scholarly journals The high-affinity immunoglobulin receptor FcγRI potentiates HIV-1 neutralization via antibodies against the gp41 N-heptad repeat

2021 ◽  
Vol 118 (3) ◽  
pp. e2018027118 ◽  
Author(s):  
David C. Montefiori ◽  
Maria V. Filsinger Interrante ◽  
Benjamin N. Bell ◽  
Adonis A. Rubio ◽  
Joseph G. Joyce ◽  
...  
Keyword(s):  
Sexual Transmission ◽  
Heptad Repeat ◽  
Dependent Manner ◽  
Tier 2 ◽  
Neutralization Activity ◽  
Immunoglobulin Receptor ◽  
Mucosal Surfaces ◽  
Tier 1 ◽  
Viral Membrane Fusion ◽  
Hiv 1

The HIV-1 gp41 N-heptad repeat (NHR) region of the prehairpin intermediate, which is transiently exposed during HIV-1 viral membrane fusion, is a validated clinical target in humans and is inhibited by the Food and Drug Administration (FDA)-approved drug enfuvirtide. However, vaccine candidates targeting the NHR have yielded only modest neutralization activities in animals; this inhibition has been largely restricted to tier-1 viruses, which are most sensitive to neutralization by sera from HIV-1–infected individuals. Here, we show that the neutralization activity of the well-characterized NHR-targeting antibody D5 is potentiated >5,000-fold in TZM-bl cells expressing FcγRI compared with those without, resulting in neutralization of many tier-2 viruses (which are less susceptible to neutralization by sera from HIV-1–infected individuals and are the target of current antibody-based vaccine efforts). Further, antisera from guinea pigs immunized with the NHR-based vaccine candidate (ccIZN36)3 neutralized tier-2 viruses from multiple clades in an FcγRI-dependent manner. As FcγRI is expressed on macrophages and dendritic cells, which are present at mucosal surfaces and are implicated in the early establishment of HIV-1 infection following sexual transmission, these results may be important in the development of a prophylactic HIV-1 vaccine.

scholarly journals The high-affinity immunoglobulin receptor FcγRI potentiates HIV-1 neutralization via antibodies against the gp41 N-heptad repeat

2020 ◽  
Author(s):  
David C. Montefiori ◽  
Maria V. Filsinger Interrante ◽  
Benjamin N. Bell ◽  
Adonis A. Rubio ◽  
Joseph G. Joyce ◽  
...  
Keyword(s):  
Sexual Transmission ◽  
Heptad Repeat ◽  
Dependent Manner ◽  
Tier 2 ◽  
Neutralization Activity ◽  
Immunoglobulin Receptor ◽  
Mucosal Surfaces ◽  
Tier 1 ◽  
Viral Membrane Fusion ◽  
Hiv 1

AbstractThe HIV-1 gp41 N-heptad repeat (NHR) region of the pre-hairpin intermediate, which is transiently exposed during HIV-1 viral membrane fusion, is a validated clinical target in humans and is inhibited by the FDA-approved drug enfuvirtide. However, vaccine candidates targeting the NHR have yielded only modest neutralization activities in animals; this inhibition has been largely restricted to tier-1 viruses, which are most sensitive to neutralization by sera from HIV-1-infected individuals. Here, we show that the neutralization activity of the well-characterized NHR-targeting antibody D5 is potentiated >5,000-fold in TZM-bl cells expressing FcγRI compared to those without, resulting in neutralization of many tier-2 viruses (which are less susceptible to neutralization by sera from HIV-1-infected individuals and are the target of current antibody-based vaccine efforts). Further, antisera from guinea pigs immunized with the NHR-based vaccine candidate (ccIZN36)3 neutralized tier-2 viruses from multiple clades in an FcγRI-dependent manner. As FcγRI is expressed on macrophages and dendritic cells, which are present at mucosal surfaces and are implicated in the early establishment of HIV-1 infection following sexual transmission, these results may be important in the development of a prophylactic HIV-1 vaccine.

scholarly journals A derivative of the D5 monoclonal antibody that targets the gp41 N-heptad repeat of HIV-1 with broad tier-2 neutralizing activity

