Editing Inflammation (section)

=== HIV and AIDS ===

It has long been recognized that infection with [[HIV]] is characterized not only by development of profound [[immunodeficiency]] but also by sustained inflammation and immune activation.<ref name="Deeks 141–155">{{Cite journal |vauthors=Deeks SG |date=2011-01-01 |title=HIV infection, inflammation, immunosenescence, and aging |journal=Annual Review of Medicine |volume=62 |pages=141–55 |doi=10.1146/annurev-med-042909-093756 |pmc=3759035 |pmid=21090961}}</ref><ref>{{Cite journal |vauthors=Klatt NR, Chomont N, Douek DC, Deeks SG |date=July 2013 |title=Immune activation and HIV persistence: implications for curative approaches to HIV infection |journal=Immunological Reviews |volume=254 |issue=1 |pages=326–42 |doi=10.1111/imr.12065 |pmc=3694608 |pmid=23772629}}</ref><ref>{{Cite journal |vauthors=Salazar-Gonzalez JF, Martinez-Maza O, Nishanian P, Aziz N, Shen LP, Grosser S, Taylor J, Detels R, Fahey JL |date=August 1998 |title=Increased immune activation precedes the inflection point of CD4 T cells and the increased serum virus load in human immunodeficiency virus infection |journal=The Journal of Infectious Diseases |volume=178 |issue=2 |pages=423–30 |doi=10.1086/515629 |pmid=9697722 |doi-access=free}}</ref> A substantial body of evidence implicates chronic inflammation as a critical driver of immune dysfunction, premature appearance of aging-related diseases, and immune deficiency.<ref name="Deeks 141–155" /><ref>{{Cite journal |vauthors=Ipp H, Zemlin A |date=February 2013 |title=The paradox of the immune response in HIV infection: when inflammation becomes harmful |journal=Clinica Chimica Acta; International Journal of Clinical Chemistry |volume=416 |pages=96–9 |doi=10.1016/j.cca.2012.11.025 |pmid=23228847}}</ref> Many now regard HIV infection not only as an evolving virus-induced immunodeficiency, but also as chronic inflammatory disease.<ref>{{Cite journal |vauthors=Nasi M, Pinti M, Mussini C, Cossarizza A |date=October 2014 |title=Persistent inflammation in HIV infection: established concepts, new perspectives |journal=Immunology Letters |volume=161 |issue=2 |pages=184–8 |doi=10.1016/j.imlet.2014.01.008 |pmid=24487059}}</ref> Even after the introduction of [[Antiretroviral therapy, highly active|effective antiretroviral therapy]] (ART) and effective suppression of viremia in HIV-infected individuals, chronic inflammation persists. Animal studies also support the relationship between immune activation and progressive cellular immune deficiency: [[Simian immunodeficiency virus|SIV]]<nowiki/>sm infection of its natural nonhuman primate hosts, the [[sooty mangabey]], causes high-level viral replication but limited evidence of disease.<ref>{{Cite journal |vauthors=Milush JM, Mir KD, Sundaravaradan V, Gordon SN, Engram J, Cano CA, Reeves JD, Anton E, O'Neill E, Butler E, Hancock K, Cole KS, Brenchley JM, Else JG, Silvestri G, Sodora DL |date=March 2011 |title=Lack of clinical AIDS in SIV-infected sooty mangabeys with significant CD4+ T cell loss is associated with double-negative T cells |journal=The Journal of Clinical Investigation |volume=121 |issue=3 |pages=1102–10 |doi=10.1172/JCI44876 |pmc=3049370 |pmid=21317533}}</ref><ref>{{Cite journal |vauthors=Rey-Cuillé MA, Berthier JL, Bomsel-Demontoy MC, Chaduc Y, Montagnier L, Hovanessian AG, Chakrabarti LA |date=May 1998 |title=Simian immunodeficiency virus replicates to high levels in sooty mangabeys without inducing disease |journal=Journal of Virology |volume=72 |issue=5 |pages=3872–86 |doi=10.1128/JVI.72.5.3872-3886.1998 |pmc=109612 |pmid=9557672}}</ref> This lack of pathogenicity is accompanied by a lack of inflammation, immune activation and cellular proliferation. In sharp contrast, experimental [[Simian immunodeficiency virus|SIV]]<nowiki/>sm infection of [[rhesus macaque]] produces immune activation and AIDS-like disease with many parallels to human HIV infection.<ref>{{Cite journal |vauthors=Chahroudi A, Bosinger SE, Vanderford TH, Paiardini M, Silvestri G |date=March 2012 |title=Natural SIV hosts: showing AIDS the door |journal=Science |volume=335 |issue=6073 |pages=1188–93 |bibcode=2012Sci...335.1188C |doi=10.1126/science.1217550 |pmc=3822437 |pmid=22403383}}</ref>

