Betamethasone induces potent immunosuppression and reduces HIV infection in a PBMC in vitro model
Genital inflammation is an established risk factor for increased HIV acquisition risk. Certain HIV-exposed seronegative populations, who are naturally resistant to HIV infection, have an immune quiescent phenotype defined by reduced immune activation and inflammatory cytokines at the genital tract....
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| Veröffentlicht in: | Journal of investigative medicine 2021-01, Vol.69 (1), p.28-40 |
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| creator | Cromarty, Ross Sigal, Alexander Liebenberg, Lenine Julie Mckinnon, Lyle Robert Abdool Karim, Salim Safurdeen Passmore, Jo-Ann Shelly Archary, Derseree |
| description | Genital inflammation is an established risk factor for increased HIV acquisition risk. Certain HIV-exposed seronegative populations, who are naturally resistant to HIV infection, have an immune quiescent phenotype defined by reduced immune activation and inflammatory cytokines at the genital tract. Therefore, the aim of this study was to create an immune quiescent environment using immunomodulatory drugs to mitigate HIV infection. Using an in vitro peripheral blood mononuclear cell (PBMC) model, we found that inflammation was induced using phytohemagglutinin and Toll-like receptor (TLR) agonists Pam3CSK4 (TLR1/2), lipopolysaccharide (LPS) (TLR4) and R848 (TLR7/8). After treatment with anti-inflammatory drugs, ibuprofen (IBF) and betamethasone (BMS), PBMCs were exposed to HIV NL4-3 AD8. Multiplexed ELISA was used to measure 28 cytokines to assess inflammation. Flow cytometry was used to measure immune activation (CD38, HLA-DR and CCR5) and HIV infection (p24 production) of CD4+ T cells. BMS potently suppressed inflammation (soluble cytokines, p |
| doi_str_mv | 10.1136/jim-2020-001424 |
| format | Article |
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Certain HIV-exposed seronegative populations, who are naturally resistant to HIV infection, have an immune quiescent phenotype defined by reduced immune activation and inflammatory cytokines at the genital tract. Therefore, the aim of this study was to create an immune quiescent environment using immunomodulatory drugs to mitigate HIV infection. Using an in vitro peripheral blood mononuclear cell (PBMC) model, we found that inflammation was induced using phytohemagglutinin and Toll-like receptor (TLR) agonists Pam3CSK4 (TLR1/2), lipopolysaccharide (LPS) (TLR4) and R848 (TLR7/8). After treatment with anti-inflammatory drugs, ibuprofen (IBF) and betamethasone (BMS), PBMCs were exposed to HIV NL4-3 AD8. Multiplexed ELISA was used to measure 28 cytokines to assess inflammation. Flow cytometry was used to measure immune activation (CD38, HLA-DR and CCR5) and HIV infection (p24 production) of CD4+ T cells. BMS potently suppressed inflammation (soluble cytokines, p<0.05) and immune activation (CD4+ T cells, p<0.05). BMS significantly reduced HIV infection of CD4+ T cells only in the LPS (0.98%) and unstimulated (1.7%) conditions (p<0.02). In contrast, IBF had minimal anti-inflammatory and immunosuppressive but no anti-HIV effects. BMS demonstrated potent anti-inflammatory effects, regardless of stimulation condition. Despite uniform immunosuppression, BMS differentially affected HIV infection according to the stimulation conditions, highlighting the complex nature of these interactions. Together, these data underscore the importance of interrogating inflammatory signaling pathways to identify novel drug targets to mitigate HIV infection.</description><identifier>ISSN: 1081-5589</identifier><identifier>EISSN: 1708-8267</identifier><identifier>DOI: 10.1136/jim-2020-001424</identifier><identifier>PMID: 33004468</identifier><language>eng</language><publisher>Los Angeles, CA: SAGE Publications</publisher><subject>Cell culture ; Chemokines ; Cytokines ; Experiments ; HIV ; Human immunodeficiency virus ; Infections ; Inflammation ; Lymphocytes ; Nonsteroidal anti-inflammatory drugs ; Original Research ; Pathogens ; Recruitment ; Vagina</subject><ispartof>Journal of investigative medicine, 2021-01, Vol.69 (1), p.28-40</ispartof><rights>American Federation for Medical Research 2021. