• Frequency of local Solicited adverse events (AEs) [ Time Frame: Measured through participant's last study visit, which will be Month 12 or 16 depending on group ]
  Local symptoms to be assessed as Solicited AEs in this trial include pain and/or tenderness at the infusion site.
• Frequency of systemic Solicited AEs [ Time Frame: Measured through participant's last study visit, which will be Month 12 or 16 depending on group ]
  Systemic symptoms to be assessed as Solicited AEs in this trial include increased body temperature, malaise and/or fatigue, myalgia, headache, chills, arthralgia, nausea, urticaria, non-exertional dyspnea, non-exertional tachycardia, generalized pruritus, facial flushing, and unexplained diaphoresis.
• Frequency of Unsolicited AEs [ Time Frame: Measured through participant's last study visit, which will be Month 12 or 16 depending on group ]
  Unsolicited AEs will be summarized using MedDRA System Organ Class and preferred terms.
• Frequency of serious adverse events (SAEs) [ Time Frame: Measured through participant's last study visit, which will be Month 12 or 16 depending on group ]
• Number of participants who discontinue administration early [ Time Frame: Measured through participant's last study visit, which will be Month 12 or 16 depending on group ]
• Number of participants who terminate the study early [ Time Frame: Measured through participant's last study visit, which will be Month 12 or 16 depending on group ]
• Serum concentrations of PGT121 among participants who received all scheduled product administrations [ Time Frame: Measured through participant's last study visit, which will be Month 12 or 16 depending on group ]
  A quantitative immunoassay will be used to determine the concentration of each mAb.
• Serum concentrations of PGDM1400 among participants who received all scheduled product administrations [ Time Frame: Measured through participant's last study visit, which will be Month 12 or 16 depending on group ]
  A quantitative immunoassay will be used to determine the concentration of each mAb.
• Serum concentrations of 10-1074 among participants who received all scheduled product administrations [ Time Frame: Measured through participant's last study visit, which will be Month 12 or 16 depending on group ]
  A quantitative immunoassay will be used to determine the concentration of each mAb.
• Serum concentrations of VRC07-523LS among participants who received all scheduled product administrations [ Time Frame: Measured through participant's last study visit, which will be Month 12 or 16 depending on group ]
  A quantitative immunoassay will be used to determine the concentration of each mAb.
• Magnitude of serum neutralizing activity among participants who received all scheduled product administrations [ Time Frame: Measured through participant's last study visit, which will be Month 12 or 16 depending on group ]
  Measured with mAb-specific Env-pseudotyped viruses in TZM-bl cells.

• Serum concentrations of PGT121 for all participants in all groups regardless of how many product administrations and how much product they received [ Time Frame: Measured through participant's last study visit, which will be Month 12 or 16 depending on group ]
  A quantitative immunoassay will be used to determine the concentration of each mAb.
• Serum concentrations of PGDM1400 for all participants in all groups regardless of how many product administrations and how much product they received [ Time Frame: Measured through participant's last study visit, which will be Month 12 or 16 depending on group ]
  A quantitative immunoassay will be used to determine the concentration of each mAb.
• Serum concentrations of 10-1074 for all participants in all groups regardless of how many product administrations and how much product they received [ Time Frame: Measured through participant's last study visit, which will be Month 12 or 16 depending on group ]
  A quantitative immunoassay will be used to determine the concentration of each mAb.
• Serum concentrations of VRC07-523LS for all participants in all groups regardless of how many product administrations and how much product they received [ Time Frame: Measured through participant's last study visit, which will be Month 12 or 16 depending on group ]
  A quantitative immunoassay will be used to determine the concentration of each mAb.
• Magnitude of serum neutralizing activity for all participants in all groups regardless of how many product administrations and how much product they received [ Time Frame: Measured through participant's last study visit, which will be Month 12 or 16 depending on group ]
  Measured with Env pseudotyped viruses in TZM-bl cells
• Magnitude of neutralizing activity for all participants in all groups regardless of how many product administrations and how much product they received [ Time Frame: Measured through participant's last study visit, which will be Month 12 or 16 depending on group ]
  Measured against a panel of Env pseudotyped reference viruses in TZM-bl cells
• Anti-drug antibody (ADA) titers for all participants in all groups regardless of how many product administrations and how much product they received [ Time Frame: Measured through participant's last study visit, which will be Month 12 or 16 depending on group ]
  A tiered testing approach will be used to identify and characterize ADAs that may arise.

