Evaluating the Safety, Tolerability, and Effect of a Human Monoclonal Antibody (VRC01) on Markers of HIV Persistence in HIV-Infected Adults Receiving Antiretroviral Therapy (ART)

Study Overview
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Brief Summary
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The purpose of this study was to evaluate the safety, tolerability, and effect of an experimental human monoclonal antibody (mAb), VRC-HIVMAB060-00-AB (VRC01), in adults infected with HIV who were receiving antiretroviral therapy (ART).

Detailed Description
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Monoclonal antibodies (mAbs) have been developed as treatment for a variety of conditions including cancer, autoimmune disorders, and infections. mAbs may also be a potential treatment for people infected with HIV. The purpose of this study was to evaluate the safety and tolerability of an experimental human mAb, VRC-HIVMAB060-00-AB (VRC01), in HIV-infected adults receiving ART. Study researchers will also evaluate the effect of VRC01 on the number of infected cells containing unspliced HIV-1 transcripts in the blood in participants. This study enrolled HIV-infected people 18 to 65 years old, who had been receiving ART for at least 2 years and who had a CD4+ count of 200 cells/mm^3 or greater. Participants were randomly assigned to Arm A or Arm B. Participants in Arm A received an intravenous (IV) infusion of VRC01 at Day 0 and Week 3 and an IV infusion of placebo (normal saline) at Weeks 6 and 9. Participants in Arm B received an IV infusion of placebo (normal saline) at Day 0 and Week 3 and an IV infusion of VRC01 at Weeks 6 and 9. Participants recorded their temperature and symptoms for 3 days after each infusion. Study visits occured at study entry (Day 0), and Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, 18, and 30. Study visits included physical examinations, clinical assessments, and blood collection. The primary safety outcome for this study was descriptive and assessed the occurrence of Grade ≥ 3 AEs including signs/symptoms, lab toxicities, and/or clinical events that are possibly, probably, or definitely related to study treatment (as judged by the core team, blinded to treatment arm) at any time from the initial dose of study treatment to the end of study follow-up. Since this outcome is descriptive, no statistical significance testing was performed.

Official Title
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A Phase I Study to Evaluate the Safety, Tolerability, and Effect of a Human Monoclonal Antibody, VRC-HIVMAB060-00-AB (VRC01), on Markers of HIV Persistence in ART-treated, HIV-infected Adults

Conditions
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HIV Infections

Intervention / Treatment
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* Biological: VRC01
* Biological: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: HIV-1 infection, documented by any FDA-approved rapid HIV test or HIV enzyme or chemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry and confirmed by a licensed Western blot or a second antibody test by a method other than the initial rapid HIV or E/CIA tests, or by HIV-1 antigen, or plasma HIV-1 RNA assay. More information on this criterion is available in the protocol. Received continuous ART for at least 2 years (defined as no interruptions longer than 14 consecutive days) and with no changes in the components of the ART for at least 90 days prior to study entry CD4+ cell count greater than or equal to 200 cells/mm^3 obtained within 60 days prior to study entry in a clinical laboratory improvement amendments (CLIA)-certified laboratory Plasma HIV-1 RNA below the limit of detection of the FDA-approved assays (limit of detection: 75, 50, 40 or 20 copies/mL) for greater than or equal to 2 years on ART. Participants must have had at least one documented HIV-1 RNA less than the limit of detection 12-24 months prior to study entry and at least one HIV-1 RNA less than the limit of detection within 12 months prior to study entry. All available HIV-1 RNA measurements must have been below the assay limit of detection during the 2 years prior to study entry except as allowed by the following note. NOTE: A single unconfirmed plasma HIV-1 RNA greater than the limit of detection but less than 200 copies/mL within 6-24 months was allowed if followed by a subsequent value below the limit of detection. Plasma HIV-1 RNA level of less than 40 copies/mL obtained by the Abbott Real-time HIV assay (m2000) or less than 20 copies/mL obtained by the Roche COBAS Taqman HIV-1 v2.0 assay within 60 days prior to entry The following laboratory values obtained within 60 days prior to entry by any U.S. laboratory that has a CLIA certification or its equivalent. Absolute neutrophil count (ANC) greater than or equal to 750 cells/mm^3 Hemoglobin greater than or equal to 11.0 g/dL for men and greater than or equal to 10.0 g/dL for women Platelet count greater than or equal to 100,000/mm^3 Creatinine clearance greater than or equal to 60 mL/min estimated by the Cockcroft-Gault equation. NOTE: A program for calculating creatinine clearance by the Cockcroft-Gault method is available on www.fstrf.org. