VGX-3100 and Electroporation in Treating Patients With HIV-Positive High-Grade Anal Lesions

Inclusion Criteria: * Biopsy-proven intra-anal or per-HSIL at baseline (anal intraepithelial neoplasia \[AIN\]2 with a positive p16 stain, PAIN2-3, AIN2-3, or PAIN3/AIN3) * At least one focus of HSIL must be large enough to be monitored for response, i.e., not completely removed after the screening biopsy * Must be positive for HPV-16 or -18 on genotyping performed on screening anal swab * HIV positive; documentation of HIV-1 infection by means of any one of the following: * Documentation of HIV diagnosis in the medical record by a licensed health care provider * Any licensed HIV screening antibody and/or HIV antibody/antigen combination assay confirmed by a second licensed HIV assay such as a HIV-1 Western blot confirmation or HIV rapid multispot antibody differentiation assay; NOTE: A ?licensed? assay refers to a U.S. Food and Drug Administration (FDA)-approved assay, which is required for all investigational new drug (IND) studies * Must be documented to be on an effective combination antiretroviral therapy (ART) regimen, generally a 3-drug regimen based on Department of Health and Human Services (DHHS) treatment guidelines by a licensed health care provider; documentation may be a record of an ART prescription in the participant?s medical record, a written prescription in the name of the participant for ART, or pill bottles for ART with a label showing the participant?s name; each component agent of a multi-class combination ART regimen will be counted toward the 3-drug requirement * Eastern Cooperative Oncology Group (ECOG) performance status =\< 1 (Karnofsky \>= 70%) * Life expectancy of greater than 5 years * Within 90 days before enrollment: Leukocytes: \>= 3,000/mm\^3 * Within 90 days before enrollment: Absolute neutrophil count: \>= 1,500/mm\^3 * Within 90 days before enrollment: Platelets: \>= 100,000/mm\^3 * Within 90 days before enrollment: CD4 count \>= 350 cells/mm\^3 * Within 90 days before enrollment: HIV plasma HIV-1 RNA below detected limit obtained by Food and Drug Administration (FDA)-approved assays (limit of detection: 75 copies/mL or less) * For females, must have cervical cytology and visual examination of the vulva, vagina, and cervix within 12 months prior to enrollment with confirmation of no evidence of carcinoma; for women who underwent hysterectomy with removal of the cervix, cytology from the vagina within 12 months is required * For women of child-bearing potential (WOCBP), they must have a negative serum or urine pregnancy test within 72 hours of receiving the first dose of VGX-3100 and be at least 3 months post-partum; WOCBP and men must agree to use adequate contraception (oral contraceptive pills, intrauterine device, Nexplanon, Depo-Provera, or permanent sterilization, etc., or another acceptable method as determined by the investigator) prior to study entry, for the duration of study participation, and 4 months after completion of VGX-3100 administration; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately * A WOCBP is a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months) * Men who could father a child must agree to use at least one form of birth control during or continued abstinence from heterosexual intercourse prior to the study, for the duration of study participation, and 4 months after completion of VGX-3100 administration * Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: * Treatment or removal of HSIL less than 3 months prior to enrollment. * Patients who received any other investigational agents within the 4 weeks before enrollment, other than investigational antiretroviral agents for HIV and investigational agents for hepatitis C * Participants should be excluded if they have a condition requiring systemic treatment with either corticosteroids (\> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 2 weeks of study drug administration; inhaled steroids and adrenal replacement doses =\< 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease; participants are permitted to use ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption); physiologic replacement doses of systemic corticosteroids are permitted, even if \>= 10 mg/day prednisone equivalents; a brief course of corticosteroids for prophylaxis (e.g., contrast dye allergy) or for treatment of non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction caused by contact allergen) is permitted; use of anabolic steroids is permitted; topical steroids are permitted as long as they are not directly applied to the area of the skin where electroporation is planned * History of anal cancer, penile, vulvar, vaginal, or cervical cancer, or signs of any of these malignancies at baseline; participants with prior carcinoma in situ will not be considered to have prior cancer for eligibility purposes * Current systemic chemotherapy or radiation therapy that potentially causes bone marrow suppression that would preclude safe treatment of HSIL * History of allergic reactions attributed to compounds of similar chemical or biologic composition to VGX-3100 * Warts so extensive that they preclude the clinician from determining the extent and location of HSIL * Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, cardiac arrhythmia, or psychiatric illness/social situations that, in the opinion of the investigator, would limit compliance with study requirements or could be negatively affected by the electroporation treatment * Presence of unstable or life-threatening cardiac disease (e.g. unstable angina, class 3 or higher congestive heart failure) * Presence of acute or chronic bleeding or clotting disorder that would be a contraindication to IM injections (which may include the use blood thinners such as anticoagulants or antiplatelets drugs within two weeks of enrollment). Exception: Over-the-counter aspirin or non-steroidal anti-inflammatory drugs is allowed. * Participants who have not recovered from adverse events due to prior anti-HSIL therapy (i.e., have residual toxicity \> grade 1), per Common Toxicity Criteria for Adverse Events (CTCAE) v4.0 * Participants who have any metal implants, implanted medical devices, tattoos, keloids or hypertrophic scars, or active lesions/rashes within 2 cm of all intended potential sites of treatment/electroporation * History of seizures, except if participants have been seizure-free for 5 years or more with the use of one or fewer anti-epileptic agents * Sustained, manually confirmed, sitting systolic blood pressure \> 150 mm Hg or \< 90 mm Hg or a diastolic blood pressure \> 95 mm Hg at screening or day 0 * Resting heart rate \< 50 beats per minute (bpm) (unless attributable to athletic conditioning) or \> 100 bpm at screening or day 0 * Participants who have less than two acceptable sites available for IM injection considering the deltoid and anterolateral quadriceps muscles * Participants who have cardioverter-defibrillator or pacemaker (to prevent a life-threatening arrhythmia) that is located ipsilateral to the deltoid injection site (unless deemed acceptable by a cardiologist) * Participants who are breastfeeding a child; investigational product should not be administered to nursing mothers * Any illness or condition that in the opinion of the investigator may affect the safety of the participant or the evaluation of any study endpoint