Residual Immune Dysregulation Syndrome in Treated HIV infection

Abrams, 2009, Interleukin-2 therapy in patients with HIV infection, The New England Journal of Medicine, 361, 1548, 10.1056/NEJMoa0903175 Achhra, 2010, Immunodeficiency and the risk of serious clinical endpoints in a well studied cohort of treated HIV-infected patients, AIDS, 24, 1877, 10.1097/QAD.0b013e32833b1b26 Andersson, 1998, Early reduction of immune activation in lymphoid tissue following highly active HIV therapy, AIDS, 12, F123, 10.1097/00002030-199811000-00004 Anton, 2003, Multiple measures of HIV burden in blood and tissue are correlated with each other but not with clinical parameters in aviremic subjects, AIDS, 17, 53, 10.1097/00002030-200301030-00008 Arthos, 2008, HIV-1 envelope protein binds to and signals through integrin alpha4beta7, the gut mucosal homing receptor for peripheral T cells, Nature Immunology, 9, 301, 10.1038/ni1566 Autran, 1997, Positive effects of combined antiretroviral therapy on CD4+ T cell homeostasis and function in advanced HIV disease [see comments], Science, 277, 112, 10.1126/science.277.5322.112 Baker, 2008, CD4+ count and risk of non-AIDS diseases following initial treatment for HIV infection, AIDS, 22, 841, 10.1097/QAD.0b013e3282f7cb76 Bazdar, 2007, Interleukin-7 enhances proliferation responses to T-cell receptor stimulation in naive CD4+ T cells from human immunodeficiency virus-infected persons, Journal of Virology, 81, 12670, 10.1128/JVI.00476-07 Beignon, 2005, Endocytosis of HIV-1 activates plasmacytoid dendritic cells via Toll-like receptor-viral RNA interactions, The Journal of Clinical Investigation, 115, 3265, 10.1172/JCI26032 Benveniste, 2005, Mechanisms involved in the low-level regeneration of CD4+ cells in HIV-1-infected patients receiving highly active antiretroviral therapy who have prolonged undetectable plasma viral loads, Journal of Infectious Diseases, 191, 1670, 10.1086/429670 Betts, 2001, Analysis of total human immunodeficiency virus (HIV)-specific CD4(+) and CD8(+) T-cell responses: Relationship to viral load in untreated HIV infection, Journal of Virology, 75, 11983, 10.1128/JVI.75.24.11983-11991.2001 Biancotto, 2007, Abnormal activation and cytokine spectra in lymph nodes of people chronically infected with HIV-1, Blood, 109, 4272, 10.1182/blood-2006-11-055764 Borkow, 2007, Helminth-HIV coinfection: Should we deworm?, PLoS Neglected Tropical Diseases, 1, e160, 10.1371/journal.pntd.0000160 Boulware, 2011, Higher levels of CRP, D-dimer, IL-6, and hyaluronic acid before initiation of antiretroviral therapy (ART) are associated with increased risk of AIDS or death, Journal of Infectious Diseases, 203, 1637, 10.1093/infdis/jir134 Breen, 2011, B-cell stimulatory cytokines and markers of immune activation are elevated several years prior to the diagnosis of systemic AIDS-associated non-Hodgkin B-cell lymphoma, Cancer Epidemiology, Biomarkers & Prevention, 20, 1303, 10.1158/1055-9965.EPI-11-0037 Brenchley, 2008, HIV infection and the gastrointestinal immune system, Mucosal Immunology, 1, 23, 10.1038/mi.2007.1 Brenchley, 2012, Microbial translocation across the GI tract, Annual Review of Immunology, 30, 149, 10.1146/annurev-immunol-020711-075001 Brenchley, 2008, Differential Th17 CD4 T-cell depletion in pathogenic and nonpathogenic lentiviral infections, Blood, 112, 2826, 10.1182/blood-2008-05-159301 Brenchley, 2006, HIV disease: Fallout from a mucosal catastrophe?, Nature Immunology, 7, 235, 10.1038/ni1316 Brenchley, 2006, Microbial translocation is a cause of systemic immune activation in chronic HIV infection, Nature Medicine, 12, 1365, 10.1038/nm1511 Brenchley, 2004, CD4+ T cell depletion during all stages of HIV disease occurs predominantly in the gastrointestinal tract, The Journal of Experimental Medicine, 200, 749, 