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) (SGPT) less than or equal to 2.0 times upper limit of normal (ULN) Hepatitis C virus (HCV) antibody negative result within 60 days prior to study entry or, if the HCV antibody result is positive, a negative HCV RNA result within 60 days prior to study entry Negative HBsAg result obtained within 60 days prior to study entry Ability and willingness of participant to provide informed consent Females of reproductive potential (women who have not been post-menopausal for at least 24 consecutive months, i.e., who have had menses within the preceding 24 months, or women who have not undergone surgical sterilization, specifically hysterectomy, or bilateral oophorectomy and/or bilateral salpingectomy), needed a negative serum or urine pregnancy test within 48 hours prior to study entry. NOTE: Acceptable documentation of hysterectomy and bilateral oophorectomy, bilateral salpingectomy, tubal micro-inserts, partner who has undergone vasectomy, and menopause is participant-reported history. All participants must have agreed not to participate in the conception process (e.g., active attempt to become pregnant or to impregnate, sperm donation, in vitro fertilization), and if participating in sexual activity that could lead to pregnancy, the participant/partner must use at least one reliable form of contraception (condoms, with or without a spermicidal agent; a diaphragm or cervical cap with spermicide; an intrauterine device (IUD); or hormone-based contraceptive), while receiving study treatment and for 12 weeks after stopping study treatment Documentation of the availability of the following stored samples from the screening visit: peripheral blood mononuclear cell (PBMC) for CD4+ T-cell associated HIV-1 RNA, DNA assay and plasma for HIV-1 SCA. Sites must receive confirmation from the processing lab via phone, email, or fax, that specimens have been entered into the AIDS Clinical Trials Group (ACTG) Laboratory Data Management System (LDMS). Exclusion Criteria: Previous receipt of humanized or human monoclonal antibody (licensed or investigational) Weight greater than 115 kg or less than 53 kg Acute or ongoing AIDS-defining illness within 60 days prior to study entry History of a severe allergic reaction with generalized urticarial, angioedema, or anaphylaxis within 2 years of study entry Currently breastfeeding or pregnant Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements Acute or serious illness that, in the opinion of the site investigator, requires systemic treatment and/or hospitalization within 60 days prior to entry Use of immunomodulators (e.g., interleukins, interferons, cyclosporine), HIV vaccine, systemic cytotoxic chemotherapy, or investigational therapy within 60 days prior to study entry. NOTE: Participants receiving stable physiologic doses of glucocorticoids, defined as the equivalent of prednisone less than or equal to 10 mg/day, will not be excluded. Stable physiologic glucocorticoid doses should not be discontinued for the duration of the study. In addition, participants receiving inhaled or topical corticosteroids will not be excluded. Treatment for hepatitis C within 24 weeks of study entry Vaccinations within 7 days prior to the screening, pre-entry, or study entry visits. NOTE: Participants are encouraged to get routine vaccinations, such as seasonal influenza vaccine more than 7 days prior to screening or between screening and pre-entry visits (outside of the 7-day window above). Initiation of ART during acute HIV-1 infection (as determined by the site investigator by history and/or available medical records)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A: VRC01 followed by placebo<br>Participants received an infusion of VRC01 at Day 0 and Week 3 and an infusion of placebo (normal saline) at Weeks 6 and 9. | Biological: VRC01<br>* 40 mg/kg of VRC01 administered as an intravenous infusion over about 30 to 60 minutes using a volumetric pump<br>* Other names: VRC-HIVMAB060-00-AB;Biological: Placebo<br>* Normal saline administered as an intravenous infusion over about 30 to 60 minutes using a volumetric pump<br>|
