Cryptic Determinant of α4β7 Binding in the V2 Loop of HIV-1 gp120

Tassaneetrithep, Boonrat; Tivon, Doreen; Swetnam, James; Karasavvas, Nicos; Michael, Nelson L.; Kim, Jerome H.; Marovich, Mary; Cardozo, Timothy

doi:10.1371/journal.pone.0108446

Cited by 35 publications

(48 citation statements)

References 20 publications

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“…In support of this hypothesis, mouse anti-V2 MAbs have been shown to inhibit binding of biotinylated gp120 MN to the ␣4␤7 ϩ ␤1 Ϫ RPMI-8866 B lymphoma cell line (14). Two human anti-V2 MAbs from our laboratory, 697 and 2158, also inhibited binding of gp120 MN to CD4 ϩ cells and activated CD8 ϩ cells (17). The extent to which such blocking by V2-specific Abs occurs in vivo is not known; however, it has been reported that the envelopes of most HIV strains do not bind to ␣4␤7 (18), a result that may be dependent upon the nature of the carbohydrate residues on the Env protein.…”

mentioning

confidence: 66%

“…Indeed, the protective role of anti-V2 Abs against HIV-1 infection may eventually prove to be polyfunctional. It may include other functions not explored here, such as additional Fc receptor-related activities and/or the inhibition of the gp120/ ␣4␤7 interaction which has been shown previously despite some remaining controversy (14,17,18).…”

Section: Discussionmentioning

confidence: 96%

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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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mentioning

confidence: 66%

Section: Discussionmentioning

confidence: 96%

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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“…ab initio folding was performed using ICM-Pro software (Molsoft LLC, La Jolla, CA, USA) as previously described [9, 15, 16]. Briefly, the 3D atomic structure corresponding to each peptide sequence was built.…”

Section: Methodsmentioning

confidence: 99%

“…The two others were secondary study variables: a gp120 peptide microarray and an ELISA using a non-biotinylated peptide equivalent to the V2 segment from positions 161 to 183 (numbering based on the Hxbc2 reference strain of HIV) of the MN strain of HIV (MN peptide) as the detection reagent [6]. Neither of these two latter probes were glycosylated entities, so they contained only natural amino acids, and they overlapped at the V2 peptide segment from positions 165 to 181[8, 9]. Two independent sieve analysis of RV144 data identified position 169 within this segment as correlating with vaccine efficacy, one of which identified a specific HLA allele/cytotoxic T-cell epitope (CTL) in the MN peptide [10, 11].…”

Section: Introductionmentioning

confidence: 99%

Peptide Targeted by Human Antibodies Associated with HIV Vaccine-Associated Protection Assumes a Dynamic α-Helical Structure

et al. 2017

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The only evidence of vaccine-induced protection from HIV acquisition in humans was obtained in the RV144 HIV vaccine clinical trial. One immune correlate of risk in RV144 was observed to be higher titers of vaccine-induced antibodies (Abs) reacting with a 23-mer non-glycosylated peptide with the same amino acid sequence as a segment in the second variable (V2) loop of the MN strain of HIV. We used NMR to analyze the dynamic 3D structure of this peptide. Distance restraints between spatially proximate inter-residue protons were calculated from NOE cross peak intensities and used to constrain a thorough search of all possible conformations of the peptide. α–helical folding was strongly preferred by part of the peptide. A high-throughput structure prediction of this segment in all circulating HIV strains demonstrated that α–helical conformations are preferred by this segment almost universally across all subtypes. Notably, α–helical conformations of this segment of the V2 loop cluster cross-subtype-conserved amino acids on one face of the helix and the variable amino acid positions on the other in a semblance of an amphipathic α–helix. Accordingly, some Abs that protected against HIV in RV144 may have targeted a specific, conserved α–helical peptide epitope in the V2 loop of HIV’s surface envelope glycoprotein.

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“…This suggests that the contribution of anti-V3 Abs in reducing infection may depend on their potential to neutralize HIV-1 while the role of anti-V2 Abs may depend on other functions, including the interference of virus that binds to T cells that express integrin α4β7, as some studies suggest (12, 13). Although anti-V3 mAbs neutralize mainly tier 1 pseudoviruses, most anti-V3 mAbs can neutralize one to several tier-2 and -3 viruses (11, 14).…”

Section: Introductionmentioning

confidence: 99%

Induction of neutralizing antibodies in rhesus macaques using V3 mimotope peptides

Hessell

McBurney

Pandey

et al. 2016

Vaccine

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RV144 vaccinees with low HIV-1 Envelope-specific IgA antibodies (Abs) also had Abs directed to the hypervariable region 3 (V3) that inversely correlated with infection risk. Thus, anti-V3 HIV-1 Abs may contribute to protection from HIV-1 infection. The V3 region contains two dominant clusters of epitopes; one is preferentially recognized by mAbs encoded by VH5-51 and VL lambda genes, while the second one is recognized by mAbs encoded by other VH genes. We designed a study in rhesus macaques to induce anti-V3 Abs specific to each of these two dominant clusters of V3 epitopes to test whether the usage of the VH5-51 gene results in different characteristics of antibodies. The two C4-V3 immunogens used for immunization were each comprised of a fusion of the C4 peptide containing the T cell epitope and a V3 mimotope peptide mimicking the V3 epitope. The C4-447 peptide was designed to target B cells with several VH1–VH4 genes, the C4-VH5-51 peptide was designed to specifically target B cells with the VH5-51 gene. Six animals in two groups were immunized five times with these two immunogens, and screening of 10 sequential plasma samples post immunization demonstrated that C4-447 induced higher titers of plasma anti-V3 Abs and significantly more potent neutralizing activities against tier 1 and some tier 2 pseudoviruses than C4-VH5-51. Levels of anti-V3 Abs in buccal secretions were significantly higher in sequential samples derived from C4-447-than from C4-VH5-51-immunized animals. The titers of anti-V3 Abs in plasma strongly correlated with their levels in mucosal secretions. The results show that high titers of vaccine-induced anti-V3 Abs in plasma determine the potency and breadth of neutralization, as well as the rate of transduction of Abs to mucosal tissues, where they can play a role in preventing HIV-1 infection.

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Cryptic Determinant of α4β7 Binding in the V2 Loop of HIV-1 gp120

Cited by 35 publications

References 20 publications

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

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

Peptide Targeted by Human Antibodies Associated with HIV Vaccine-Associated Protection Assumes a Dynamic α-Helical Structure

Induction of neutralizing antibodies in rhesus macaques using V3 mimotope peptides

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