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ.</rights><rights>2021 American Federation for Medical Research</rights><rights>2021 American Federation for Medical Research 2021. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ. This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, an indication of whether changes were made, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/ . Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>American Federation for Medical Research 2021. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ. 2021</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-b493t-26a9b0d95918602aeb419fac5f390fddfb1f597b1026a6a79b3c85e2d0ed63803</citedby><cites>FETCH-LOGICAL-b493t-26a9b0d95918602aeb419fac5f390fddfb1f597b1026a6a79b3c85e2d0ed63803</cites><orcidid>0000-0001-6386-615X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://journals.sagepub.com/doi/pdf/10.1136/jim-2020-001424$$EPDF$$P50$$Gsage$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://journals.sagepub.com/doi/10.1136/jim-2020-001424$$EHTML$$P50$$Gsage$$Hfree_for_read</linktohtml><link.rule.ids>230,314,776,780,881,21798,27901,27902,43597,43598</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33004468$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Cromarty, Ross</creatorcontrib><creatorcontrib>Sigal, Alexander</creatorcontrib><creatorcontrib>Liebenberg, Lenine Julie</creatorcontrib><creatorcontrib>Mckinnon, Lyle Robert</creatorcontrib><creatorcontrib>Abdool Karim, Salim Safurdeen</creatorcontrib><creatorcontrib>Passmore, Jo-Ann Shelly</creatorcontrib><creatorcontrib>Archary, Derseree</creatorcontrib><title>Betamethasone induces potent immunosuppression and reduces HIV infection in a PBMC in vitro model</title><title>Journal of investigative medicine</title><addtitle>J Investig Med</addtitle><description>Genital inflammation is an established risk factor for increased HIV acquisition risk. Certain HIV-exposed seronegative populations, who are naturally resistant to HIV infection, have an immune quiescent phenotype defined by reduced immune activation and inflammatory cytokines at the genital tract. Therefore, the aim of this study was to create an immune quiescent environment using immunomodulatory drugs to mitigate HIV infection. Using an in vitro peripheral blood mononuclear cell (PBMC) model, we found that inflammation was induced using phytohemagglutinin and Toll-like receptor (TLR) agonists Pam3CSK4 (TLR1/2), lipopolysaccharide (LPS) (TLR4) and R848 (TLR7/8). After treatment with anti-inflammatory drugs, ibuprofen (IBF) and betamethasone (BMS), PBMCs were exposed to HIV NL4-3 AD8. Multiplexed ELISA was used to measure 28 cytokines to assess inflammation. Flow cytometry was used to measure immune activation (CD38, HLA-DR and CCR5) and HIV infection (p24 production) of CD4+ T cells. BMS potently suppressed inflammation (soluble cytokines, p<0.05) and immune activation (CD4+ T cells, p<0.05). BMS significantly reduced HIV infection of CD4+ T cells only in the LPS (0.98%) and unstimulated (1.7%) conditions (p<0.02). In contrast, IBF had minimal anti-inflammatory and immunosuppressive but no anti-HIV effects. BMS demonstrated potent anti-inflammatory effects, regardless of stimulation condition. Despite uniform immunosuppression, BMS differentially affected HIV infection according to the stimulation conditions, highlighting the complex nature of these interactions. Together, these data underscore the importance of interrogating inflammatory signaling pathways to identify novel drug targets to mitigate HIV infection.