| Experimental: Arm B: placebo followed by VRC01<br>Participants received an infusion of placebo (normal saline) at Day 0 and Week 3 and an infusion of VRC01 at Weeks 6 and 9. | Biological: VRC01<br>* 40 mg/kg of VRC01 administered as an intravenous infusion over about 30 to 60 minutes using a volumetric pump<br>* Other names: VRC-HIVMAB060-00-AB;Biological: Placebo<br>* Normal saline administered as an intravenous infusion over about 30 to 60 minutes using a volumetric pump<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Experienced Grade 3 or Greater, Treatment Related, Adverse Event (AE) | Refer to detailed description in the protocol section. Includes signs/symptoms, lab toxicities, and/or clinical events that are possibly, probably, or definitely related to study treatment (as judged by the core team, blinded to treatment arm) at any time from the initial dose of VRC01 to end of study follow-up. This analysis was primarily descriptive and no significance testing was performed. | Measured from study treatment initiation to study discontinuation (study duration is 30 weeks) | 
| Change in Cell-associated HIV-1 RNA/DNA Ratio in Total CD4+ Cells | Change from baseline (geometric average of screening and entry results) to week 6 in log10 transformed cell-associated HIV-1 RNA/DNA ratio in total CD4+ cells | Screening, entry and week 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Premature Treatment Discontinuation, for Reasons Related to Study Treatment | Study treatment was taken from entry through week 12 - this outcome assesses the number of participants who permanently and prematurely discontinued study treatment due to reasons related to the study treatment | Measured from study treatment initiation to study treatment discontinuation (study treatment dispensed through week 12) | 
| Change in Cell-associated HIV-1 RNA/DNA Ratio in Total CD4+ Cells - Last Value Carried Forward (LVCF) | Change from baseline (geometric average of screening and entry results) to week 6 in cell-associated HIV-1 RNA/DNA ratio in total CD4+ cells, using a last value carried forward approach if week 6 cell-associated HIV-1 RNA/DNA ratio was missing. In the event that the week 6 value was missing, the week 3 value was carried forward to be used. This comparison is the change from the average of screening and entry results to the week 6 value (if available), and if week 6 result was not available, the week 3 value was used instead of the week 6 value. | Screening, entry, week 3 and week 6 (week 3 used as LVCF if necessary) | 
| Change in Cell-associated HIV-1 RNA/DNA Ratio in Total CD4+ Cells - Across Arms | Summary of within-participant change across treatment arms from the pre-VRC01 time point to the post-VRC01 time point. For Arm A, the pre-VRC01 time point used was the baseline measure (geometric average of screening and entry results) and the post-VRC01 time point was the week 6 measure. For Arm B, the pre-VRC01 time point used was the week 6 measure and the post-VRC01 time point was the week 12 measure. Change in CA-RNA/DNA ratio was calculated on the log10 scale. | Screening, entry and weeks 6 and 12 | 
| Cell-associated HIV-1 RNA in Total CD4+ Cells | Testing priority was given to samples from screening, entry and weeks 3, 6, 9 and 12. Baseline values are the geometric mean of screening and entry results. Testing of specimens at weeks 1, 4, 7, 10, 15, 18 and 30 has not been performed. The study team has decided in favor of saving these samples for future research purposes. | Measured at screening, entry, weeks 1, 3, 4, 6, 7, 9, 10, 12, 15, 18 and 30 | 
| Cell-associated HIV-1 DNA in Total CD4+ Cells | Testing priority was given to samples from screening, entry and weeks 3, 6, 9 and 12. Baseline values are the geometric mean of screening and entry results. Testing of specimens at weeks 1, 4, 7, 10, 15, 18 and 30 has not been performed. The study team has decided in favor of saving these samples for future research purposes. | Measured at screening, entry, weeks 1, 3, 4, 6, 7, 9, 10, 12, 15, 18 and 30 | 
| Cell-associated HIV-1 RNA/DNA Ratio in Total CD4+ Cells | Testing priority was given to samples from screening, entry and weeks 3, 6, 9 and 12. Baseline values are the geometric mean of screening and entry results. Testing of specimens at weeks 1, 4, 7, 10, 15, 18 and 30 has not been performed. The study team has decided in favor of saving these samples for future research purposes. | Measured at screening, entry, weeks 1, 3, 4, 6, 7, 9, 10, 12, 15, 18 and 30 | 
| Number of Participants With Plasma HIV-1 RNA by Single Copy Assay (SCA) Below Assay Lower Limit | The analysis of HIV-1 RNA SCA assessed the number of participants below the assay lower limit (1 copy/mL) at each measurement week. Specific specimens and time points were targeted based on Arm. Samples were not tested for Arm A at the Week 7 and Week 10 time points. Samples were not tested for Arm B at the Week 1 and Week 4 time points. Testing of specimens at weeks 15, 18 and 30 has not been performed. The study team has decided in favor of saving these samples for future research purposes. | Measured at screening, entry and weeks 1, 3, 4, 6, 7, 9, 10, 12, 15, 18 and 30 | 
| CD4+ T-cell Counts | Baseline measure represents the average of screening and entry results | Measured at screening, entry and weeks 6, 12, 18 and 30 | 
| CD8+ T-cell Counts | Baseline measure represents the average of screening and entry results | Measured at screening, entry and weeks 6, 12, 18 and 30 | 
