This study is testing a lab-made antibody called ePGT121v1-LS that targets a specific part of HIV. Researchers will give it by vein (IV) and under the skin (SC), both on its own and together with two other antibodies, VRC07-523LS and PGDM1400LS, which target different parts of the virus. They will assess safety and side effects, determine the right dose, study how the body processes the drug (pharmacokinetics or PK), and measure how well it neutralizes HIV in the blood (serum neutralizing activity). The expectation is that ePGT121v1-LS, whether given alone or with PGDM1400LS and VRC07-523LS, by IV or SC, will be safe in generally healthy adults and that the antibodies will not interfere with each other when used together.

Approximately 83 volunteers in overall good health and without HIV-1 will be enrolled into two parts (A and B).

Part A has six groups. In Groups 1-3, participants will get ePGT121v1-LS given by IV at one of three dose levels: 5 mg/kg, 20 mg/kg, or 40 mg/kg. In Groups 4-6, participants will receive three antibodies-first ePGT121v1-LS, then PGDM1400LS and VRC07-523LS-given by IV at two separate visits that are 24 weeks apart. The total study duration for participants in Part A is 48 weeks of scheduled clinic visits.

Part B has two groups. In Group 7, people will get ePGT121v1-LS as SC shots at two visits 12 weeks apart. Each visit will give a total of 375 mg, split into three injections of 125 mg each. In Group 8, people will also have two visits 12 weeks apart and will receive three antibodies as SC shots in this order: first ePGT121v1-LS (125 mg), then PGDM1400LS (100 mg), and then VRC07-523LS (100 mg). The total study duration for participants in Part B is 24 weeks of scheduled clinic visits.

Inclusion Criteria:

1. Age 18 to 55 years.

2. Can visit a participating clinic and is willing to stay in the study for its full duration.

3. Understands the study and is able and willing to give informed consent.

4. Agrees not to join another experimental study until the final required clinic visit.

5. In good overall health based on medical history, physical exam, and screening lab tests.

6. Willing to receive HIV test results.

7. Willing to discuss personal risk of getting HIV and to have HIV prevention counseling.

8. Judged by clinic staff to have a low risk of getting HIV and agrees to avoid higher risk behaviors through the last clinic visit.

9. Hemoglobin levels:

   • Women: at least 11.0 g/dL
   • Men: at least 13.0 g/dL

10. White blood cell count between 2,500 and 12,000 cells/mm³.

11. White blood cell differential is normal or acceptable to clinic staff.

12. Platelet count between 125,000 and 550,000 cells/mm³.

13. ALT (liver enzyme) less than 1.25 times the lab's upper limit of normal.

14. Creatinine (kidney test) less than 1.1 times the lab's upper limit of normal.

15. Negative tests for HIV 1 and HIV 2.

16. Negative hepatitis B surface antigen.

17. Negative hepatitis C antibody, or a negative HCV PCR if the antibody test is positive.

18. Urine protein is negative or only trace.

19. If a woman who could become pregnant: negative pregnancy test within 72 hours before the first study treatment. Women with a documented total hysterectomy, both ovaries removed, both fallopian tubes removed, or menopause (no periods for at least 1 year) do not need pregnancy testing.

20. Women who could become pregnant agree to use effective birth control for sex that could lead to pregnancy starting at least 21 days before enrollment and continuing through the last study visit.

21. Women who could become pregnant also agree not to try to become pregnant using methods like egg retrieval, artificial insemination, or in vitro fertilization starting at least 21 days before enrollment and continuing through the last clinic visit.

Exclusion Criteria:

1. Received blood products within 120 days before the first study dose (unless the safety review team approves earlier enrollment).

2. Took any experimental (investigational) research drug within 30 days before the first study dose.

3. Weighs less than 35 kg or more than 115 kg.

4. Plans to join another study using an experimental product, or any study that requires non Network HIV antibody testing, during this study.

5. Pregnant or breastfeeding.

6. Previously received an HIV vaccine in a vaccine trial. If a potential participant received placebo/control only, eligibility will be decided case by case by the safety review team.

7. Received any non HIV vaccine within 14 days before enrollment or plan to get one within 14 days after enrollment. Exception: ACAM2000 smallpox vaccine within 28 days before enrollment (or scab still present if earlier) or planned within 14 days after enrollment.

8. Received humanized or human monoclonal antibodies (mAbs), whether approved or experimental.

9. Previously received monoclonal antibodies that target HIV.

10. Receiving allergy shots within 30 days before the first study dose or scheduled within 14 days after the first dose.

11. Took immune suppressing medicines within 30 days before the first study dose. Not excluded: nasal steroid sprays; inhaled steroids (see asthma item); topical steroids for mild skin conditions; or one short course of oral/IV prednisone (less than 20 mg/day for under 14 days) finished at least 7 days before the first infusion/injection.

12. History of serious reactions to components of the study products, including anaphylaxis or symptoms like hives, trouble breathing, swelling (angioedema), or abdominal pain.

13. Received immunoglobulin within 60 days before the first study dose (separate from mAbs listed above).

14. Autoimmune disease that is not mild, stable, and uncomplicated. Mild, stable cases not needing immune suppressing drugs may be allowed if the investigator judges low risk.

15. Immunodeficiency.

16. Any significant medical issue, abnormal exam or lab result, or past condition that could:

    • Affect the immune system or its response,
    • Require medicines that affect the immune system,
    • Make repeated injections, infusions, or blood draws unsafe or not feasible (for example, very difficult veins),
    • Need active medical care to prevent serious harm during the study,
    • Have symptoms that could be mistaken for reactions to the study product,
    • Or is otherwise listed among these exclusions.

17. Any medical or skin condition, social situation, or job duty that, in the investigator's judgment, would interfere with following the study, safety assessments, or giving informed consent.

18. A psychiatric condition that prevents following the study. Specifically excluded: psychosis, current suicide risk, or a suicide attempt within the past 3 years.

19. Currently on tuberculosis treatment.

20. Asthma that is more than mild and well controlled.

21. Diabetes (type 1 or type 2). Not excluded: type 2 controlled with diet only, or a past history of gestational diabetes.

22. High blood pressure (hypertension).

23. Diagnosed bleeding disorder.

24. Cancer. Not excluded: surgically removed cancers with good assurance of cure or very low risk of recurrence during the study period.

25. Seizure disorder with any seizure in the past 3 years, or use of seizure prevention or seizure treatment medicines at any time in the past 3 years.

26. Asplenia (no functioning spleen).

27. History of widespread hives, swelling (angioedema), or anaphylaxis. Not excluded if due to a known trigger and there have been no reactions for at least 5 years, showing successful avoidance of the trigger.