10.1084/jem.20040874 Brown, 2005, Antiretroviral therapy and the prevalence and incidence of diabetes mellitus in the multicenter AIDS cohort study, Archives of Internal Medicine, 165, 1179, 10.1001/archinte.165.10.1179 Brown, 2006, Antiretroviral therapy and the prevalence of osteopenia and osteoporosis: A meta-analytic review, AIDS, 20, 2165, 10.1097/QAD.0b013e32801022eb Brown, 2010, Association between systemic inflammation and incident diabetes in HIV-infected patients after initiation of antiretroviral therapy, Diabetes Care, 33, 2244, 10.2337/dc10-0633 Bucy, 1999, Initial increase in blood CD4(+) lymphocytes after HIV antiretroviral therapy reflects redistribution from lymphoid tissues, The Journal of Clinical Investigation, 103, 1391, 10.1172/JCI5863 Burdo, 2013, Elevated sCD163 is a marker of neurocognitive impairment in HIV infection, AIDS, 10.1097/QAD.0b013e32836010bd Buzon, 2010, HIV-1 replication and immune dynamics are affected by raltegravir intensification of HAART-suppressed subjects, Nature Medicine, 16, 460, 10.1038/nm.2111 Byakwaga, 2011, Intensification of antiretroviral therapy with raltegravir or addition of hyperimmune bovine colostrum in HIV-infected patients with suboptimal CD4+ T-cell response: A randomized controlled trial, Journal of Infectious Diseases, 10.1093/infdis/jir559 Chege, 2011, Sigmoid Th17 populations, the HIV latent reservoir, and microbial translocation in men on long-term antiretroviral therapy, AIDS, 25, 741, 10.1097/QAD.0b013e328344cefb Chehimi, 2002, Persistent decreases in blood plasmacytoid dendritic cell number and function despite effective highly active antiretroviral therapy and increased blood myeloid dendritic cells in HIV-infected individuals, The Journal of Immunology, 168, 4796, 10.4049/jimmunol.168.9.4796 Chun, 1997, Quantification of latent tissue reservoirs and total body viral load in HIV-1 infection, Nature, 387, 183, 10.1038/387183a0 Cimbro, 2012, IL-7 induces expression and activation of integrin alpha4beta7 promoting naive T-cell homing to the intestinal mucosa, Blood, 120, 2610, 10.1182/blood-2012-06-434779 Colle, 2006, Regulatory dysfunction of the interleukin-7 receptor in CD4 and CD8 lymphocytes from HIV-infected patients—Effects of antiretroviral therapy, Journal of Acquired Immune Deficiency Syndromes, 42, 277, 10.1097/01.qai.0000214823.11034.4e Copur, 2002, HIV infection is a risk factor for venous thromboembolism, AIDS Patient Care and STDs, 16, 205, 10.1089/10872910252972258 Cory, 2013, Overcoming pharmacologic sanctuaries, Current Opinion in HIV and AIDS, 8, 190, 10.1097/COH.0b013e32835fc68a Deeken, 2012, The rising challenge of non-AIDS-defining cancers in HIV-infected patients, Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America, 55, 1228, 10.1093/cid/cis613 Desquilbet, 2007, HIV-1 infection is associated with an earlier occurrence of a phenotype related to frailty, The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences, 62, 1279, 10.1093/gerona/62.11.1279 Desquilbet, 2009, Relationship between a frailty-related phenotype and progressive deterioration of the immune system in HIV-infected men, Journal of Acquired Immune Deficiency Syndromes, 50, 299, 10.1097/QAI.0b013e3181945eb0 Dinoso, 2009, Treatment intensification does not reduce residual HIV-1 viremia in patients on highly active antiretroviral therapy, Proceedings of the National Academy of Sciences of the United States of America, 106, 9403, 10.1073/pnas.0903107106 Douek, 2002, HIV preferentially infects HIV-specific CD4+ T cells, Nature, 417, 95, 10.1038/417095a Duprez, 2009, Lipoprotein particle subclasses, cardiovascular disease and HIV infection, Atherosclerosis, 207, 524, 10.1016/j.atherosclerosis.2009.05.001 Ellis, 2011, CD4 nadir is a predictor of HIV neurocognitive impairment in the era of combination antiretroviral