This study will evaluate the safety, tolerability, pharmacokinetics, and antiviral activity of combinations of monoclonal antibodies PGT121, PGDM1400, 10-1074, and VRC07-523LS administered via intravenous infusion in healthy, HIV-uninfected adults.

Participants will initially be enrolled into one of three groups. At Day 0, Groups 1, 2, and 3 will receive dual combinations of mAbs administered sequentially via IV. Group 1 will receive a combination of PGT121 and VRC07-523LS, Group 2 will receive PGDM1400 and VRC07-523LS, and Group 3 will receive 10-1074 and VRC07-523LS.

Study staff will review study data from Groups 1, 2, and 3 and determine if Group 4 may begin to enroll. Participants in Group 4 will receive PGDM1400, PGT121, and VRC07-523LS administered in sequence via IV on Day 0 and at Month 4.

Study duration will be 12 months for participants in Groups 1, 2, and 3, and 16 months for participants in Group 4. Participants will attend several study visits, which may include physical examinations, blood and urine collection, HIV testing and pretest counseling, risk reduction counseling, and questionnaires.

• Biological: PGT121
  20 mg/kg administered intravenously
• Biological: PGDM1400
  20 mg/kg administered intravenously
• Biological: 10-1074
  20 mg/kg administered intravenously
• Biological: VRC07-523LS
  20 mg/kg administered intravenously

• Experimental: Group 1: PGT121 + VRC07-523LS
  Participants will receive PGT121 and VRC07-523LS administered sequentially in this order at Day 0.
  Interventions:

  • Biological: PGT121
  • Biological: VRC07-523LS
• Experimental: Group 2: PGDM1400 + VRC07-523LS
  Participants will receive PGDM1400 and VRC07-523LS administered sequentially in this order at Day 0.
  Interventions:

  • Biological: PGDM1400
  • Biological: VRC07-523LS
• Experimental: Group 3: 10-1074 + VRC07-523LS
  Participants will receive 10-1074 and VRC07-523LS administered sequentially in this order at Day 0.
  Interventions:

  • Biological: 10-1074
  • Biological: VRC07-523LS
• Experimental: Group 4: PGDM1400 + PGT121 + VRC07-523LS
  Participants will receive PGDM1400, PGT121, and VRC07-523LS administered sequentially in this order at Day 0 and Month 4.
  Interventions:

  • Biological: PGT121
  • Biological: PGDM1400
  • Biological: VRC07-523LS

Inclusion Criteria:

General and Demographic Criteria

• Age of 18 to 50 years
• Access to a participating clinical research site (CRS) and willingness to be followed for the planned duration of the study
• Ability and willingness to provide informed consent
• Assessment of understanding: volunteer demonstrates understanding of this study and completes a questionnaire prior to first study product administration with verbal demonstration of understanding of all questionnaire items answered incorrectly
• Agrees not to enroll in another study of an investigational research agent until completion of the last required protocol clinic visit
• Good general health as shown by medical history, physical exam, and screening laboratory tests

HIV-Related Criteria:

• Willingness to receive HIV test results
• Willingness to discuss HIV infection risks and amenable to HIV risk reduction counseling
• Assessed by the clinic staff as being at "low risk" for HIV infection and committed to maintaining behavior consistent with low risk of HIV exposure through the last required protocol clinic visit (see the protocol for more information)