2021 ◽  
Author(s):  
Adonis A. Rubio ◽  
Maria V. Filsinger Interrante ◽  
Benjamin N. Bell ◽  
Clayton L. Brown ◽  
Theodora U. J. Bruun ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Vaccine Development ◽  
Passive Immunization ◽  
Heptad Repeat ◽  
Target Cells ◽  
Tier 2 ◽  
Viral Glycoprotein ◽  
Neutralizing Activity ◽  
Tier 1 ◽  
Hiv 1

HIV-1 infection is initiated by the viral glycoprotein Env, which, after interaction with cellular coreceptors, adopts a transient conformation known as the pre-hairpin intermediate (PHI). The N-heptad repeat (NHR) is a highly conserved region of gp41 exposed in the PHI; it is the target of the FDA-approved drug enfuvirtide and of neutralizing monoclonal antibodies (mAbs). However, to date these mAbs have only been weakly effective against tier-1 HIV-1 strains, which are most sensitive to neutralizing antibodies. Here, we engineered and tested 11 IgG variants of D5, an anti-NHR mAb, by recombining previously described mutations in four of D5’s six antibody complementarity-determining regions. One variant, D5_AR, demonstrated 6-fold enhancement in ID50 against lentivirus pseudotyped with HXB2 Env. D5_AR exhibited weak cross-clade neutralizing activity against a diverse set of tier-2 HIV-1 viruses, which are less sensitive to neutralizing antibodies than tier-1 viruses and are the target of current antibody-based vaccine efforts. In addition, the neutralization potency of D5_AR IgG was greatly enhanced in target cells expressing FcγRI, with ID50 values below 0.1 μg/mL; this immunoglobulin receptor is expressed on macrophages and dendritic cells, which are implicated in the early stages of HIV-1 infection of mucosal surfaces. D5 and D5_AR have equivalent neutralization potency in IgG, Fab, and scFv formats, indicating that neutralization is not impacted by steric hindrance. Taken together, these results provide support for vaccine strategies that target the PHI by eliciting antibodies against the gp41 NHR and support investigation of anti-NHR mAbs in non-human primate passive immunization studies. Importance Despite advances in anti-retroviral therapy, HIV remains a global epidemic and has claimed more than 32 million lives. Accordingly, developing an effective HIV vaccine remains an urgent public health need. The gp41 N-heptad repeat (NHR) of the HIV-1 pre-hairpin intermediate (PHI) is highly conserved (>90%) and is inhibited by the FDA-approved drug enfuvirtide, making it an attractive vaccine target. However, to date anti-NHR antibodies have not been potent. Here, we engineered D5_AR, a more potent variant of the anti-NHR antibody D5, and established its ability to inhibit HIV-1 strains that are more difficult to neutralize and are more representative of circulating strains (tier-2 strains). The neutralizing activity of D5_AR was greatly potentiated in cells expressing FcγRI; FcγRI is expressed on cells that are implicated at the earliest stages of sexual HIV-1 transmission. Taken together, these results bolster efforts to target the gp41 NHR and the PHI for vaccine development.

scholarly journals A derivative of the D5 monoclonal antibody that targets the gp41 N-heptad repeat of HIV-1 with broad tier-2 neutralizing activity

2020 ◽  
Author(s):  
Adonis A. Rubio ◽  
Maria V. Filsinger Interrante ◽  
Benjamin N. Bell ◽  
Clayton L. Brown ◽  
Celia C. LaBranche ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Vaccine Development ◽  
Heptad Repeat ◽  
Effective Vaccine ◽  
Target Cells ◽  
Tier 2 ◽  
Viral Glycoprotein ◽  
Neutralizing Activity ◽  
Tier 1 ◽  
Hiv 1