therapy, AIDS, 25, 1747, 10.1097/QAD.0b013e32834a40cd Erlandson, 2013, Association of functional impairment with inflammation and immune activation in HIV-1-infected adults on effective antiretroviral therapy, The Journal of Infectious Diseases, 10.1093/infdis/jit147 Erridge, 2009, The roles of toll-like receptors in atherosclerosis, Journal of Innate Immunity, 1, 340, 10.1159/000191413 Estes, 2008, Collagen deposition limits immune reconstitution in the gut, Journal of Infectious Diseases, 198, 456, 10.1086/590112 Estes, 2008, Early resolution of acute immune activation and induction of PD-1 in SIV-infected sooty mangabeys distinguishes nonpathogenic from pathogenic infection in rhesus macaques, The Journal of Immunology, 180, 6798, 10.4049/jimmunol.180.10.6798 Estes, 2008, The role of collagen deposition in depleting CD4+ T cells and limiting reconstitution in HIV-1 and SIV infections through damage to the secondary lymphoid organ niche, Seminars in Immunology, 20, 181, 10.1016/j.smim.2008.04.002 Estes, 2010, Damaged intestinal epithelial integrity linked to microbial translocation in pathogenic simian immunodeficiency virus infections, PLoS Pathogens, 6, e1001052, 10.1371/journal.ppat.1001052 Estes, 2007, Simian immunodeficiency virus-induced lymphatic tissue fibrosis is mediated by transforming growth factor beta 1-positive regulatory T cells and begins in early infection, Journal of Infectious Diseases, 195, 551, 10.1086/510852 Favre, 2010, Tryptophan catabolism by indoleamine 2,3-dioxygenase 1 alters the balance of TH17 to regulatory T cells in HIV disease, Science Translational Medicine, 2, 32ra36, 10.1126/scitranslmed.3000632 Fernandez, 2011, CD4+ T-cell deficiency in HIV patients responding to antiretroviral therapy is associated with increased expression of interferon-stimulated genes in CD4+ T cells, Journal of Infectious Diseases, 204, 1927, 10.1093/infdis/jir659 Ford, 2010, Traditional risk factors and D-dimer predict incident cardiovascular disease events in chronic HIV infection, AIDS, 24, 1509, 10.1097/QAD.0b013e32833ad914 Fox, 1989, Detection of HIV-1 RNA in the lamina propria of patients with AIDS and gastrointestinal disease, Journal of Infectious Diseases, 159, 467, 10.1093/infdis/159.3.467 Freiberg, 2013, HIV infection and the risk of acute myocardial infarction, JAMA Internal Medicine, 1–9, 173, 614, 10.1001/jamainternmed.2013.3728 Fry, 2001, A potential role for interleukin-7 in T-cell homeostasis, Blood, 97, 2983, 10.1182/blood.V97.10.2983 Fultz, 2004, Association of venous thromboembolism with human immunodeficiency virus and mortality in veterans, The American Journal of Medicine, 116, 420, 10.1016/j.amjmed.2003.10.011 Funderburg, 2008, Toll-like receptor ligands induce human T cell activation and death, a model for HIV pathogenesis, PLoS One, 3, e1915, 10.1371/journal.pone.0001915 Funderburg, 2010, Increased tissue factor expression on circulating monocytes in chronic HIV infection: Relationship to in vivo coagulation and immune activation, Blood, 115, 161, 10.1182/blood-2009-03-210179 Funderburg, 2012, Shared monocyte subset phenotypes in HIV-1 infection and in uninfected subjects with acute coronary syndrome, Blood, 120, 4599, 10.1182/blood-2012-05-433946 Gandhi, 2011, No effect of raltegravir intensification on viral replication markers in the blood of HIV-1-infected patients receiving antiretroviral therapy, Journal of Acquired Immune Deficiency Syndromes, 59, 229, 10.1097/QAI.0b013e31823fd1f2 Gandhi, 2006, Effect of baseline- and treatment-related factors on immunologic recovery after initiation of antiretroviral therapy in HIV-1-positive subjects: Results from ACTG 384, Journal of Acquired Immune Deficiency Syndromes, 42, 426, 10.1097/01.qai.0000226789.51992.3f Gandhi, 2010, The effect of raltegravir intensification