Laboratory Inclusion Values

Hemogram/Complete Blood Count

• Hemoglobin greater than or equal to 11.0 g/dL for volunteers who were assigned female sex at birth, greater than or equal to 13.0 g/dL for volunteers who were assigned male sex at birth. For transgender participants who have been on feminizing hormone therapy for more than 6 consecutive months, determine hemoglobin eligibility based on the gender with which they identify (ie, a transgender female who has been on hormone therapy for more than 6 consecutive months should be assessed for eligibility using the hemoglobin parameters for persons assigned female sex at birth).
• White blood cell count equal to 2,500 to 12,000 cells/mm^3
• White blood cell (WBC) differential either within institutional normal range or with site clinician approval
• Platelets equal to 125,000 to 550,000/mm^3

Chemistry

• Chemistry panel: Alanine aminotransferase (ALT) less than 1.25 times the institutional upper limit of normal; creatinine less than or equal to institutional upper limit of normal

Virology

• Negative HIV-1 and -2 blood test: US volunteers must have a negative Food and Drug Administration (FDA)-approved enzyme immunoassay (EIA) or chemiluminescent microparticle immunoassay (CMIA).
• Negative Hepatitis B surface antigen (HBsAg)
• Negative anti-Hepatitis C virus antibodies (anti-HCV), or negative HCV polymerase chain reaction (PCR) if the anti-HCV is positive

Urine

• Negative or trace urine protein

Reproductive Status

• Volunteers who were assigned female sex at birth: negative serum or urine beta human chorionic gonadotropin (β-HCG) pregnancy test performed prior to study product administration on the day of initial study product administration. Persons who are NOT of reproductive potential due to having undergone total hysterectomy or bilateral oophorectomy (verified by medical records), are not required to undergo pregnancy testing.

• Reproductive status: A volunteer who was assigned female sex at birth must:

  • Agree to use effective contraception for sexual activity that could lead to pregnancy from at least 21 days prior to enrollment through the last required protocol clinic visit. Effective contraception is defined as using one of the following methods:
  • Condoms (male or female) with or without a spermicide,
  • Diaphragm or cervical cap with spermicide,
  • Intrauterine device (IUD),
  • Hormonal contraception,
  • Tubal ligation,
  • Any other contraceptive method approved by the HVTN 130/HPTN 089 Protocol Safety Review Team (PSRT)
  • Successful vasectomy in any partner assigned male sex at birth (considered successful if a volunteer reports that a male partner has [1] documentation of azoospermia by microscopy, or [2] a vasectomy more than 2 years ago with no resultant pregnancy despite sexual activity postvasectomy);
  • Or not be of reproductive potential, such as having reached menopause (no menses for 1 year) or having undergone hysterectomy or bilateral oophorectomy;
  • Or be sexually abstinent.
• Volunteers who were assigned female sex at birth must also agree not to seek pregnancy through alternative methods, such as artificial insemination or in vitro fertilization until after the last required protocol clinic visit.

Exclusion Criteria:

General

• Weight greater than 115 kg
• Blood products received within 120 days before first study product administration, unless eligibility for earlier enrollment is determined by the HVTN 130/HPTN 089 PSRT
• Investigational research agents received within 30 days before first study product administration
• Intent to participate in another study of an investigational research agent or any other study that requires non-Network HIV antibody testing during the planned duration of the HVTN 130/HPTN 089 study
• Pregnant or breastfeeding

Vaccines and other Injections

• HIV vaccine(s) received in a prior HIV vaccine trial. For volunteers who have received control/placebo in an HIV vaccine trial, the HVTN 130/HPTN 089 PSRT will determine eligibility on a case-by-case basis.
• Previous receipt of humanized or human mAbs, whether licensed or investigational; the HVTN 130/HPTN 089 PSRT will determine eligibility on a case-by-case basis.
• Previous receipt of monoclonal antibodies VRC01, VRC01LS, VRC07-523LS, PGT121, PGDM1400, or 10-1074