AbstractHIV-1 infection is initiated by the viral glycoprotein Env, which, after interaction with cellular coreceptors, adopts a transient conformation known as the pre-hairpin intermediate (PHI). The N-heptad repeat (NHR) is a highly conserved region of gp41 exposed in the PHI; it is the target of the FDA-approved drug enfuvirtide and of neutralizing monoclonal antibodies (mAbs). However, to date these mAbs have only been weakly effective against tier-1 HIV-1 strains, which are most sensitive to neutralizing antibodies. Here, we engineered and tested 11 IgG variants of D5, an anti-NHR mAb, by recombining previously described mutations in four of D5’s six antibody complementarity-determining regions. One variant, D5_AR, demonstrated 6-fold enhancement in ID50 against lentivirus pseudotyped with HXB2 Env. Importantly, D5_AR exhibited weak cross-clade neutralizing activity against a diverse set of tier-2 HIV-1 viruses, which are less sensitive to neutralizing antibodies than tier-1 viruses and are the target of current antibody-based vaccine efforts. In addition, the neutralization potency of D5_AR IgG was greatly enhanced in target cells expressing FcγRI with ID50 values below 0.1 μg/mL; this immunoglobulin receptor is expressed on macrophages and dendritic cells, which are implicated in the early stages of HIV-1 infection of mucosal surfaces. D5 and D5_AR have equivalent neutralization potency in IgG, Fab, and scFv formats, indicating that neutralization is not impacted by steric hindrance. Taken together, these results provide support for vaccine strategies that target the PHI by eliciting antibodies against the gp41 NHR.ImportanceDespite advances in anti-retroviral therapy, HIV remains a global epidemic and has claimed more than 32 million lives. Accordingly, developing an effective vaccine remains an urgent public health need. The gp41 N-heptad repeat (NHR) of the HIV-1 pre-hairpin intermediate (PHI) is highly conserved (>90%) and is inhibited by the FDA-approved drug enfuvirtide, making it an attractive vaccine target. However, to date NHR antibodies have not been potent. Here, we engineered D5_AR, a more potent variant of the anti-NHR antibody D5, and established its ability to inhibit HIV-1 strains that are more difficult to neutralize and are more representative of circulating strains (tier-2 strains). The neutralizing activity of D5_AR was greatly potentiated in cells expressing FcγRI; FcγRI is expressed on cells that are implicated at the earliest stages of sexual HIV-1 transmission. Taken together, these results bolster efforts to target the gp41 NHR and the PHI for vaccine development.

scholarly journals DNA Vaccine Molecular Adjuvants SP-D-BAFF and SP-D-APRIL Enhance Anti-gp120 Immune Response and Increase HIV-1 Neutralizing Antibody Titers

2015 ◽  
Vol 89 (8) ◽  
pp. 4158-4169 ◽  
Author(s):  
Sachin Gupta ◽  
Emily S. Clark ◽  
James M. Termini ◽  
Justin Boucher ◽  
Saravana Kanagavelu ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Surfactant Protein ◽  
Surfactant Protein D ◽  
Tier 2 ◽  
Tier 1 ◽  
Membrane Bound ◽  
Molecular Adjuvants ◽  
Anti Hiv ◽  
Hiv 1 ◽  
Antibody Secreting Cells