on low-level residual viremia in HIV-infected patients on antiretroviral therapy: A randomized controlled trial, PLoS Medicine, 7, 10.1371/journal.pmed.1000321 Gazzola, 2009, The absence of CD4+ T cell count recovery despite receipt of virologically suppressive highly active antiretroviral therapy: Clinical risk, immunological gaps, and therapeutic options, Clinical Infectious Diseases, 48, 328, 10.1086/595851 Giorgi, 1999, Shorter survival in advanced human immunodeficiency virus type 1 infection is more closely associated with T lymphocyte activation than with plasma virus burden or virus chemokine coreceptor usage, Journal of Infectious Diseases, 179, 859, 10.1086/314660 Giorgi, 1993, Elevated levels of CD38+ CD8+ T cells in HIV infection add to the prognostic value of low CD4+ T cell levels: Results of 6 years of follow-up. The Los Angeles Center, Multicenter AIDS Cohort Study, Journal of Acquired Immune Deficiency Syndromes, 6, 904 Giorgi, 2002, Predictive value of immunologic and virologic markers after long or short duration of HIV-1 infection, Journal of Acquired Immune Deficiency Syndromes, 29, 346, 10.1097/00126334-200204010-00004 Gordon, 2010, Disruption of intestinal CD4+ T cell homeostasis is a key marker of systemic CD4+ T cell activation in HIV-infected individuals, The Journal of Immunology, 185, 5169, 10.4049/jimmunol.1001801 Gori, 2011, Specific prebiotics modulate gut microbiota and immune activation in HAART-naive HIV-infected adults: Results of the “COPA” pilot randomized trial, Mucosal Immunology, 4, 554, 10.1038/mi.2011.15 Gottlieb, 1981, Pneumocystis carinii pneumonia and mucosal candidiasis in previously healthy homosexual men: Evidence of a new acquired cellular immunodeficiency, The New England Journal of Medicine, 305, 1425, 10.1056/NEJM198112103052401 Gray, 1999, Frequency of class I HLA-restricted anti-HIV CD8+ T cells in individuals receiving highly active antiretroviral therapy (HAART), The Journal of Immunology, 162, 1780, 10.4049/jimmunol.162.3.1780 Grinspoon, 2005, Cardiovascular risk and body-fat abnormalities in HIV-infected adults, The New England Journal of Medicine, 352, 48, 10.1056/NEJMra041811 Grulich, 2007, Incidence of cancers in people with HIV/AIDS compared with immunosuppressed transplant recipients: A meta-analysis, The Lancet, 370, 59, 10.1016/S0140-6736(07)61050-2 Harris, 1999, Associations of elevated interleukin-6 and C-reactive protein levels with mortality in the elderly, The American Journal of Medicine, 106, 506, 10.1016/S0002-9343(99)00066-2 Harris, 2010, Downregulation of robust acute type I interferon responses distinguishes nonpathogenic simian immunodeficiency virus (SIV) infection of natural hosts from pathogenic SIV infection of rhesus macaques, Journal of Virology, 84, 7886, 10.1128/JVI.02612-09 Hatano, 2010, Evidence of persistent low-level viremia in long-term HAART-suppressed, HIV-infected individuals, AIDS, 24, 2535, 10.1097/QAD.0b013e32833dba03 Hatano, 2011, A randomized, controlled trial of raltegravir intensification in antiretroviral-treated, HIV-infected patients with a suboptimal CD4+ T cell response, Journal of Infectious Diseases, 203, 960, 10.1093/infdis/jiq138 Hatano, H., Strain, M., Scherzer, R., Sinclair, E., Palmer, S., Busch, M., et al. (2013). Increase in 2-LTR circles after raltegravir intensification in HAART-suppressed patients with high CD4+ T Cell counts: A randomized, controlled trial. Paper presented at the in the Program and Abstracts from the 20th Conference on Retroviruses and Opportunistic Infections, Atlanta, GA, Abstract # 42. Heaton, 2010, HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy: CHARTER Study, Neurology, 75, 2087, 10.1212/WNL.0b013e318200d727 Heil, 2004, Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8, Science, 303, 1526, 10.1126/science.1093620 