Delineating how [[CD4]] T cells are depleted and how chronic inflammation and immune activation are induced lies at the heart of understanding HIV pathogenesis{{emdash}}one of the top priorities for HIV research by the Office of AIDS Research, [[National Institute of Allergy and Infectious Diseases|National Institutes of Health]]. Recent studies demonstrated that [[Caspase 1|caspase-1]]-mediated [[pyroptosis]], a highly inflammatory form of programmed cell death, drives CD4 T-cell depletion and inflammation by HIV.<ref name="Doitsh 509–514">{{Cite journal |vauthors=Doitsh G, Galloway NL, Geng X, Yang Z, Monroe KM, Zepeda O, Hunt PW, Hatano H, Sowinski S, Muñoz-Arias I, Greene WC |date=January 2014 |title=Cell death by pyroptosis drives CD4 T-cell depletion in HIV-1 infection |journal=Nature |volume=505 |issue=7484 |pages=509–14 |bibcode=2014Natur.505..509D |doi=10.1038/nature12940 |pmc=4047036 |pmid=24356306}}</ref><ref>{{Cite journal |vauthors=Monroe KM, Yang Z, Johnson JR, Geng X, Doitsh G, Krogan NJ, Greene WC |date=January 2014 |title=IFI16 DNA sensor is required for death of lymphoid CD4 T cells abortively infected with HIV |journal=Science |volume=343 |issue=6169 |pages=428–32 |bibcode=2014Sci...343..428M |doi=10.1126/science.1243640 |pmc=3976200 |pmid=24356113}}</ref><ref>{{Cite journal |vauthors=Galloway NL, Doitsh G, Monroe KM, Yang Z, Muñoz-Arias I, Levy DN, Greene WC |date=September 2015 |title=Cell-to-Cell Transmission of HIV-1 Is Required to Trigger Pyroptotic Death of Lymphoid-Tissue-Derived CD4 T Cells |journal=Cell Reports |volume=12 |issue=10 |pages=1555–1563 |doi=10.1016/j.celrep.2015.08.011 |pmc=4565731 |pmid=26321639}}</ref> These are the two signature events that propel HIV disease progression to [[HIV/AIDS|AIDS]]. Pyroptosis appears to create a pathogenic vicious cycle in which dying CD4 T cells and other immune cells (including macrophages and neutrophils) release inflammatory signals that recruit more cells into the infected lymphoid tissues to die. The feed-forward nature of this inflammatory response produces chronic inflammation and tissue injury.<ref>{{Cite journal |vauthors=Doitsh G, Greene WC |date=March 2016 |title=Dissecting How CD4 T Cells Are Lost During HIV Infection |journal=Cell Host & Microbe |volume=19 |issue=3 |pages=280–91 |doi=10.1016/j.chom.2016.02.012 |pmc=4835240 |pmid=26962940}}</ref> Identifying pyroptosis as the predominant mechanism that causes CD4 T-cell depletion and chronic inflammation, provides novel therapeutic opportunities, namely caspase-1 which controls the pyroptotic pathway. In this regard, pyroptosis of CD4 T cells and secretion of pro-inflammatory cytokines such as [[Interleukin 1 beta|IL-1β]] and [[Interleukin 18|IL-18]] can be blocked in HIV-infected human lymphoid tissues by addition of the caspase-1 inhibitor VX-765,<ref name="Doitsh 509–514" /> which has already proven to be safe and well tolerated in phase II human clinical trials.<ref>{{Cite journal |date=19 December 2013 |title=Study of VX-765 in Subjects With Treatment-resistant Partial Epilepsy – Full Text View – ClinicalTrials.gov |url=https://clinicaltrials.gov/ct2/show/NCT01048255 |url-status=live |archive-url=https://web.archive.org/web/20220926164557/https://clinicaltrials.gov/ct2/show/NCT01048255 |archive-date=26 September 2022 |access-date=2016-05-21 |website=clinicaltrials.gov}}</ref> These findings could propel development of an entirely new class of "anti-AIDS" therapies that act by targeting the host rather than the virus. Such agents would almost certainly be used in combination with ART. By promoting "tolerance" of the virus instead of suppressing its replication, VX-765 or related drugs may mimic the evolutionary solutions occurring in multiple monkey hosts (e.g. the sooty mangabey) infected with species-specific lentiviruses that have led to a lack of disease, no decline in CD4 T-cell counts, and no chronic inflammation.