ABSTRACTBroadly neutralizing antibodies (bNAbs) specific for conserved epitopes on the HIV-1 envelope (Env) are believed to be essential for protection against multiple HIV-1 clades. However, vaccines capable of stimulating the production of bNAbs remain a major challenge. Given that polyreactivity and autoreactivity are considered important characteristics of anti-HIV bNAbs, we designed an HIV vaccine incorporating the molecular adjuvants BAFF (B cell activating factor) and APRIL (a proliferation-inducing ligand) with the potential to facilitate the maturation of polyreactive and autoreactive B cells as well as to enhance the affinity and/or avidity of Env-specific antibodies. We designed recombinant DNA plasmids encoding soluble multitrimers of BAFF and APRIL using surfactant protein D as a scaffold, and we vaccinated mice with these molecular adjuvants using DNA and DNA-protein vaccination strategies. We found that immunization of mice with a DNA vaccine encoding BAFF or APRIL multitrimers, together with interleukin 12 (IL-12) and membrane-bound HIV-1 Env gp140, induced neutralizing antibodies against tier 1 and tier 2 (vaccine strain) viruses. The APRIL-containing vaccine was particularly effective at generating tier 2 neutralizing antibodies following a protein boost. These BAFF and APRIL effects coincided with an enhanced germinal center (GC) reaction, increased anti-gp120 antibody-secreting cells, and increased anti-gp120 functional avidity. Notably, BAFF and APRIL did not cause indiscriminate B cell expansion or an increase in total IgG. We propose that BAFF and APRIL multitrimers are promising molecular adjuvants for vaccines designed to induce bNAbs against HIV-1.IMPORTANCERecent identification of antibodies that neutralize most HIV-1 strains has revived hopes and efforts to create novel vaccines that can effectively stimulate HIV-1 neutralizing antibodies. However, the multiple immune evasion properties of HIV have hampered these efforts. These include the instability of the gp120 trimer, the inaccessibility of the conserved sequences, highly variable protein sequences, and the loss of HIV-1-specific antibody-producing cells during development. We have shown previously that tumor necrosis factor (TNF) superfamily ligands, including BAFF and APRIL, can be multitrimerized using the lung protein SP-D (surfactant protein D), enhancing immune responses. Here we show that DNA or DNA-protein vaccines encoding BAFF or APRIL multitrimers, IL-12p70, and membrane-bound HIV-1 Env gp140 induced tier 1 and tier 2 neutralizing antibodies in a mouse model. BAFF and APRIL enhanced the immune reaction, improved antibody binding, and increased the numbers of anti-HIV-1 antibody-secreting cells. Adaptation of this vaccine design may prove useful in designing preventive HIV-1 vaccines for humans.

scholarly journals Reducing V3 Antigenicity and Immunogenicity on Soluble, Native-Like HIV-1 Env SOSIP Trimers

2017 ◽  
Vol 91 (15) ◽  
Author(s):  
Rajesh P. Ringe ◽  
Gabriel Ozorowski ◽  
Kimmo Rantalainen ◽  
Weston B. Struwe ◽  
Katie Matthews ◽  
...  
Keyword(s):  
Animal Models ◽  
Neutralizing Antibodies ◽  
Vaccine Development ◽  
Tier 2 ◽  
Present Generation ◽  
Coreceptor Binding ◽  
Tier 1 ◽  
Immunogen Design ◽  
V3 Region ◽  
Hiv 1

ABSTRACT Native-like trimers of the SOSIP design are being developed as immunogens in human immunodeficiency virus type 1 (HIV-1) vaccine development programs. These trimers display the epitopes for multiple broadly neutralizing antibodies (bNAbs) but can also expose binding sites for some types of nonneutralizing antibodies (non-NAbs). Among the latter are epitopes in the gp120 V3 region that are highly immunogenic when SOSIP trimers are evaluated in animal models. It is presently uncertain whether antibodies against V3 can interfere with the induction of NAbs, but there are good arguments in favor of suppressing such “off-target” immune responses. Accordingly, we have assessed how to minimize the exposure of V3 non-NAb epitopes and thereby reduce their immunogenicity by introducing N-glycans within the V3 region of BG505 SOSIP trimers. We found that inserting glycans at positions 306 and 314 (termed M1 and M7) markedly reduced V3 antigenicity while improving the presentation of trimer apex bNAb epitopes. Both added glycans were shown to be predominantly of the Man6GlcNAc2 form. The additional introduction of the E64K ground-state stabilizing substitution markedly reduced or ablated soluble CD4 (sCD4) induction of non-NAb epitopes in V3 and/or associated with the coreceptor binding site. When a V3 glycan- and E64K-modified trimer variant, BG505 SOSIP.664-E64K.M1M7, was tested in rabbits, V3 immunogenicity was eliminated while the autologous NAb response was unchanged. IMPORTANCE Trimeric proteins are being developed for future HIV-1 vaccine trials in humans, with the goal of eliciting broadly active neutralizing antibodies (NAbs) that are active against a wide variety of circulating strains. In animal models, the present generation of native-like trimer immunogens, exemplified by the BG505 SOSIP.664 construct, induces narrow-specificity antibodies against the neutralization-resistant (tier-2), sequence-matched virus and more broadly active antibodies against sequence-divergent atypically neutralization-sensitive (tier-1) viruses. A concern in the trimer immunogen design field has been whether the latter off-target antibodies might interfere with the induction of the more desired responses to tier-2 epitopes. Here, we have inserted two glycans into the dominant site for tier-1 NAbs, the gp120 V3 region, to block the induction of off-target antibodies. We characterized the new trimers, tested them as immunogens in rabbits, and found that the blocking glycans eliminated the induction of tier-1 NAbs to V3-epitopes.