Hunt, 2011, Impact of CD8+ T-cell activation on CD4+ T-cell recovery and mortality in HIV-infected Ugandans initiating antiretroviral therapy, AIDS, 25, 2123, 10.1097/QAD.0b013e32834c4ac1 Hunt, 2003, Continued CD4 cell count increases in HIV-infected adults experiencing 4 years of viral suppression on antiretroviral therapy, AIDS, 17, 1907, 10.1097/00002030-200309050-00009 Hunt, 2011, Valganciclovir reduces T cell activation in HIV-infected individuals with incomplete CD4+ T cell recovery on antiretroviral therapy, Journal of Infectious Diseases, 203, 1474, 10.1093/infdis/jir060 Hunt, P., Rodriguez, B., Shive, C., Clagett, B., Funderburg, N., Natta, M. V., et al. (2012). Gut epithelial barrier dysfunction, inflammation, and coagulation predict higher mortality during treated HIV/AIDS. Paper presented at the in the Program and Abstracts from the 19th Conference on Retroviruses and Opportunistic Infections, Seattle, WA, Abstract #278. Hunt, 2013, The immunologic effects of maraviroc intensification in treated HIV-infected individuals with incomplete CD4+ T cell recovery: A randomized trial, Blood, 121, 4635, 10.1182/blood-2012-06-436345 Jasny, 2012, Characterization of peripheral and mucosal immune responses in rhesus macaques on long-term tenofovir and emtricitabine combination antiretroviral therapy, Journal of Acquired Immune Deficiency Syndromes, 61, 425, 10.1097/QAI.0b013e318266be53 Jiang, 2009, Plasma levels of bacterial DNA correlate with immune activation and the magnitude of immune restoration in persons with antiretroviral-treated HIV infection, Journal of Infectious Diseases, 199, 1177, 10.1086/597476 Justice, 2012, Does an index composed of clinical data reflect effects of inflammation, coagulation, and monocyte activation on mortality among those aging with HIV?, Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America, 54, 984, 10.1093/cid/cir989 Kalayjian, 2010, Pretreatment levels of soluble cellular receptors and interleukin-6 are associated with HIV disease progression in subjects treated with highly active antiretroviral therapy, Journal of Infectious Diseases, 201, 1796, 10.1086/652750 Kalinowska, 2013, Decreased IL-7 responsiveness is related to oxidative stress in HIV disease, PLoS One, 8, e58764, 10.1371/journal.pone.0058764 Kelley, 2009, Incomplete peripheral CD4+ cell count restoration in HIV-infected patients receiving long-term antiretroviral treatment, Clinical Infectious Diseases, 48, 787, 10.1086/597093 Kiviat, 1998, Determinants of human immunodeficiency virus DNA and RNA shedding in the anal-rectal canal of homosexual men, Journal of Infectious Diseases, 177, 571, 10.1086/514239 Klatt, 2010, Th17 cell dynamics in HIV infection, Current Opinion in HIV and AIDS, 5, 135, 10.1097/COH.0b013e3283364846 Klatt, 2013, Probiotic/prebiotic supplementation of antiretrovirals improves gastrointestinal immunity in SIV-infected macaques, The Journal of Clinical Investigation, 123, 903 Klatt, 2012, Loss of mucosal CD103+ DCs and IL-17+ and IL-22+ lymphocytes is associated with mucosal damage in SIV infection, Mucosal Immunology, 5, 646, 10.1038/mi.2012.38 Klatt, 2013, Microbial translocation, immune activation, and HIV disease, Trends in Microbiology, 21, 6, 10.1016/j.tim.2012.09.001 Klatt, 2010, Compromised gastrointestinal integrity in pigtail macaques is associated with increased microbial translocation, immune activation, and IL-17 production in the absence of SIV infection, Mucosal Immunology, 3, 387, 10.1038/mi.2010.14 Klatt, 2012, Nonpathogenic simian immunodeficiency virus infections, Cold Spring Harbor Perspectives in Medicine, 2, a007153, 10.1101/cshperspect.a007153 Kuller, 2008, Inflammatory and coagulation biomarkers and mortality in patients with HIV infection, PLoS Medicine, 5, e203, 10.1371/journal.pmed.0050203 Lane, 