Immune System

• Immunosuppressive medications received within 30 days before first study product administration (Not exclusionary: [1] corticosteroid nasal spray; [2] inhaled corticosteroids; [3] topical corticosteroids for mild, uncomplicated dermatological condition; or [4] a single course of oral/parenteral prednisone or equivalent at doses less than 20 mg/day and length of therapy less than 14 days.)
• Serious adverse reactions to VRC07-523LS, PGT121, PGDM1400, or 10-1074 formulation components (acetate, sucrose, polysorbate 80, histidine, and sorbitol; see the protocol for more information), including history of anaphylaxis and related symptoms such as hives, respiratory difficulty, angioedema, and/or abdominal pain
• Immunoglobulin received within 90 days before first study product administration, unless eligibility for earlier enrollment is determined by the HVTN 130/HPTN 089 PSRT (for mAb see criterion above)
• Autoimmune disease (Not excluded from participation: Volunteer with mild, stable and uncomplicated autoimmune disease that does not require immunosuppressive medication and that, in the judgment of the site investigator, is likely not subject to exacerbation and likely not to complicate Solicited and Unsolicited AE assessments)
• Immunodeficiency

Clinically significant medical conditions

• Clinically significant medical condition, physical examination findings, clinically significant abnormal laboratory results, or past medical history with clinically significant implications for current health. A clinically significant condition or process includes but is not limited to:

  • A process that would affect the immune response,
  • A process that would require medication that affects the immune response,
  • Any contraindication to repeated infusions, or blood draws, including inability to establish venous or sub-cutaneous access.
  • A condition that requires active medical intervention or monitoring to avert grave danger to the volunteer's health or well-being during the study period,
  • A condition or process (eg, chronic urticaria or recent injection or infusion with evidence of residual inflammation) for which signs or symptoms could be confused with reactions to the study product, or
  • Any condition specifically listed among the exclusion criteria.
• Any medical, psychiatric, occupational, or skin condition (eg, tattoos) that, in the judgment of the investigator, would interfere with, or serve as a contraindication to, protocol adherence, assessment of safety, Solicited AEs, or a volunteer's ability to give informed consent
• Psychiatric condition that precludes compliance with the protocol. Specifically excluded are persons with psychoses within the past 3 years, ongoing risk for suicide, or history of suicide attempt or gesture within the past 3 years.
• Current anti-tuberculosis (TB) therapy

• Asthma other than mild, well-controlled asthma (Symptoms of asthma severity as defined in the most recent National Asthma Education and Prevention Program (NAEPP) Expert Panel report). Exclude a volunteer who:

  • Uses a short-acting rescue inhaler (typically a beta 2 agonist) daily, or
  • Uses moderate/high-dose, inhaled corticosteroids, or
  • In the past year has had either of the following:
  • Greater than 1 exacerbation of symptoms treated with oral/parenteral corticosteroids;
  • Needed emergency care, urgent care, hospitalization, or intubation for asthma.
• Diabetes mellitus type 1 or type 2 (Not exclusionary: type 2 cases controlled with diet alone or a history of isolated gestational diabetes)

• Hypertension:

  • If a person has been found to have elevated blood pressure or hypertension during screening or previously, exclude for blood pressure that is not well controlled. Well-controlled blood pressure is defined as consistently less than or equal to 140 mm Hg systolic and less than or equal to 90 mm Hg diastolic, with or without medication, with only isolated, brief instances of higher readings, which must be less than or equal to 150 mm Hg systolic and less than or equal to 100 mm Hg diastolic. For these volunteers, blood pressure must be less than or equal to 140 mm Hg systolic and less than or equal to 90 mm Hg diastolic at enrollment.
  • If a person has NOT been found to have elevated blood pressure or hypertension during screening or previously, exclude for systolic blood pressure greater than or equal to 150 mm Hg at enrollment or diastolic blood pressure greater than or equal to 100 mm Hg at enrollment.
• Bleeding disorder diagnosed by a clinician (eg, factor deficiency, coagulopathy, or platelet disorder requiring special precautions)
• Malignancy (Not excluded from participation: Volunteer who has had malignancy excised surgically and who, in the investigator's estimation, has a reasonable assurance of sustained cure, or who is unlikely to experience recurrence of malignancy during the period of the study.)
• Seizure disorder: History of seizure(s) within past three years. Also exclude if volunteer has used medications in order to prevent or treat seizure(s) at any time within the past 3 years.
• Asplenia: any condition resulting in the absence of a functional spleen
• History of hereditary angioedema, acquired angioedema, or idiopathic angioedema