designed vaccine constructs that induced an Fc-mediated activity associated with protection from infection with HIV, SIV, and SHIV. IMPORTANCENovel immunogens were designed to focus the antibody response of rabbits on the V1V2 epitopes of HIV-1 gp120 since such antibodies were associated with reduced infection rates of HIV, SIV, and SHIV. The vaccine-induced antibodies were broadly cross-reactive with the V1V2 regions of HIV subtypes B, C and E and, importantly, facilitated Fc-mediated phagocytosis, an activity not induced upon immunization of rabbits with gp120. This is the first immunogenicity study of vaccine constructs that focuses the antibody response on V1V2 and induces V2-specific antibodies with the ability to mediate phagocytosis, an activity that has been associated with protection from infection with HIV, SIV, and SHIV. N onneutralizing antibodies (Abs) can protect against various viral infections, contributing to protection from alphaviruses, flaviviruses, respiratory syncytial virus (RSV), and cytomegalovirus, among others (reviewed in references 1 and 2). While the specificity and affinity of nonneutralizing Abs are dependent on the Fab fragment of Abs to target virions and infected cells, many of the biologic activities of these Abs are a function of the Fc fragment. Such activities include Ab-dependent cellular cytotoxicity (ADCC), Ab-dependent cellular phagocytosis (ADCP), Abdependent cell-media...

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Section: Discussionmentioning

confidence: 50%

Rationally Designed Vaccines Targeting the V2 Region of HIV-1 gp120 Induce a Focused, Cross-Clade-Reactive, Biologically Functional Antibody Response

Zolla‐Pazner

Powell

Yahyaei

et al. 2016

J Virol

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“…ADCP may contribute more to vaccine-elicited protection than ADCC, particularly in mucosal tissues (33). ADCP was enhanced in recipients of the RV144 vaccine with a high level of IgG3/IgG1 Abs to V1-V2 (34) and was associated with protection in nonhuman primates (29).…”

mentioning

confidence: 99%

Monoclonal Antibodies Specific for the V2, V3, CD4-Binding Site, and gp41 of HIV-1 Mediate Phagocytosis in a Dose-Dependent Manner

Musich

Liu

et al. 2017

J Virol

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In light of the weak or absent neutralizing activity mediated by anti-V2 monoclonal antibodies (MAbs), we tested whether they can mediate Ab-dependent cellular phagocytosis (ADCP), which is an important element of anti-HIV-1 immunity. We tested six anti-V2 MAbs and compared them with 21 MAbs specific for V3, the CD4-binding site (CD4bs), and gp41 derived from chronically HIV-1-infected individuals and produced by hybridoma cells. ADCP activity was measured by flow cytometry using uptake by THP-1 monocytic cells of fluorescent beads coated with gp120, gp41, BG505 SOSIP.664, or BG505 DS-SOSIP.664 complexed with MAbs. The measurement of ADCP activity by the area under the curve showed significantly higher activity of anti-gp41 MAbs than of the members of the three other groups of MAbs tested using beads coated with monomeric gp41 or gp120; anti-V2 MAbs were dominant compared to anti-V3 and anti-CD4bs MAbs against clade C gp120 ZM109 . ADCP activity mediated by V2 and V3 MAbs was positive against stabilized DS-SOSIP.664 trimer but negligible against SOSIP.664 targets, suggesting that a closed envelope conformation better exposes the variable loops. Two IgG3 MAbs against the V2 and V3 regions displayed dominant ADCP activity compared to a panel of IgG1 MAbs. This superior ADCP activity was confirmed when two of three recombinant IgG3 anti-V2 MAbs were compared to their IgG1 counterparts. The study demonstrated dominant ADCP activity of anti-gp41 against monomers but not trimers, with some higher activity of anti-V2 MAbs than of anti-V3 and anti-CD4bs MAbs. The ability to mediate ADCP suggests a mechanism by which anti-HIV-1 envelope Abs can contribute to protective efficacy.IMPORTANCE Anti-V2 antibodies (Abs) correlated with reduced risk of HIV-1 infection in recipients of the RV144 vaccine, suggesting that they play a protective role, but a mechanism providing such protection remains to be determined. The rare and weak neutralizing activities of anti-V2 MAbs prompted us to study Fc-mediated activities. We compared anti-V2 MAbs with other MAbs specific for V3, CD4bs, and gp41 for Ab-dependent cellular phagocytosis (ADCP) activity, implicated in protective immunity. The anti-V2 MAbs displayed stronger activity than other anti-gp120 MAbs in screening against one of two gp120s and against DS-SOSIP, which mimics the native trimer. The activity of anti-gp41 MAbs was superior in targeting monomeric gp41 but was comparable to that seen against trimers, which may not adequately expose gp41 epitopes. While anti-envelope MAbs in general mediated ADCP activity, anti-V2 MAbs displayed some dominance compared to other MAbs. Our demonstration that anti-V2 MAbs mediate ADCP activity suggests a functional mechanism for their contribution to protective efficacy.