1983, Abnormalities of B-cell activation and immunoregulation in patients with the acquired immunodeficiency syndrome, The New England Journal of Medicine, 309, 453, 10.1056/NEJM198308253090803 Lederman, 2011, Immunologic failure despite suppressive antiretroviral therapy is related to activation and turnover of memory CD4 cells, Journal of Infectious Diseases, 204, 1217, 10.1093/infdis/jir507 Lederman, 1998, Immunologic responses associated with 12 weeks of combination antiretroviral therapy consisting of zidovudine, lamivudine, and ritonavir: Results of AIDS Clinical Trials Group Protocol 315, Journal of Infectious Diseases, 178, 70, 10.1086/515591 Letendre, S., Marcotte, T., Deutsch, R., Franklin, D., Rosario, D., Alexander, T., et al. (2012). A concise panel of biomarkers diagnoses and predicts neurocognitive status in HIV-infected individuals. Paper presented at the in the Program and Abstracts from the 19th Conference on Retroviruses and Opportunistic Infections, Seattle, WA, Abstract #82. Lewden, 2012, All-cause mortality in treated HIV-infected adults with CD4 ≥500/mm3 compared with the general population: Evidence from a large European observational cohort collaboration, International Journal of Epidemiology, 41, 433, 10.1093/ije/dyr164 Lewden, 2007, HIV-infected adults with a CD4 cell count greater than 500 cells/mm3 on long-term combination antiretroviral therapy reach same mortality rates as the general population, Journal of Acquired Immune Deficiency Syndromes, 46, 72, 10.1097/QAI.0b013e318134257a Lichtenstein, 2010, Low CD4+ T cell count is a risk factor for cardiovascular disease events in the HIV outpatient study, Clinical Infectious Diseases, 51, 435, 10.1086/655144 Lichtfuss, 2011, Biomarkers of immune dysfunction following combination antiretroviral therapy for HIV infection, Biomarkers in Medicine, 5, 171, 10.2217/bmm.11.15 Lohse, 2007, Survival of persons with and without HIV infection in Denmark, 1995–2005, Annals of Internal Medicine, 146, 87, 10.7326/0003-4819-146-2-200701160-00003 Lyons, 2011, Plasma sCD14 is a biomarker associated with impaired neurocognitive test performance in attention and learning domains in HIV infection, Journal of Acquired Immune Deficiency Syndromes, 57, 371, 10.1097/QAI.0b013e3182237e54 Macal, 2008, Effective CD4+ T-cell restoration in gut-associated lymphoid tissue of HIV-infected patients is associated with enhanced Th17 cells and polyfunctional HIV-specific T-cell responses, Mucosal Immunology, 1, 475, 10.1038/mi.2008.35 Maldarelli, 2007, ART suppresses plasma HIV-1 RNA to a stable set point predicted by pretherapy viremia, PLoS Pathogens, 3, e46, 10.1371/journal.ppat.0030046 Marchetti, 2008, Microbial translocation is associated with sustained failure in CD4+ T-cell reconstitution in HIV-infected patients on long-term highly active antiretroviral therapy, AIDS, 22, 2035, 10.1097/QAD.0b013e3283112d29 Marin, 2009, Non-AIDS-defining deaths and immunodeficiency in the era of combination antiretroviral therapy, AIDS, 23, 1743, 10.1097/QAD.0b013e32832e9b78 Martinez, 2012, Changes in cardiovascular biomarkers in HIV-infected patients switching from ritonavir-boosted protease inhibitors to raltegravir, AIDS, 26, 2315, 10.1097/QAD.0b013e328359f29c Marziali, 2006, T-cell homeostasis alteration in HIV-1 infected subjects with low CD4 T-cell count despite undetectable virus load during HAART, AIDS, 20, 2033, 10.1097/01.aids.0000247588.69438.fd Massanella, 2012, Raltegravir intensification shows differing effects on CD8 and CD4T cells in HIV-infected HAART-suppressed individuals with poor CD4T-cell recovery, AIDS, 26, 2285, 10.1097/QAD.0b013e328359f20f Masur, 1981, An outbreak of community-acquired Pneumocystis carinii pneumonia: Initial manifestation of cellular immune dysfunction, The New England Journal of