adoptive transfer of haploidentical nk cells and n-803

Conditions: Hiv; HIV Infections; Immune Deficiency

Summary: this is a pilot therapeutic study of related donor hla-haploidentical nk-cell based therapy to determine if the treatment is safe and well-tolerated and if there is any measureable impact on virus reservoirs.

human immunodeficiency virus (hiv) infection causes profound and often irreversible changes to the adaptive and innate immune system. in the absence of antiretroviral therapy (art), cluster of differentiation (cd)4+ t cells are progressively depleted, cd8+ t cells are often expanded, and much of the immune system is chronically activated. much of these abnormalities improve during long-term art, but the system rarely returns to normal. notably, chronic inflammation persists indefinitely during art, and is driven by multiple factors, including hiv production (and perhaps replication), irreversible loss of the mucosal integrity and exposure to gut microbes, and an excess burden of other pathogens such as cytomegalovirus (cmv). how the virus and its host interact during effective art is the focus of intense investigation. hiv-1 preferentially infects activated memory cd4+ t cells that express the chemokine receptor ccr5, although resting cd4+ t cells, naïve cd4+ t cells and macrophages can also be infected. the majority of infected and activated cd4+ t cells die quickly, but a small fraction reverts to a resting state and persistent indefinitely as the latent reservoir. because art blocks all or nearly all new infection events, the reservoir that exists at the time art is initiated becomes the reservoir that persists for the life of the individual. this memory t cell viral reservoir is maintained during art by the long half-life of the infected cell, homeostatic proliferation of these cells and perhaps by low levels of persistent viral replication. the viral reservoir in peripheral blood exists predominantly in those longer-lived memory cd4+ cells endowed with regenerative potential, including memory stem cells, central memory cells and transitional memory. the reservoir also persists in potentially shorter-lived cd4+ t effector cell populations, but whether these cells represent a stable reservoir or one that is constantly being regenerated via proliferation and differentiation is unknown. "shock and kill". one approach to curing hiv infection that has generated broad support in the field is to induce latently infected cells to produce virus (the "shock") while enhancing the ability of the host to clear these virus-producing cells (the "kill"). histone deacetylase (hdac) inhibitors have been shown to increase production of hiv-1 rna and to a lesser degree virus particles from the viral reservoir in vivo. the magnitude of the effect of hdac inhibitors is modest at best, and as of yet this class of drugs has had no consistent effect on the frequency of cells that harbor replication-competent hiv. other classes of anti-latency drugs and immunomodulators are therefore being explored for their capacity to stimulate the viral reservoir. to augment the capacity of the host to eliminate reservoir cells following activation, several immunologic strategies are being explored. these strategies include therapeutic vaccines, monoclonal antibodies, and immune checkpoint inhibitors.

Eligibility criteria:
inclusion criteria: * age-18-65 * stable art for at least 12 months. * screening plasma hiv rna levels below level of quantification (\<40 to \<50 copies rna/ml depending on the assay). * screening cd4 count ≥500 cells/µl * laboratory tests (complete blood count, comprehensive metabolic panel, mg, phosphorus, international normalized ratio/partial thromboplastin time (inr/ptt), thyroid stimulating hormone (tsh)/t4,) performed within 14 days of infusion of donor nk cells. all laboratory results (unless otherwise specified) must be grade 1 or normal based on the daids adverse event grading scale (division of aids (daids) table for grading the severity of adult and pediatric adverse events v2.0) * adequate kidney function defined by estimated glomerular filtration rate (crcl) \> 60 ml/min or ml/min/1.73 m2 (≤ grade 2 per daids) and creatinine ≤ 1.5 x uln * pulmonary function testing (pft) must show fev1 and dlcocorr \> 50% of predicted if subjects have symptomatic or prior known impairment. * normal transthoracic echocardiogram * ability to be off prednisone and other immunosuppressive drugs for at least 14 days before infusion of cells * women of child bearing potential and men with partners of child bearing potential must agree to use effective contraception during therapy and for 4 months after completion of therapy * voluntary written consent provided by the subject exclusion criteria: * any condition that precludes leukapheresis, lymph node biopsy or colonoscopy with biopsy * active infection other than hiv currently requiring systemic antimicrobial therapy * history of deep vein thrombosis * active significant, tissue invasive fungal infection requiring systemic antifungal therapy (dermatologic conditions requiring only topical therapy are allowed). * chronic active hepatitis b or c (defined as antibody positive and dna+ or hepbsag+). * breastfeeding * intended modification of antiretroviral therapy in the next 24 weeks * nyha (new york heart association) class iii or iv heart failure, uncontrollable supraventricular arrhythmias, any history of a ventricular arrhythmia, or other clinical signs of severe cardiac dysfunction * symptomatic congestive heart failure, unstable angina pectoris, or myocardial infarction within 6 months prior to screening * marked baseline prolongation of qt/qtc interval (e.g. demonstration of a qtc interval greater than 500 milliseconds) * on-going chronic systemic corticosteroid use or other immunosuppressive therapy (a history of mild asthma not requiring therapy is eligible and inhaled corticosteroids is allowed. topical steroids are allowed.) * psychiatric illness/social situations that would limit compliance with study requirements * previous diagnosis of an autoimmune disease (e.g. rheumatoid arthritis, lupus, inflammatory bowel disease, multiple sclerosis, vasculitis) * use of any anticoagulants within the previous 4 weeks. * other illness that in the opinion of the investigator would exclude the patient from participating in this study

Keywords: suppressive antiretroviral therapy (art)