</description><subject>Cell culture</subject><subject>Chemokines</subject><subject>Cytokines</subject><subject>Experiments</subject><subject>HIV</subject><subject>Human immunodeficiency virus</subject><subject>Infections</subject><subject>Inflammation</subject><subject>Lymphocytes</subject><subject>Nonsteroidal anti-inflammatory drugs</subject><subject>Original Research</subject><subject>Pathogens</subject><subject>Recruitment</subject><subject>Vagina</subject><issn>1081-5589</issn><issn>1708-8267</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>9YT</sourceid><sourceid>ACMMV</sourceid><sourceid>AFRWT</sourceid><sourceid>8G5</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNqFkc1LxDAQxYMofp-9ScGbWHeStmlzEXTxCxQ9qNeQNlPNsm1q0gr-92aprnoQTxl4v3lvwiNkj8IxpQmfzEwTM2AQA9CUpStkk-ZQxAXj-WqYoaBxlhVig2x5PwNgPBNsnWwkCUCa8mKTqDPsVYP9i_K2xci0eqjQR53tse0j0zRDa_3QdQ69N7aNVKsjhyN0df0UFmqs-oVighjdn91OF9Ob6Z2NGqtxvkPWajX3uPv5bpPHi_OH6VV8c3d5PT29ictUJH3MuBIlaJEJWnBgCsuUilpVWZ0IqLWuS1pnIi9p-ITiKhdlUhUZMg2oeVJAsk1ORt9uKBvUVbjfqbnsnGmUe5dWGflbac2LfLZvMg_LgvJgcPBp4OzrgL6XMzu4NtwsWZpTzlLgWaAmI1U5673DeplAQS46kaETuehEjp2Ejf2fhy35rxICcDQCXj3jd-jffocjXjazf8M_ANo0o_A</recordid><startdate>20210101</startdate><enddate>20210101</enddate><creator>Cromarty, Ross</creator><creator>Sigal, Alexander</creator><creator>Liebenberg, Lenine Julie</creator><creator>Mckinnon, Lyle Robert</creator><creator>Abdool Karim, Salim Safurdeen</creator><creator>Passmore, Jo-Ann Shelly</creator><creator>Archary, Derseree</creator><general>SAGE Publications</general><general>Sage Publications Ltd</general><general>BMJ Publishing Group</general><scope>9YT</scope><scope>ACMMV</scope><scope>AFRWT</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>0-V</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AM</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>ALSLI</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>BGRYB</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>K7.</scope><scope>K9.</scope><scope>M0O</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>MBDVC</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-6386-615X</orcidid></search><sort><creationdate>20210101</creationdate><title>Betamethasone induces potent immunosuppression and reduces HIV infection in a PBMC in vitro model</title><author>Cromarty, Ross ; 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Certain HIV-exposed seronegative populations, who are naturally resistant to HIV infection, have an immune quiescent phenotype defined by reduced immune activation and inflammatory cytokines at the genital tract. Therefore, the aim of this study was to create an immune quiescent environment using immunomodulatory drugs to mitigate HIV infection. Using an in vitro peripheral blood mononuclear cell (PBMC) model, we found that inflammation was induced using phytohemagglutinin and Toll-like receptor (TLR) agonists Pam3CSK4 (TLR1/2), lipopolysaccharide (LPS) (TLR4) and R848 (TLR7/8). After treatment with anti-inflammatory drugs, ibuprofen (IBF) and betamethasone (BMS), PBMCs were exposed to HIV NL4-3 AD8. Multiplexed ELISA was used to measure 28 cytokines to assess inflammation. Flow cytometry was used to measure immune activation (CD38, HLA-DR and CCR5) and HIV infection (p24 production) of CD4+ T cells. BMS potently suppressed inflammation (soluble cytokines, p<0.05) and immune activation (CD4+ T cells, p<0.05). BMS significantly reduced HIV infection of CD4+ T cells only in the LPS (0.98%) and unstimulated (1.7%) conditions (p<0.02). In contrast, IBF had minimal anti-inflammatory and immunosuppressive but no anti-HIV effects. BMS demonstrated potent anti-inflammatory effects, regardless of stimulation condition. Despite uniform immunosuppression, BMS differentially affected HIV infection according to the stimulation conditions, highlighting the complex nature of these interactions. Together, these data underscore the importance of interrogating inflammatory signaling pathways to identify novel drug targets to mitigate HIV infection.</abstract><cop>Los Angeles, CA</cop><pub>SAGE Publications</pub><pmid>33004468</pmid><doi>10.1136/jim-2020-001424</doi><tpages>13</tpages><orcidid>https://orcid.org/0000-0001-6386-615X</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Cell culture Chemokines Cytokines Experiments HIV Human immunodeficiency virus Infections Inflammation Lymphocytes Nonsteroidal anti-inflammatory drugs Original Research Pathogens Recruitment Vagina |
| title | Betamethasone induces potent immunosuppression and reduces HIV infection in a PBMC in vitro model |
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