Medicine, 305, 1431, 10.1056/NEJM198112103052402 Mattapallil, 2005, Massive infection and loss of memory CD4+ T cells in multiple tissues during acute SIV infection, Nature, 434, 1093, 10.1038/nature03501 Mavigner, 2012, Altered CD4+ T cell homing to the gut impairs mucosal immune reconstitution in treated HIV-infected individuals, The Journal of Clinical Investigation, 122, 62, 10.1172/JCI59011 McComsey, G., Jiang, Y., Debanne, S., Clagett, B., Robinson, J., Labbato, D., et al. (2013). Effect of statins on immune activation and inflammation in HIV+subjects on ART: A randomized placebo controlled trial. Paper presented at the In the Program and Abstracts from the 20th Conference on Retroviruses and Opportunistic Infections, Atlanta, GA, Abstract #186LB. Mehandru, 2006, Lack of mucosal immune reconstitution during prolonged treatment of acute and early HIV-1 infection, PLoS Medicine, 3, e484, 10.1371/journal.pmed.0030484 Meier, 2007, MyD88-dependent immune activation mediated by human immunodeficiency virus type 1-encoded toll-like receptor ligands, Journal of Virology, 81, 8180, 10.1128/JVI.00421-07 Merlini, 2011, Evidence for polymicrobic flora translocating in peripheral blood of HIV-infected patients with poor immune response to antiretroviral therapy, PLoS One, 6, e18580, 10.1371/journal.pone.0018580 Miller, 2012, Plasma factors during chronic HIV-1 infection impair IL-12 secretion by myeloid dendritic cells via a virus-independent pathway, Journal of Acquired Immune Deficiency Syndromes, 61, 535, 10.1097/QAI.0b013e31826afbce Mocroft, 2010, Serious fatal and nonfatal non-AIDS-defining illnesses in Europe, Journal of Acquired Immune Deficiency Syndromes, 55, 262, 10.1097/QAI.0b013e3181e9be6b Modjarrad, 2010, Effect of treating co-infections on HIV-1 viral load: A systematic review, The Lancet Infectious Diseases, 10, 455, 10.1016/S1473-3099(10)70093-1 Mudd, 2013, Impaired T cell responses to sphingosine-1-phosphate in HIV-1 infected lymph nodes, Blood, 121, 2914, 10.1182/blood-2012-07-445783 Murray, 2010, Reduction of immune activation with chloroquine therapy during chronic HIV infection, Journal of Virology, 84, 12082, 10.1128/JVI.01466-10 Musselwhite, 2011, Markers of endothelial dysfunction, coagulation and tissue fibrosis independently predict venous thromboembolism in HIV, AIDS, 25, 787, 10.1097/QAD.0b013e3283453fcb Naeger, 2010, Cytomegalovirus-specific T cells persist at very high levels during long-term antiretroviral treatment of HIV disease, PLoS One, 5, e8886, 10.1371/journal.pone.0008886 Napolitano, 2001, Increased production of IL-7 accompanies HIV-1-mediated T-cell depletion: Implications for T-cell homeostasis, Nature Medicine, 7, 73, 10.1038/83381 Nazli, 2010, Exposure to HIV-1 directly impairs mucosal epithelial barrier integrity allowing microbial translocation, PLoS Pathogens, 6, e1000852, 10.1371/journal.ppat.1000852 O’Brien, 2013, Aspirin attenuates platelet activation and immune activation in HIV-infected subjects on antiretroviral therapy: A pilot study, Journal of Acquired Immune Deficiency Syndromes, 63, 280, 10.1097/QAI.0b013e31828a292c Pakker, 1998, Biphasic kinetics of peripheral blood T cells after triple combination therapy in HIV-1 infection: A composite of redistribution and proliferation, Nature Medicine, 4, 208, 10.1038/nm0298-208 Palmer, 2008, Low-level viremia persists for at least 7 years in patients on suppressive antiretroviral therapy, Proceedings of the National Academy of Sciences of the United States of America, 105, 3879, 10.1073/pnas.0800050105 Pandrea, I. (2013). Therapeutic interventions to modulate microbial translocation, immune activation and cardiovascular comorbidities. Lessons from nonhuman primate models. Paper presented at the Keystone Symposia on Molecular and Cellular Biology. Immune Activation in