Inclusion Criteria:

• Willing to be followed for the planned duration of the study
• Able and willing to provide informed consent
• Assessment of understanding, including the completion of a questionnaire prior to vaccination; verbally demonstrated understanding of all questionnaire items answered incorrectly
• Willing to receive HIV test results
• In good general health as shown by medical history, physical exam, and screening laboratory tests
• Hemoglobin levels greater than or equal to 11.0 g/dL for women and greater than or equal to 12.5 g/dL for men
• White blood cell (WBC) count between 3,300 and 12,000 cells/mm3
• Total lymphocyte count greater than or equal to 800 cells/mm3
• Remaining differential either within institutional normal range or accompanied by site physician approval
• Platelet levels between 125,000 and 550,000/mm3
• Alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, and total bilirubin less than 1.25 times the institutional upper limit of normal; and creatinine less than or equal to the institutional upper limit of normal
• Negative HIV-1 and 2 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 test; more information about this criterion can be found in the protocol
• Female participants must have a negative serum or urine beta human chorionic gonadotropin (β-HCG) pregnancy test performed on the day of vaccination prior to vaccination
• Female participants must agree to consistently use contraception from at least 21 days prior to study entry through the last study visit. More information on this criterion can be found in the protocol.

Exclusion Criteria:

• Received HIV vaccine(s) in a prior HIV vaccine trial. Participants who received a control/placebo in an HIV vaccine trial are not excluded but documentation of the identity of the study control/placebo must be obtained.
• Immunosuppressive medications received within 168 days before vaccination (e.g., 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.
• Blood products received within 120 days before vaccination
• Immunoglobulin received within 60 days before vaccination
• Live attenuated vaccines received within 30 days before vaccination (e.g., measles, mumps, and rubella [MMR]; oral polio vaccine [OPV]; varicella; yellow fever; Flumist® influenza)
• Investigational research agents received within 30 days before vaccination
• Any vaccines that are not live attenuated vaccines and were received within 14 days prior to vaccination (e.g., influenza, tetanus, pneumococcal, Hepatitis A or B)
• 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, 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. People who had a nonanaphylactic adverse reaction to the pertussis vaccine as a child are not excluded.
• Known autoimmune disease
• Known immunodeficiency
• Active syphilis infection. People who had syphilis that was fully treated more than 6 months before study entry are not excluded.
• 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. People with a history of isolated gestational diabetes are not excluded.
• Thyroidectomy, or thyroid disease requiring medication in the 12 months before study entry
• Angioedema in the 3 years before study entry if episodes are considered serious or have required medication in the 2 years before study entry
• If a person has been diagnosed with high blood pressure during screening or previously, they will be excluded for high blood pressure that is not well controlled. If a person has NOT been diagnosed with high blood pressure during screening or previously, they will be excluded 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.
• Body mass index (BMI) greater than or equal to 40, or BMI greater than or equal to 35 and two or more of the following conditions: 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. People 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 study period are not excluded.
• Seizure disorder or experienced a seizure in the 3 years before study entry. People with a history of seizures who have not required medications or had a seizure in the 3 years before study entry are not excluded.
• Absence of a functional spleen
• Psychiatric condition that makes study compliance difficult (e.g., people with psychoses in the 3 years before study entry, ongoing risk for suicide, history of suicide attempt or gesture in the 3 years before study entry)
• Pregnant or breastfeeding
• Abnormality of the rectum or rectal mucosa, which in the opinion of the clinician represents a contraindication to rectal biopsy
• Use of medication interfering with normal coagulation that may increase the risk for bleeding at the time of the rectal biopsy
• Experimental vaccine(s) received in a prior vaccine trial in the 5 years before study entry. Exceptions may be made for vaccines that are currently licensed or have subsequently undergone licensure. For potential participants who have received control/placebo in an experimental vaccine trial, the protocol safety review team (PSRT) will determine eligibility on a case-by-case basis. For potential participants who have received an experimental vaccine(s) more than 5 years ago, eligibility for enrollment will be determined by the PSRT on a case-by-case basis.
• Men who have sex with men (MSM) who have had receptive anal intercourse in the 12 months before study entry must have a positive rectal gonorrhea or chlamydia test by nucleic acid amplification test (NAAT) or culture
• Perianal herpes simplex virus (HSV) outbreak in the 30 days before study entry
• History of newly acquired syphilis, gonorrhea, non-gonococcal urethritis, HSV2, chlamydia, pelvic inflammatory disease (PID), trichomonas, mucopurulent cervicitis, epididymitis, proctitis, lymphogranuloma venereum, chancroid, or hepatitis B in the 12 months prior to study entry
• Individuals who are classified as not low-risk for acquisition of HIV-1 infection, on the basis of sexual behaviors within the 12 months prior to study entry. More information on this criterion can be found in the protocol.