scholarly journals Breadth of Neutralizing Antibodies Elicited by Stable, Homogeneous Clade A and Clade C HIV-1 gp140 Envelope Trimers in Guinea Pigs

2010 ◽  
Vol 84 (7) ◽  
pp. 3270-3279 ◽  
Author(s):  
Joseph P. Nkolola ◽  
Hanqin Peng ◽  
Ethan C. Settembre ◽  
Michael Freeman ◽  
Lauren E. Grandpre ◽  
...  
Keyword(s):  
Guinea Pigs ◽  
Neutralizing Antibodies ◽  
Recombinant Adenovirus ◽  
Neutralizing Antibody ◽  
Tier 2 ◽  
Antigenic Properties ◽  
Tier 1 ◽  
Clade C ◽  
Gp140 Envelope ◽  
Hiv 1

ABSTRACT The native envelope (Env) spike on the surface of human immunodeficiency virus type 1 (HIV-1) is trimeric, and thus trimeric Env vaccine immunogens are currently being explored in preclinical immunogenicity studies. Key challenges have included the production and purification of biochemically homogeneous and stable trimers and the evaluation of these immunogens utilizing standardized virus panels for neutralization assays. Here we report the binding and neutralizing antibody (NAb) responses elicited by clade A (92UG037.8) and clade C (CZA97.012) Env gp140 trimer immunogens in guinea pigs. These trimers have been selected and engineered for optimal biochemical stability and have defined antigenic properties. Purified gp140 trimers with Ribi adjuvant elicited potent, cross-clade NAb responses against tier 1 viruses as well as detectable but low-titer NAb responses against select tier 2 viruses from clades A, B, and C. In particular, the clade C trimer elicited NAbs that neutralized 27%, 20%, and 47% of tier 2 viruses from clades A, B, and C, respectively. Heterologous DNA prime, protein boost as well as DNA prime, recombinant adenovirus boost regimens expressing these antigens, however, did not result in an increased magnitude or breadth of NAb responses in this system. These data demonstrate the immunogenicity of stable, homogeneous clade A and clade C gp140 trimers and exemplify the utility of standardized tier 1 and tier 2 virus panels for assessing the NAb responses of candidate HIV-1 Env immunogens.

scholarly journals Detection of Broadly Neutralizing Activity within the First Months of HIV-1 Infection

2016 ◽  
Vol 90 (11) ◽  
pp. 5231-5245 ◽  
Author(s):  
V. Sanchez-Merino ◽  
A. Fabra-Garcia ◽  
N. Gonzalez ◽  
D. Nicolas ◽  
A. Merino-Mansilla ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Geometric Mean ◽  
First Year ◽  
Tier 2 ◽  
Chronic Infections ◽  
Neutralizing Activity ◽  
Recombinant Viruses ◽  
Tier 1 ◽  
Tier 3 ◽  
Hiv 1

