The most commonly used illicit stimulant in people with HIV (PWH) is methamphetamine (MA). Prior studies demonstrate strong evidence that MA promotes increased HIV transcription as well as immune dysregulation. A challenge in achieving worldwide HIV eradication is targeting specific marginalized populations who are most likely to benefit from an HIV cure but possess poorer immune responses. For this study, N = ~20 PWH virally-suppressed on antiretroviral therapy (ART) with no prior history of MA use disorder will be administered oral methamphetamine to determine the effects of short-term MA exposure on residual virus production, gene expression, and inflammation. Measures of MA exposure in urine and serum will then be associated with residual virus production, gene expression, cell surface immune marker protein expression, and systemic markers of inflammation. Thus, the proposed work will leverage a unique clinical trial design to generate advanced gene expression and immunologic data to identify potential novel targets for reversing HIV latency, reducing inflammation, and personalizing future therapies in PWH who use MA.

Inclusion Criteria:

• Willing and able to provide written informed consent
• Any gender, age ≥ 18 years < 65 years
• Laboratory confirmed documentation of HIV-1 infection.
• Continuous therapy with a Department of Health and Human Services (DHHS) recommended/alternative combination ART for least 12 months (at least 3 agents) at study entry with no regimen changes in the preceding 12 weeks
• Maintenance of undetectable plasma HIV-1 RNA ( <40copies/ml) below the limit of quantification for at least 12 months. Episodes of single HIV plasma RNA 50-500 copies/ml will not exclude participation if subsequent HIV plasma RNA is below the limit of assay detection
• No plans to modify ART during the study period (approximately 4-5 months)
• Participant and partner(s) are willing to use two forms of contraception throughout the study period as well as up to 60 days after the last day of study completion
• Ability and availability to participate in the full duration of the study (approximately 4-5 months) and maintain the inclusion/exclusion criteria
• No current or prior history of methamphetamine (MA) use disorder by DSM-5 diagnostic criteria. Participants may have a prior history of taking prescription medications containing amphetamines- type stimulants such as Adderall® or Dexedrine® or Ritalin for the treatment of conditions such as attention deficit hyperactivity disorder as long as the participant has not taken these medications in the last 12 months or plans to take these medications during the entire study period

Exclusion Criteria:

• History of methamphetamine ("meth") use disorder by DSM-5 diagnostic criteria using the 11-symptom checklist.
• Evidence of MA use other than due to the administered oral methamphetamine study drug, based on urine, hair, or serum MA measurements collected at baseline and follow-up study visits.
• Current use of prescription medications containing amphetamine-type stimulants (e. g.,Adderall®, Dexedrine®, Ritalin, etc.) within the past 1 year.
• Sensitivity or allergy to amphetamine-type stimulants.
• Current use of any other "psychoactive" drug within the last 1 month. These include cocaine, ecstasy, lysergic acid diethylamide (LSD), mushrooms, or other recreational drugs - but cannabis, nicotine or caffeine use is ok.
• Use of illicit opioids (heroin, fentanyl)- but ok if use of prescription opioid agonists with known prescribed doses, such as methadone, hydrocodone (Norco®), buprenorphine/naloxone (Suboxone®), oxycodone (Oxycontin®), hydromorphone (Dilaudid®) within the past 3 months by self-report and/or urine qualitative screening.
• Current moderate to severe use of alcohol use disorder (DSM-5 criteria) as this might put patient at risk of withdrawal during the study.
• Recent use within the last month of the following medications given potential interactions with oral methamphetamine: acebrophylline, iobenguane, isocarboxazid, methylene blue, moclobemide, phenelzine, procarbazine, rasagiline, safinamide, selegiline, tranylcypromine, asunaprevir, bupropion, topical cocaine, fluoxetine, iohexol, linezolid, paroxetine, potassium citrate, quinidine, sodium bicarbonate, sodium citrate, sodium lactate, tipranavir, and tromethamine.
• Recent hospitalization in the last 90 days.
• Recent infection in the last 90 days requiring prolonged (e.g., >3 weeks) of systemic intravenous antibiotics.
• Known anemia (HIV+ males Hct< 34; females Hct< 32) or contraindication to donating blood.
• Screening hemoglobin below 12.5 g/dL
• Poorly controlled hypertension or systolic blood pressure > 140 on repeat measurement in the last 3 months, on more than one occasion.
• Significant myocardial disease (e.g., current myocarditis or reduced left ventricular ejection fraction below the lower limit of normal) or diagnosed coronary artery disease.
• History of cardiac arrhythmia that needs to be medically treated.
• History of psychotic symptoms (e.g., hallucinations, delusional thinking) in the prior 3 months.
• History of seizures, abnormal electroencephalogram or brain damage with significant persisting neurological deficit in the past 3 months or currently on anti- seizure medications
• Significant respiratory disease requiring oxygen.
• Exposure to any immunomodulatory drug (including maraviroc) in the 12 weeks prior to study
• Prior or current use of experimental agents used with the intent to perturb the HIV-1 viral reservoir in the 12 weeks prior to study.
• Participants of reproductive potential or breastfeeding. Women of childbearing potential must have a negative serum pregnancy test at screening. All participants of childbearing potential must agree to use a double-barrier method of contraception throughout the study period and up to 90 days after the last dose of MA.
• Pregnancy. A serum pregnancy test will be performed. If this test is positive, the participant will not be allowed to enter the study since body changes occurring during pregnancy will alter the study results.
• Recent vaccination within the last 2 weeks prior to study baseline visit.* *Note: Routine or standard of care vaccinations (such as SARS-CoV-2, influenza, pneumococcal, and meningococcal vaccinations) are allowed, but must be administered greater than 14 days prior to baseline study visit. For SARS-CoV-2 vaccination, the last dose must be administered at least 14 days prior to baseline study visit.