| Total/Inducible Virus Recovery - Stimulated HIV-1 RNA | As part of the total virus recovery assay, results for stimulated HIV-1 RNA (copies/mL) are generated | Measured at pre-entry, week 6 and week 12 | 
| Total/Inducible Virus Recovery - Unstimulated HIV-1 RNA | As part of the total virus recovery assay, results for unstimulated HIV-1 RNA (copies/mL) are generated | Measured at pre-entry, week 6 and week 12 | 
| Total/Inducible Virus Recovery - Stimulated to Unstimulated HIV-1 RNA Ratio | As part of the total virus recovery assay, results for stimulated and unstimulated HIV-1 RNA (copies/mL) are generated. At each time point, the ratio of the stimulated to unstimulated HIV-1 RNA was calculated. | Measured at pre-entry, week 6 and week 12 | 
| Total/Inducible Virus Recovery - Stimulated Cell Fluor | As part of the total virus recovery assay, results for stimulated cell fluor (light units) are generated. | Measured at pre-entry, week 6 and week 12 | 
| Total/Inducible Virus Recovery - Unstimulated Cell Fluor | As part of the total virus recovery assay, results for unstimulated cell fluor (light units) are generated. | Measured at pre-entry, week 6 and week 12 | 
| Total/Inducible Virus Recovery - Stimulated to Unstimulated Cell Fluor Ratio | As part of the total virus recovery assay, results for stimulated and unstimulated cell fluor (light units) are generated. At each time point, the ratio of the stimulated to unstimulated cell fluor was calculated. | Measured at pre-entry, week 6 and week 12 | 
| Total/Inducible Virus Recovery - Percentage of Total CD4 Yield | As part of the total virus recovery assay, results for %tCD4 yield are generated. | Measured at pre-entry, week 6 and week 12 | 
| Change in Total/Inducible Virus Recovery - Stimulated HIV-1 RNA | As part of the total virus recovery assay, results for stimulated HIV-1 RNA (copies/mL) are generated. The change from the pre-treatment time point to week 6 was assessed as a fold change (week 6 / pre-entry) | Measured at pre-entry, week 6 | 
| Change in Total/Inducible Virus Recovery - Unstimulated HIV-1 RNA | As part of the total virus recovery assay, results for unstimulated HIV-1 RNA (copies/mL) are generated. The change from the pre-treatment time point to week 6 was assessed as a fold change (week 6 / pre-entry) | Measured at pre-entry, week 6 | 
| Change in Total/Inducible Virus Recovery - Stimulated to Unstimulated HIV-1 RNA Ratio | As part of the total virus recovery assay, results for stimulated and unstimulated HIV-1 RNA (copies/mL) are generated. At each time point, the ratio of the stimulated to unstimulated HIV-1 RNA was calculated. The fold change of this ratio from pre-entry to the week 6 time point was calculated for each arm (week 6 / pre-entry) | Measured at pre-entry and week 6 | 
| Change in Total/Inducible Virus Recovery - Stimulated Cell Fluor | As part of the total virus recovery assay, results for stimulated cell fluor (light units) are generated. The fold change from pre-entry to the week 6 time point was calculated for each arm (week 6 / pre-entry) | Measured at pre-entry, week 6 | 
| Change in Total/Inducible Virus Recovery - Unstimulated Cell Fluor | As part of the total virus recovery assay, results for unstimulated cell fluor (light units) are generated. The fold change from pre-entry to the week 6 time point was calculated for each arm (week 6 / pre-entry) | Measured at pre-entry, week 6 | 
| Change in Total/Inducible Virus Recovery - Stimulated to Unstimulated Cell Fluor Ratio | As part of the total virus recovery assay, results for stimulated and unstimulated cell fluor (light units) are generated. At each time point, the ratio of the stimulated to unstimulated cell fluor was calculated. The fold change of this ratio from pre-entry to the week 6 time point was calculated for each arm (week 6 / pre-entry) | Measured at pre-entry, week 6 | 
| Change in Total/Inducible Virus Recovery - Percentage of Total CD4 Yield | As part of the total virus recovery assay, results for %tCD4 yield are generated. The fold change from pre-entry to the week 6 time point was calculated for each arm (week 6 / pre-entry) | Measured at pre-entry, week 6 | 
| VRC01 Antibody Level | Summarize the pharmacokinetics (PK) of two infusions of VRC01 during study follow up Specific specimens and time points were targeted for testing based on Arm. Samples for Arm A were not tested for the Week 6 and Week 9 post-infusion time points. Samples for Arm B were not tested for the Week 0 and Week 3 post-infusion time points. | Measured at entry and weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, 18 and 30 | 
| Detectability of Antibody to VRC01 as Measured in Serum | Assess the detectability of antibody to VRC01 in samples collected during study follow-up. Intended to be result from specimen at week 30 time point. Due to specimen availability, four participants in Arm A had results from specimens from the week 18 time point. Counts provided are number of participants with detectable anti-VRC01 antibody result. | Measured at week 30 | 