ABSTRACTA fraction of HIV-1 patients are able to generate broadly neutralizing antibodies (bNAbs) after 2 to 4 years of infection. In rare occasions such antibodies are observed close to the first year of HIV-1 infection but never within the first 6 months. In this study, we analyzed the neutralization breadth of sera from 157 antiretroviral-naive individuals who were infected for less than 1 year. A range of neutralizing activities was observed with a previously described panel of six recombinant viruses from five different subtypes (M. Medina-Ramirez et al., J Virol85:5804–5813, 2011,http://dx.doi.org/10.1128/JVI.02482-10). Some sera were broadly reactive, predominantly targeting envelope epitopes within the V2 glycan-dependent region. The neutralization breadth was positively associated with time postinfection (P= 0.0001), but contrary to what has been reported for chronic infections, no association with the viral load was observed. Notably, five individuals within the first 6 months of infection (two as early as 77 and 96 days postinfection) showed substantial cross-neutralization. This was confirmed with an extended panel of 20 Env pseudoviruses from four different subtypes (two in tier 3, 14 in tier 2, and four in tier 1). Sera from these individuals were capable of neutralizing viruses from four different subtypes with a geometric mean 50% infective dose (ID50) between 100 and 800. These results indicate that induction of cross-neutralizing responses, albeit rare, is achievable even within 6 months of HIV-1 infection. These observations encourage the search for immunogens able to elicit this kind of response in preventive HIV-1 vaccine approaches.IMPORTANCEThere are very few individuals able to mount broadly neutralizing activity (bNA) close to the first year postinfection. It is not known how early in the infection cross-neutralizing responses can be induced. In the present study, we show that bNAbs, despite being rare, can be induced much earlier than previously thought. The identification of HIV-1-infected patients with these activities within the first months of infection and characterization of these responses will help in defining new immunogen designs and neutralization targets for vaccine-mediated induction of bNAbs.

scholarly journals PO 8597 NEUTRALISING AND NON-NEUTRALISING ANTIBODIES RESPONSE IN HIV-1-INFECTED INDIVIDUALS FROM MOZAMBIQUE

2019 ◽  
Vol 4 (Suppl 3) ◽  
pp. A61.2-A61
Author(s):  
Paloma Gonçalves ◽  
Francisco Martin ◽  
Patricia Borges ◽  
Maria Espirito Santo ◽  
Nuno Taveira ◽  
...  
Keyword(s):  
Antibody Response ◽  
Hiv Vaccine ◽  
Tier 2 ◽  
Neutralising Antibodies ◽  
Positive Antibody ◽  
Tier 1 ◽  
Binding Antibody ◽  
Positive Antibody Response ◽  
Hiv 1 ◽  
Hiv Subtypes

BackgroundA vaccine that protects against the different HIV subtypes circulating around the world is essential to control and eliminate HIV infection. The immunogens are the key to develop an effective HIV vaccine. In this study, we characterised the antibody response against recombinant C2V3C3 polypeptides from several HIV-1 subtypes and evaluated the neutralising antibody response.MethodsPlasmas from HIV-1-infected individuals under treatment (n=39) and drugs-naïve individuals (n=8) were tested in an ELISA assay to determine the presence of antibodies against polypeptides from HIV-1 subtypes (CRF02_AG, B, C, G and H). The neutralising activity of plasma was evaluated with a panel of six HIV-1 viruses from a reference panel, [one tier 1 (NL4.3), and five tier 2 (PCH119_CRF07, PCE1176_C, TRO11_B, 246 F3_AC and CRF07_BJOX2000)] in a TZM-bl cells-based assay.ResultsOut of 48 plasmas, 44 (89.6%) reacted at least with one polypeptide and four (10.4%) did not react with any polypeptide. Interestingly, 56% of the plasmas recognise ≥3 peptides and 6 reacted with all polypeptides. The polypeptide from virus CRF02_AG was the most antigenic (77%) followed by the polypeptide C (58.3%), G (58.3%), H (50%) and B (35.4%). There was a positive correlation between polypeptides number recognised and binding antibody reactivity (r=0.4895, p=0.0111). All plasmas from drugs-naïve individuals neutralised at least one virus with neutralising activity between 39.3% and 95.7%. Four plasmas showed neutralising activity >50% against five viruses. The virus 249 F3 was the easiest to neutralise (median, 65.7%), whereas PCH119_CRF07 was the most difficult to neutralise (median, 43.6%). Neutralising activity of plasmas from patients under treatment are ongoing.ConclusionIn summary, these polypeptides could be useful in vaccine design once they are very antigenic and we observed a heterologous neutralising antibody response in naïve patients that expressed positive antibody-response anti-peptides.

