Inclusion Criteria:
1. Signed informed consent
2. Participant in ULACNet-101 or participant screened specifically for ULACNet-102.
3. Biopsy-proven anal HSIL (men or women) shown as part of participation in the ULACNet-101 study or at a screening visit for ULACNet-102.
4. At least one focus of anal HSIL must be large enough to be monitored for response, i.e.,not completely removed after the screening biopsy.
5. Total volume of HSIL is less than 50% of the anal canal or perianal region.
6. Must be actively on treatment with effective antiretroviral therapy (ART) regimen for at least three months preceding enrollment (Visit 1, Day 1) in ULACNet-101 or at screening for ULACNet-102.
7. HIV RNA \<200 copies/ml at baseline.
8. Cluster of differentiation 4 (CD4) nadir above 200 cells per microliter (uL)
9. Eastern Cooperative Oncology Group (ECOG) performance status \<=1 (Karnofsky \>= 70%).
10. Participants must meet the following laboratory parameters within 3 months before enrollment:
1. Leukocytes: ≥3,000/mm\^3.
2. Absolute neutrophil count: ≥1,500/mm\^3.
3. Platelets: ≥100,000/mm\^3.
4. Elevation of aspartate aminotransferase (AST), alanine aminotransferase (ALT), or bilirubin \<2 times the upper limit of normal.
11. Not pregnant or breast feeding and one of the following:
1. Of non-childbearing potential (i.e. persons aged 60 years or older or who have had a hysterectomy or tubal ligation or are postmenopausal, as defined by no menses for at least 12 months and without an alternative medical cause).
2. Persons aged less than 60 years of childbearing potential and agree to practice highly effective contraception from initiation of taking EXE-346 or placebo through 14 days after taking the last dose of EXE-346 or placebo. Highly effective methods of contraception include one or more of the following:
i.Male partner who is sterile (medically effective vasectomy) prior to the female participant's entry into the study and is the sole sexual partner for the female participant.
ii.Hormonal (oral, intravaginal, transdermal, implantable or injectable); Progestogen-only hormonal contraceptives without inhibition of ovulation are not considered to be highly effective.
iii. An intrauterine hormone-releasing system. iv. An intrauterine device. v. Bilateral tubal occlusion or removal. vi. Sexual abstinence, only if the participant refrains from heterosexual intercourse from initiation taking EXE-346 or placebo through 14 days after taking the last dose of EXE-346 or placebo and it is the usual lifestyle of the participant.
Exclusion Criteria:
1. History of any anogenital cancer.
2. Presence of untreated cervical HSIL or cervical cancer.
3. Anal HSIL on clinical examination or biopsy that clinicians are concerned for cancer.
4. Receipt of chemotherapy, radiotherapy or immunosuppressive medication in three months preceding enrollment in ULACNet-101 or at the screening visit for ULACNet-102.
5. Immunosuppression as a result of underlying illness or treatment including:
1. Use of high dose corticosteroids (\>10 mg/day prednisone or equivalent) for \>=7 days (inhaled, otic, topical and ophthalmic corticosteroids are permitted).
2. Primary immune deficiency disease.
3. Use of synthetic or biologic disease-modifying anti-rheumatic drugs.
4. History of bone marrow or solid organ transplant.
5. History of any other clinically significant autoimmune or immunosuppressive disease.
6. Participant initiated a new treatment with antibiotics within the 2 weeks prior to screening or plans to start antibiotic therapy during the study period.
7. Participant is taking NSAIDs as a long-term treatment (ie, consistent use for at least 4 days/week each month). Acute use of NSAIDs is allowed.
8. Participant has known hypersensitivity to EXE-346 or any product components.
9. Current known infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
10. Warts so extensive that they preclude the clinician from determining the extent and location of HSIL.
11. Sustained, manually confirmed, sitting systolic blood pressure \>150 mm Hg or \<90 mm Hg or a diastolic blood pressure \>95 mm Hg as measured by 3 readings taken 15 minutes apart at screening or Visit 1.
12. History of significant thrombocytopenia, history of thrombosis with thrombocytopenia (TTS) syndrome or heparin-induced thrombocytopenia.
13. 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.
14. Participant has participated in any clinical study of an approved or unapproved investigational medicinal product within the 30 days prior to screening.
15. Any other finding that, in the opinion of the Investigator deems the participant unsuitable for the study
