Structure-based Design of Trimeric V1V2 Antigens

Abstract

Oral Abstract Sessions

B Cell Immunogen Design A7–A9

Microbicides: Male Partner Engagement and Sexual Behaviors A9–A11

Animal Model Studies of Microbicides and Injectables A11–A14

Innate Immunity A14–A16

Vaccine, Viral Latency, and Cure A16–A19

B Cell Repertoires for Protection A19–A21

Risk and Prevention for MSM A21–A24

Correlates of Protection and Exposure A24–A26

Engaging, Recruiting and Retaining Trial Participants A26–A29

Bacterial Vaginosis and HSV-2: Impact on Genital Immunity A29–A31

Vaccine Development: Emerging Insights A31–A34

Towards Broadly Neutralizing Antibody Induction A34–A36

ARV Exposure & Efficacy in the Genital Tract A36–A39

Host Factors: Injury, Acquisition and Infection A39–A41

PrEP and Microbicide Adherence in Women A41–A44

Novel Vaccine Concepts A44–A46

Mucosal Target and Effector Cells A46–A48

Evaluation of Novel Interventions A49–A51

Good Participatory Practices in HIV Prevention A51–A53

Reproductive Hormones and HIV Risk A53–A55

Viral Transmission Studies A55–A58

Cell and Tissue Models of ARVs for Prevention A58–A60

Pregnancy Intentions, Safe Conception and PMTCT A60–A62

Mucosal Responses A62–A64

Adjuvants and Immunogens A64–A67

Microbicides and Multipurpose Prevention Technologies A67–A69

PrEP: Self-testing, Safety and Modeling A69–A71

Treating and Preventing: The Role of ARVs A71–A74

T Cell Immunity A74–A76

Antibody Functions and Protection A76–A79

Poster Discussions

Community Engagement and Advocacy A80–A82

Correlates of Protection in Highly Exposed Seronegative People A82–A83

Preclinical and Clinical Vaccine Trials A84–A86

Behavioral and Social Sciences A86–A88

Glycans and Antibody Effector Functions A88–A90

Policy, Advocacy and Modeling A90–A92

Poster Presentation Themes

Acute Seroconversion A93–A94

Community Engagement and Advocacy A94–A97

Correlates of Protection and Exposure A97–A100

Correlates of Protection in Highly Exposed Seronegative People A100

Family Planning A100–A103

Financial Incentives A103–A105

Good Participatory Practices and Community Involvement A105–A108

HIV Care A108–A109

HIV Testing and Counseling A110–A117

Immunogens A117–A122

Informed Consent A122–A124

Innate Immunity A124–A130

Key Populations A130–A137

MPT Development A137–A141

Novel Formulations, Agents and Microbicides A141–A151

Passive Antibody Functions A151–A155

Post-exposure Prophylaxis A155

Preclinical Evaluation of Vaginal Films and Gels A155–A158

PrEP Implementation A158–A161

PrEP: Resistance, Modeling and Acceptability A161–A162

Product Acceptability and Adherence A163–A164

Resistance and Treatment Failure A164–A166

Retention and Adherence in Trials A166–A173

T-Cell (CD4 & CD8) Responses A173–A181

Transmission and Viral Diversity A181–A185

Vaccine Clinical Trials A185–A193

Adjuvants A194–A196

Behavioral and Social Sciences A196

Circumcision and Acceptability A196–A199

Condoms: Attitudes, Use and How to Increase A199–A201

Drug Transporters A201–A202

Ethics and the Law A202–A203

Evaluation of Novel Compounds in Cell-Based Systems A203–A207

Glycans and Antibody Effector Functions A207–A212

HIV Drug Resistance In Vitro A212–A213

HIV Incidence and Prevalence A213–A217

Immunogenetics A217–A220

Innovations in Vaccine and Microbicides Studies in Lab and Monitoring A220–A223

Molecular Epidemiology A223–A228

Mucosal Immune Activation and Inflammation A228–A240

Novel Vaccine and Prevention Concepts A240–A251

Participation in Trials: Willingness, Benefits and Challenges A251–A255

Policy, Advocacy and Modeling A255–A260

Preclinical Evaluation of Biomedical Agents in Animal Models Tissues Explants A261–A265

Pregnancy and PMTCT A265–A268

PrEP Trials: Preparing for Demos, Participant Experiences A268–A271

Resource Tracking and Economics A271–A273

Risk Perception A273–A276

Sexually Transmitted Infections A276–A281

Tenofovir Gel: Acceptability and Adherence A281–A284

Therapeutic Vaccine and Viral Latency A284–A285

Treatment as Prevention: Initiation, Adherence, and Monitoring on ARV A285–A289

Vaginal Rings: Baseline Characteristics, Impact on Condoms and Flora A289–A290

Abstract Author Index A292–A312

OA01.01

Background: Broadly neutralizing antibodies (bNAbs) targeted against V1V2 of HIV-1 Env are among the most prevalent elicited by natural infection and require less somatic mutation than those targeting other sites, making antibodies of this class attractive targets of elicitation for an HIV-1 vaccine. The quaternary specificity exhibited by V1V2 bNAbs necessitates the development immunogens that effectively mimic the trimeric cap of the functional native spike.

Methods: Recent structural work has defined the trimeric orientation of the V1V2 domains at the apex of the viral spike, the V1V2 cap. This V1V2 trimeric supersite was transplanted onto heterologous trimeric scaffolds and screened for binding to quaternary specific antibodies.

Results: Here we present a trimeric V1V2 cap which recapitulates the quaternary alignment of the three V1V2 domains present in the native spike, as assessed by binding to quaternary specific V1V2-directed bNAbs. High throughput screening of over a hundred constructs revealed a single trimerization domain capable of presenting an appropriate mimic of the V1V2 cap. Antibody binding was observed to multiple strains transplanted onto the trimeric scaffold while gp120s of the same strain did not bind. The transplanted V1V2 construct was able to bind V1V2-bNAbs from multiple donors and importantly this trimeric construct bound only to a single fab as observed with V1V2-directed antibodies on the HIV-1 Spike.

Conclusions: Recent structural studies of HIV-1 trimers have provided data to allow rational design of quaternary supersite transplants onto scaffolds. High throughput screening with V1V2-directed antibodies identified a construct which presents the V1V2 cap in an antigenically similar manner to that observed with the BG505.SOSIP. The scaffolded protein provides a simplified, well behaved alternative for use as a probe and a candidate immunogen to focus the immune response on this specific epitope.