scholarly journals Neutralizing Antibody Responses following Long-Term Vaccination with HIV-1 Env gp140 in Guinea Pigs

2018 ◽  
Vol 92 (13) ◽  
pp. e00369-18 ◽  
Author(s):  
Christine A. Bricault ◽  
James M. Kovacs ◽  
Alexander Badamchi-Zadeh ◽  
Krisha McKee ◽  
Jennifer L. Shields ◽  
...  
Keyword(s):  
Guinea Pigs ◽  
Neutralizing Antibodies ◽  
Antibody Responses ◽  
Tier 2 ◽  
Broadly Neutralizing Antibodies ◽  
Vaccination Regimen ◽  
Tier 1 ◽  
Clade C ◽  
Hiv 1

ABSTRACTA vaccination regimen capable of eliciting potent and broadly neutralizing antibodies (bNAbs) remains an unachieved goal of the HIV-1 vaccine field. Here, we report the immunogenicity of longitudinal prime/boost vaccination regimens with a panel of HIV-1 envelope (Env) gp140 protein immunogens over a period of 200 weeks in guinea pigs. We assessed vaccine regimens that included a monovalent clade C gp140 (C97ZA012 [C97]), a tetravalent regimen consisting of four clade C gp140s (C97ZA012, 459C, 405C, and 939C [4C]), and a tetravalent regimen consisting of clade A, B, C, and mosaic gp140s (92UG037, PVO.4, C97ZA012, and Mosaic 3.1, respectively [ABCM]). We found that the 4C and ABCM prime/boost regimens were capable of eliciting greater magnitude and breadth of binding antibody responses targeting variable loop 2 (V2) over time than the monovalent C97-only regimen. The longitudinal boosting regimen conducted over more than 2 years increased the magnitude of certain tier 1 NAb responses but did not increase the magnitude or breadth of heterologous tier 2 NAb responses. These data suggest that additional immunogen design strategies are needed to induce broad, high-titer tier 2 NAb responses.IMPORTANCEThe elicitation of potent, broadly neutralizing antibodies (bNAbs) remains an elusive goal for the HIV-1 vaccine field. In this study, we explored the use of a long-term vaccination regimen with different immunogens to determine if we could elicit bNAbs in guinea pigs. We found that longitudinal boosting over more than 2 years increased tier 1 NAb responses but did not increase the magnitude and breadth of tier 2 NAb responses. These data suggest that additional immunogen designs and vaccination strategies will be necessary to induce broad tier 2 NAb responses.

scholarly journals Broadly Neutralizing Antibody Responses in a Subset of HIV-1-Infected Individuals in Chennai, India

2016 ◽  
Vol 16 (2) ◽  
pp. 201-208
Author(s):  
Syed Iqbal Hussain ◽  
Nandagopal Panneerselvam ◽  
Suniti Solomon ◽  
Sunil S. Solomon ◽  
Kaavya Adam ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Neutralizing Antibody ◽  
Effective Vaccine ◽  
Tier 2 ◽  
Neutralizing Activity ◽  
Tier 1 ◽  
Clade C ◽  
Treatment Naïve ◽  
Broadly Neutralizing Antibody ◽  
Hiv 1

Identification of broadly neutralizing antibodies (NAbs) generated during the course of HIV-1 infection is essential for effective HIV-1 vaccine design. The magnitude and breadth of neutralizing activity in the sera from 46 antiretroviral treatment–naive HIV-1 clade C-infected individuals was measured in a single round infection assay using TZM-bl cells and multisubtype panel of env-pseudotyped viruses. Higher levels of NAb response (NAb titer 500 to >40 000) were measured in these patients against tier 1 and tier 2 viruses. The average magnitude of the NAb responses of chronically infected individuals against heterologous viruses was consistently higher than the response observed from individuals with long-term nonprogressor ( P = .086). To conclude, high titers of HIV-1 cross-neutralizing activity were observed in the sera from a subset of HIV-1-infected individuals in Chennai, India. Additional studies of the epitopes recognized by these antibodies may facilitate the discovery of an effective vaccine immunogen.

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