Inclusion Criteria:

• Assessment of understanding: volunteer demonstrates 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
• Willingness to receive HIV test results
• Willingness to discuss HIV infection risks, amenable to HIV risk reduction counseling, committed to maintaining behavior consistent with low risk of HIV exposure through the last required clinic visit, and willing to continue annual followup contact after the last required clinic visit, for a total of 5 years following enrollment
• Assessed by clinic staff as being at "low risk" for HIV infection. More information on this criterion can be found in the protocol.
• Good general health as shown by medical history, physical exam, and screening laboratory tests. More information on this criterion can be found in the protocol.
• Negative HIV-1 and 2 blood test: participants must have a negative FDA-approved enzyme immunoassay (EIA)
• For volunteers born female, normal Pap smear or ASCUS with no evidence of high risk HPV within 12 months prior to enrollment.
• Willing to use acceptable methods of birth control and not seek pregnancy through alternative forms of conception.

Exclusion Criteria:

• Excessive daily alcohol use or frequent binge drinking or chronic marijuana abuse or any other use of illicit drugs within the past 12 months
• A 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 in the past 12 months
• 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 076 PSRT will determine eligibility on a case-by-case basis.
• Experimental vaccine(s) received within the last 5 years in a prior vaccine trial. More information on this criterion can be found in the protocol.
• Immunosuppressive medications received within 168 days before first vaccination (eg, oral/parenteral corticosteroids, and/or cytotoxic medications). People taking corticosteroid nasal spray for allergic rhinitis and topical corticosteroids for mild, uncomplicated dermatitis are not excluded.
• Abnormality of the colorectal mucosa, or significant colorectal symptom(s), which in the opinion of the clinician represents a contraindication to biopsy (including but not limited to presence of any unresolved injury, infectious or inflammatory condition of the local mucosa, and presence of hemorrhoids)
• Blood products received within 120 days before first vaccination
• Immunoglobulin received within 60 days before first vaccination
• Live attenuated vaccines received within 30 days before first vaccination
• Any vaccines that are not live attenuated vaccines and were received within 14 days prior to first vaccination (eg, influenza, tetanus, pneumococcal, Hepatitis A or B)
• 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
• Allergy treatment with antigen injections within 30 days before first vaccination or scheduled within 14 days after injection
• 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.
• 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, protocol 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. Participants who had a nonanaphylactic adverse reaction to pertussis vaccine as a child are not excluded.
• Autoimmune disease
• Immunodeficiency
• Active syphilis infection
• Reports 1 or more perianal HSV outbreaks within 30 days prior to enrollment
• Positive gonorrhea or Chlamydia urine nucleic acid amplification test (NAAT)
• Volunteers reporting receptive anal intercourse in the last 12 months: positive rectal gonorrhea or Chlamydia test by NAAT or culture
• Asthma other than mild, well-controlled asthma.
• History of partial or complete hysterectomy
• History of valvular heart disease
• Diabetes mellitus type 1 or type 2, including cases controlled with diet alone.
• Thyroidectomy, or thyroid disease requiring medication during the last 12 months
• Angioedema within the last 3 years if episodes are considered serious or have required medication within the last 2 years
• Hypertension
• Bleeding disorder diagnosed by a doctor (eg, factor deficiency, coagulopathy, or platelet disorder requiring special precautions)
• Malignancy
• Seizure disorder (Not excluded: a participant with a history of seizures who has not required medications or had a seizure for 3 years.)
• Asplenia: any condition resulting in the absence of a functional spleen
• Psychiatric condition that precludes compliance with the protocol
• Pregnant or breastfeeding