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Here, we assessed if innate and adaptive immune responses are compromised ex vivo in persons who inject drugs (PWID) and whether long-term injection drug use may impact host susceptibility to in vitro HIV infection. We measured the frequency, activation state, and functional profile of NK cells, dendritic cells, and CD4+ and CD8+ T cells in low-risk PWID who do not share needles, high-risk needle-sharing PWID, and control donors who did not inject drugs. We also assessed plasma levels of inflammatory markers and CD4+ T cell susceptibility to HIV infection. We observed a significant increase in the amount of sCD14 (P\u00a0=\u00a00.0023, n\u00a0=\u00a016) and sCD163 (P\u00a0=\u00a00.0001, n\u00a0=\u00a016) in the plasma of PWID compared to controls. Evidence of constitutive activation was noted in PWID as compared to controls with increased CD69 expression in CD56dim NK cells (P\u00a0=\u00a00.0103, n\u00a0=\u00a026) and increased CD38 and HLA-DR expression in CD4+ T cells (P\u00a0=\u00a00.0355, n\u00a0=\u00a023). However, no innate or adaptive functional differences were detected between PWID and controls, including: NK cell direct or antibody-dependent cellular cytotoxicity poly-functional response, TLR-stimulated dendritic cell\/NK crosstalk, CD8+ T cell response to Staphylococcal enterotoxin B or CMV\/EBV\/FLU peptides, or constitutive or anti-CD3\/CD28-stimulated CD4+ T cell infectivity with CCR5-tropic or CXCR4-tropic HIV-1 isolates. Our data indicate that PWID who utilize opioids over as prolonged time frame can retain a functional ex vivo immune response without a measurable increase in CD4+ T cell infectivity suggesting that leukocytes from PWID are not intrinsically more susceptibility to infection with HIV than non-PWID controls.<\/jats:p>","DOI":"10.1002\/jlb.5a0920-604r","type":"journal-article","created":{"date-parts":[[2020,12,2]],"date-time":"2020-12-02T20:46:11Z","timestamp":1606941971000},"page":"385-396","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Persons who inject drugs (PWID) retain functional NK cells, dendritic cell stimulation, and adaptive immune recall responses despite prolonged opioid use"],"prefix":"10.1093","volume":"110","author":[{"given":"Costin","family":"Tomescu","sequence":"first","affiliation":[{"name":"HIV Immunopathogenesis Laboratory, The Wistar Institute , Philadelphia, Pennsylvania, USA"},{"name":"HIV Immunopathogenesis Laboratory, The Wistar Institute , Philadelphia, Pennsylvania, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Krystal","family":"Colon","sequence":"additional","affiliation":[{"name":"HIV Immunopathogenesis Laboratory, The Wistar Institute , Philadelphia, Pennsylvania, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, HIV Prevention Division, The University of Pennsylvania , Philadelphia, Pennsylvania, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mack","family":"Taylor","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, HIV Prevention Division, The University of Pennsylvania , Philadelphia, Pennsylvania, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Livio","family":"Azzoni","sequence":"additional","affiliation":[{"name":"HIV Immunopathogenesis Laboratory, The Wistar Institute , Philadelphia, Pennsylvania, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David S","family":"Metzger","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, HIV Prevention Division, The University of Pennsylvania , Philadelphia, Pennsylvania, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5799-6759","authenticated-orcid":false,"given":"Luis J","family":"Montaner","sequence":"additional","affiliation":[{"name":"HIV Immunopathogenesis Laboratory, The Wistar Institute , Philadelphia, Pennsylvania, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2020,12,2]]},"reference":[{"key":"2023032108485251800_","first-page":"220","article-title":"Opioid peptides, receptors, and immune function","volume":"96","author":"Bhargava","year":"1990","journal-title":"NIDA Res Monogr"},{"issue":"14","key":"2023032108485251800_","doi-asserted-by":"crossref","first-page":"2726","DOI":"10.1111\/bph.13903","article-title":"Influence of opioids on immune function in patients with cancer pain: from bench to bedside","volume":"175","author":"Boland","year":"2018","journal-title":"Br J Pharmacol"},{"issue":"6","key":"2023032108485251800_","first-page":"503","article-title":"Opiates and immune function. 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