| Levels of T-cell Activation | % CD4+ and CD8+ T-cells co-expressing human leukocyte antigen (HLA)-DR and CD38 Not conducted as part of primary analysis and there are no future plans to assess this outcome. Samples were collected for this outcome in order to assess associations with virologic effects observed. Due to the lack of virologic effect observed, the study team has decided that this outcome is no longer of priority/interest and will be abandoned in favor of saving these samples for future research purposes. | Measured at screening, entry and weeks 1, 3, 4, 6, 7, 9, 10, 12, 15, 18 and 30 | 
| Levels of NK Cell Activation | % NK cells expressing CD69 or CD95 Not conducted as part of primary analysis and there are no future plans to assess this outcome. Samples were collected for this outcome in order to assess associations with virologic effects observed. Due to the lack of virologic effect observed, the study team has decided that this outcome is no longer of priority/interest and will be abandoned in favor of saving these samples for future research purposes. | Measured at screening, entry and weeks 1, 3, 4, 6, 7, 9, 10, 12, 15, 18 and 30 | 
| Plasma Levels of sCD163 | Not conducted as part of primary analysis and there are no future plans to assess this outcome. Samples were collected for this outcome in order to assess associations with virologic effects observed. Due to the lack of virologic effect observed, the study team has decided that this outcome is no longer of priority/interest and will be abandoned in favor of saving these samples for future research purposes. | Measured at screening, entry and weeks 1, 3, 4, 6, 7, 9, 10, 12, 15, 18 and 30 | 
| Plasma Levels of sCD14 | Not conducted as part of primary analysis and there are no future plans to assess this outcome. Samples were collected for this outcome in order to assess associations with virologic effects observed. Due to the lack of virologic effect observed, the study team has decided that this outcome is no longer of priority/interest and will be abandoned in favor of saving these samples for future research purposes. | Measured at screening, entry and weeks 1, 3, 4, 6, 7, 9, 10, 12, 15, 18 and 30 | 
| Plasma Levels of Interleukin-6 (IL-6) | Not conducted as part of primary analysis and there are no future plans to assess this outcome. Samples were collected for this outcome in order to assess associations with virologic effects observed. Due to the lack of virologic effect observed, the study team has decided that this outcome is no longer of priority/interest and will be abandoned in favor of saving these samples for future research purposes. | Measured at screening, entry and weeks 1, 3, 4, 6, 7, 9, 10, 12, 15, 18 and 30 | 
| Plasma Levels of Human Soluble Tumor Necrosis Factor Alpha-receptor (sTNFαR) | Not conducted as part of primary analysis and there are no future plans to assess this outcome. Samples were collected for this outcome in order to assess associations with virologic effects observed. Due to the lack of virologic effect observed, the study team has decided that this outcome is no longer of priority/interest and will be abandoned in favor of saving these samples for future research purposes. | Measured at screening, entry and weeks 1, 3, 4, 6, 7, 9, 10, 12, 15, 18 and 30 | 
| Plasma Levels of Tumor Necrosis Factor Alpha (TNFα) | Not conducted as part of primary analysis and there are no future plans to assess this outcome. Samples were collected for this outcome in order to assess associations with virologic effects observed. Due to the lack of virologic effect observed, the study team has decided that this outcome is no longer of priority/interest and will be abandoned in favor of saving these samples for future research purposes. | Measured at screening, entry and weeks 1, 3, 4, 6, 7, 9, 10, 12, 15, 18 and 30 | 
| Plasma Levels of High-sensitivity C-reactive Protein (hsCRP) | Not conducted as part of primary analysis and there are no future plans to assess this outcome. Samples were collected for this outcome in order to assess associations with virologic effects observed. Due to the lack of virologic effect observed, the study team has decided that this outcome is no longer of priority/interest and will be abandoned in favor of saving these samples for future research purposes. | Measured at screening, entry and weeks 1, 3, 4, 6, 7, 9, 10, 12, 15, 18 and 30 | 
| VRC01 Antibody Level Relative to Infusion Timing | Summarize the pharmacokinetics (PK) of two infusions of VRC01 during study follow up - aligning the timing of PK samples/results to the respective VRC01 infusions for each Arm | Measured immediately after first infusion (and 1, 2, and 3 weeks after), and immediately after second infusion (and 1, 2, 3, 6 and 9 weeks after) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV, VRC01