Evaluating the Safety and Immune Response to an HIV Vaccine in Healthy, HIV-Uninfected Adults Who Have Participated in Previous HIV Vaccine Clinical Trials and in Adults Who Have Not Participated in Previous HIV Vaccine Clinical Trials

Inclusion Criteria: * Access to a participating HVTN Clinical Research Site (CRS) and willing to be followed for the planned duration of the study * Able and willing to provide informed consent * Assessment of understanding: must demonstrate understanding of this study and the Step Study results; completes a questionnaire prior to first vaccination with verbal demonstration of understanding of all questionnaire items answered incorrectly * Willing to receive HIV test results * Willing to discuss HIV infection risks, amenable to HIV risk reduction counseling, and committed to maintaining behavior consistent with low risk of HIV exposure through the last required study clinic visit * Assessed by the clinic staff as being at low risk for HIV infection * Agrees not to enroll in another study of an investigational research agent prior to completion of last required study clinic visit * In good general health as shown by medical history, physical exam, and screening laboratory tests * For Group 1: Prior receipt of an HIV-1 subtype B envelope subunit vaccine (gp120, gp140) with MF59 adjuvant. More information on this criterion can be found in the protocol. * Hemoglobin greater than or equal to 11.0 g/dL for participants who were born female, greater than or equal to 13.0 g/dL for participants who were born male * White blood cell (WBC) count equal to 3,300 to 12,000 cells/mm\^3 * Total lymphocyte count greater than or equal to 800 cells/mm\^3 * Remaining differential either within institutional normal range or with site physician approval * Platelets equal to 125,000 to 550,000/mm\^3 * Chemistry panel: Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) less than 1.25 times the upper limit of normal; creatinine less than or equal to the institutional upper limits of normal * Negative HIV-1 and -2 blood test: Group 1 (primed) participants must have a negative test result for HIV infection following the HVTN Lab Program's in-study HIV testing algorithm. Group 2 (unprimed) participants must have a negative test result for HIV-infection following the CRS's routine HIV screening procedures with an FDA-approved blood test. * 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 * Normal urine: Negative urine glucose, negative or trace urine protein, and negative or trace urine hemoglobin (if trace hemoglobin is present on dipstick, a microscopic urinalysis within institutional normal range) * Participants who were born female: negative serum or urine beta human chorionic gonadotropin (β-HCG) pregnancy test performed prior to vaccination on the day of initial vaccination * Participants who were born female must agree to consistently use effective contraception from at least 21 days prior to enrollment through the last required protocol clinic visit for sexual activity that could lead to pregnancy, or not be of reproductive potential, or be sexually abstinent. More information on this criterion can be found in the protocol. * Participants who were born female must also agree not to seek pregnancy through alternative methods, such as artificial insemination or in vitro fertilization, until after the last required study clinic visit * Participants who were born female and agree to cervical fluid collection must report having a normal Pap smear or atypical squamous cells of undetermined significance (ASCUS) with no evidence of high risk HPV within 3 years prior to enrollment in order to participate in cervical mucosal sampling. This is not a requirement for study entry. Inclusion Criteria for Study Extension: Prior to participation in the study extension, participants will be rescreened for eligibility. The participant must have received the two earlier vaccinations in the study. Participants must demonstrate understanding of the study extension and complete a questionnaire prior to receiving the third vaccination; however, understanding of the Step study results will not be specifically reassessed. Study extension participants must have a negative test result for HIV infection following the HVTN Lab Program's in-study HIV testing algorithm, within 21 days prior to receipt of the third vaccination. All inclusion criteria listed above for the study still apply EXCEPT the following criteria: * Age of 18 to 55 years * Assessment of understanding * Prior receipt of an HIV-1 subtype B envelope subunit vaccine (gp120, gp140) with MF59 adjuvant (Group 1 participants) * Negative hepatitis B surface antigen (HBsAg), and negative anti-hepatitis C virus antibodies (anti-HCV), or negative HCV polymerase chain reaction (PCR) if the anti-HCV is positive. Repeat testing is not necessary for syphilis and hepatitis B and C, which will be excluded based on updated participant medical history. * Normal Pap smear or atypical squamous cells of undetermined significance (ASCUS) criteria with no evidence of high risk HPV within 3 years prior to enrollment in order to participate in cervical mucosal sampling. Exclusion Criteria: * History of newly acquired syphilis, gonorrhea, non-gonococcal urethritis, herpes simplex virus type 2 (HSV2), chlamydia, pelvic inflammatory disease (PID), trichomonas, mucopurulent cervicitis, epididymitis, proctitis, lymphogranuloma venereum, chancroid, or hepatitis B within the 12 months prior to study entry * Untreated or incompletely treated syphilis infection * For Group 2 only: HIV vaccine(s) received in a prior HIV vaccine trial. For potential participants who have received control/placebo in an HIV vaccine trial, the HVTN 088 Protocol Safety Review Team (PSRT) will determine eligibility on a case-by-case