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“…This suggests that the in vivo antitumor activity of this fusion protein can be retained by its apoptotic effects and CDC in mice with diminished NK cell activity. Macrophages and neutrophils are also known to exhibit ADCC function (13). It is possible that macrophages and neutrophils can replace the ADCC function of NK cells for this fusion protein in SCID-beige mice.…”

Section: Discussionmentioning

confidence: 99%

“…This finding suggests that although 2B8T2M induces antitumor activity through ADCC, the in vivo antitumor activity of this fusion protein is retained by its apoptotic effects and CDC against tumor cells in mice with diminished NK cell activity. Macrophages and neutrophils are also known to exhibit ADCC and antibody-dependent cellular phagocytosis functions (13). It is possible that macrophages and neutrophils contribute to the antitumor activity of this fusion protein in the SCID-beige mice.…”

Section: Journal Of Biological Chemistry 23875mentioning

confidence: 99%

A Novel Fusion of ALT-803 (Interleukin (IL)-15 Superagonist) with an Antibody Demonstrates Antigen-specific Antitumor Responses

Liu

Kong

Han

et al. 2016

Journal of Biological Chemistry

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Edited by Luke O'Neill IL-15 and its receptor ␣ (IL-15R␣IL-15, a four-helix, common ␥ chain (␥ C ) 2 cytokine, is a critical factor for the development, proliferation, and activation of natural killer (NK) cells and CD8 ϩ T cells (1, 2). IL-15 is co-expressed with its ␣ chain receptor (IL-15R␣) by antigen-presenting cells, and the two proteins form a complex on the cell surface that is transpresented to NK and T cells bearing the IL-2R␤␥ C complex (2). IL-15 binds to IL-15R␣ at high affinity, and IL-15R␣ functions as a chaperone and conformational stabilizer to enhance the interaction between IL-15 and IL-2R␤␥ C (2). We identified a novel IL-15 variant carrying an asparagineto-aspartic acid mutation at amino acid 72 (N72D) that exhibits superior binding to IL-2R␤␥ C on immune cells and increased immunostimulatory activity (3). Our previous studies have demonstrated that this IL-15 variant, when associated with a soluble IL-15R␣ sushi domain fusion to IgG1 Fc (IL15R␣SuFc), could form a heterodimeric complex, IL-15N72D⅐ IL-15R␣SuFc (designated ALT-803), that also exhibits increased binding activity to the IL-2R␤␥ C complex, enhanced capacity to stimulate NK and T cells, and has a longer biological half-life compared with native IL-15 (4). In various animal models, ALT-803 acts as a potent immunostimulant that is capable of simultaneously activating the innate and adaptive arms of the immune system to elicit both rapid and long-lasting protective responses against neoplastic challenges (5). Moreover, ALT-803, in combination with checkpoint blockade or therapeutic antibodies, is effective in reducing the tumor burden and prolonging survival in mouse tumor models (6, 7). To make ALT-803-based molecules more specific and efficient in combating disease, we converted ALT-803 into a targeted immunotherapeutic agent by genetically fusing it with singlechain antibodies (scFv) at the N termini of IL-15N72D and IL-15R␣SuFc proteins. In this study, we used the anti-CD20 scFv as the target recognition domain to demonstrate that ALT-803 is a versatile, functional scaffold for creating diseasetargeted immunostimulatory molecules. This novel single fusion protein approach was also found to improve the antibody-dependent cellular cytotoxicity (ADCC) and apoptotic functions of the anti-CD20 therapeutic antibody rituximab.

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Fc receptor-mediated phagocytosis in tissues as a potent mechanism for preventive and therapeutic HIV vaccine strategies

Cited by 86 publications

References 59 publications

Rationally Designed Vaccines Targeting the V2 Region of HIV-1 gp120 Induce a Focused, Cross-Clade-Reactive, Biologically Functional Antibody Response

Rationally Designed Vaccines Targeting the V2 Region of HIV-1 gp120 Induce a Focused, Cross-Clade-Reactive, Biologically Functional Antibody Response

Monoclonal Antibodies Specific for the V2, V3, CD4-Binding Site, and gp41 of HIV-1 Mediate Phagocytosis in a Dose-Dependent Manner

A Novel Fusion of ALT-803 (Interleukin (IL)-15 Superagonist) with an Antibody Demonstrates Antigen-specific Antitumor Responses

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