basis. * Non-HIV experimental vaccine(s) or adjuvant(s) other than MF59 received within the 5 years prior to study entry in a prior vaccine trial. Exceptions may be made for vaccines/adjuvants that have subsequently undergone licensure by the FDA. For potential participants who have received an experimental vaccine(s)/adjuvant(s) greater than 5 years before study entry, eligibility for enrollment will be determined by the PSRT on a case-by-case basis. For potential participants who have received control/placebo in an experimental vaccine trial, the HVTN 088 PSRT will determine eligibility on a case-by-case basis. * Live attenuated vaccines other than influenza vaccine received within 30 days before first vaccination or scheduled within 14 days after injection (e.g., measles, mumps, and rubella \[MMR\]; oral polio vaccine \[OPV\]; varicella; yellow fever) * Influenza vaccine or any vaccines that are not live attenuated vaccines (e.g., pneumococcal, tetanus, hepatitis A or B) and were received within 14 days prior to any vaccination * Allergy treatment with antigen injections within 30 days before first vaccination or that are scheduled within 14 days after first vaccination * Immunosuppressive medications received within 168 days before first vaccination. (Not excluded: \[1\] corticosteroid nasal spray for allergic rhinitis; \[2\] topical corticosteroids for mild, uncomplicated dermatitis; or \[3\] oral/parenteral corticosteroids given for non-chronic conditions not expected to recur \[length of therapy 10 days or less with completion at least 30 days prior to study entry\].) * Blood products received within 120 days before first vaccination * Immunoglobulin received within 60 days before first vaccination * Investigational research agents received within 30 days before first vaccination * Intent to participate in another study of an investigational research agent during the planned duration of the study * Current anti-tuberculosis (TB) prophylaxis or therapy * Clinically significant medical condition, physical examination findings, clinically significant abnormal laboratory results, or past medical history with clinically significant implications for current health. More information on this criterion can be found in the protocol. * Any medical, psychiatric, occupational, or other condition that, in the judgment of the investigator, would interfere with, or serve as a contraindication to, study adherence, assessment of safety or reactogenicity, or a participant's ability to give informed consent * Serious adverse reactions to vaccines, including anaphylaxis and related symptoms such as hives, respiratory difficulty, angioedema, and/or abdominal pain. (Not excluded: a participant who had a nonanaphylactic adverse reaction to pertussis vaccine as a child.) * Autoimmune disease * Immunodeficiency * Asthma other than mild, well-controlled asthma. More information on this criterion can be found in the protocol. * Diabetes mellitus type 1 or type 2, including cases controlled with diet alone. (Not excluded: history of isolated gestational diabetes.) * Thyroidectomy, or thyroid disease requiring medication during the 12 months before study entry * History of hereditary angioedema, acquired angioedema, or idiopathic forms of angioedema * Hypertension: If a person has been diagnosed with hypertension during screening or previously, exclude for hypertension that is not well controlled. If a person has NOT been diagnosed with hypertension during screening or previously, exclude for systolic blood pressure greater than or equal to 150 mm Hg at study entry or diastolic blood pressure greater than or equal to 100 mm Hg at study entry. More information on this criterion can be found in the protocol. * Body mass index (BMI) greater than or equal to 40; or BMI greater than or equal to 35 with two or more of the following: age greater than 45, systolic blood pressure greater than 140 mm Hg, diastolic blood pressure greater than 90 mm Hg, current smoker, or known hyperlipidemia * Bleeding disorder diagnosed by a doctor (e.g., factor deficiency, coagulopathy, platelet disorder requiring special precautions) * Cancer (Not excluded: a participant with a surgical excision and subsequent observation period that in the investigator's estimation has a reasonable assurance of sustained cure or is unlikely to recur during the period of the study.) * Seizure disorder (Not excluded: a participant with a history of seizures who has not required medications or had a seizure within the 3 years prior to study entry.) * Asplenia: any condition resulting in the absence of a functional spleen * Psychiatric condition that precludes compliance with the study. Specifically excluded are people with psychoses within the 3 years prior to study entry, ongoing risk for suicide, or history of suicide attempt or gesture within the 3 years prior to study entry. * Pregnant or breastfeeding Exclusion Criteria for Optional Mucosal Sampling: * Any medical, psychiatric, or social condition, or occupational or other responsibility that, in the judgment of the investigator, would interfere with, or serve as a contraindication to the planned procedure Exclusion Criteria for Study Extension: Prior to participation in the study extension, participants will be rescreened for eligibility. The participant must have received the two earlier vaccinations in the study. All exclusion criteria listed above for the study still apply EXCEPT the following criteria: * HIV vaccine(s) received in a prior HIV vaccine trial (Group 2 participants) * BMI greater than or equal to 40; or BMI greater than or equal to 35 with two or more of the following: age greater than 45, systolic blood pressure greater than 140 mm Hg, diastolic blood pressure greater than 90 mm Hg, current smoker, or known hyperlipidemia