HIV infection: Basic mechanisms and clinical implications, Breckenridge, Colorado. Pantaleo, 1991, Lymphoid organs function as major reservoirs for human immunodeficiency virus, Proceedings of the National Academy of Sciences of the United States of America, 88, 9838, 10.1073/pnas.88.21.9838 Pantaleo, 1993, HIV infection is active and progressive in lymphoid tissue during the clinically latent stage of disease, Nature, 362, 355, 10.1038/362355a0 Pasare, 2004, Toll-dependent control mechanisms of CD4T cell activation, Immunity, 21, 733, 10.1016/j.immuni.2004.10.006 Patel, 2008, Incidence of types of cancer among HIV-infected persons compared with the general population in the United States, 1992–2003, Annals of Internal Medicine, 148, 728, 10.7326/0003-4819-148-10-200805200-00005 Paton, 2012, Effects of hydroxychloroquine on immune activation and disease progression among HIV-infected patients not receiving antiretroviral therapy: A randomized controlled trial, JAMA: The Journal of the American Medical Association, 308, 353, 10.1001/jama.2012.6936 Picker, 2006, Immunopathogenesis of acute AIDS virus infection, Current Opinion in Immunology, 18, 399, 10.1016/j.coi.2006.05.001 Piconi, 2013, Atherosclerosis is associated with multiple pathogenic mechanisms in HIV-infected antiretroviral-naive or treated individuals, AIDS, 27, 381, 10.1097/QAD.0b013e32835abcc9 Piconi, 2011, Hydroxychloroquine drastically reduces immune activation in HIV-infected, antiretroviral therapy-treated immunologic nonresponders, Blood, 118, 3263, 10.1182/blood-2011-01-329060 Pilakka-Kanthikeel, 2012, Increased Gut microbial translocation in HIV-infected children persists in virologic responders and virologic failures after antiretroviral therapy, The Pediatric Infectious Disease Journal, 31, 583, 10.1097/INF.0b013e31824da0f5 Reeves, 2012, SIV infection induces accumulation of plasmacytoid dendritic cells in the gut mucosa, Journal of Infectious Diseases, 206, 1462, 10.1093/infdis/jis408 Reeves, 2011, Gut inflammation and indoleamine deoxygenase inhibit IL-17 production and promote cytotoxic potential in NKp44+ mucosal NK cells during SIV infection, Blood, 118, 3321, 10.1182/blood-2011-04-347260 Reuben, 2002, Peripheral blood markers of inflammation predict mortality and functional decline in high-functioning community-dwelling older persons, Journal of the American Geriatrics Society, 50, 638, 10.1046/j.1532-5415.2002.50157.x Rodger, 2009, Activation and coagulation biomarkers are independent predictors of the development of opportunistic disease in patients with HIV infection, Journal of Infectious Diseases, 200, 973, 10.1086/605447 Rose, 2008, HIV infection and high density lipoprotein metabolism, Atherosclerosis, 199, 79, 10.1016/j.atherosclerosis.2007.10.018 Sacre, 2012, A role for cytomegalovirus-specific CD4+CX3CR1+ T cells and cytomegalovirus-induced T-cell immunopathology in HIV-associated atherosclerosis, AIDS, 26, 805, 10.1097/QAD.0b013e328351f780 Sandler, 2011, Plasma levels of soluble CD14 independently predict mortality in HIV infection, Journal of Infectious Diseases, 203, 780, 10.1093/infdis/jiq118 Schacker, 1996, Clinical and epidemiologic features of primary HIV infection, Annals of Internal Medicine, 125, 257, 10.7326/0003-4819-125-4-199608150-00001 Schacker, 2002, Collagen deposition in HIV-1 infected lymphatic tissues and T cell homeostasis, The Journal of Clinical Investigation, 110, 1133, 10.1172/JCI0216413 Schacker, 2002, Persistent abnormalities in lymphoid tissues of human immunodeficiency virus-infected patients successfully treated with highly active antiretroviral therapy, Journal of Infectious Diseases, 186, 1092, 10.1086/343802 Sereti, I., Estes, J., Thompson, W., Fischl, M., Croughs, T., Beq, S., et al. (2012). Gut mucosa T lymphocyte restoration in chronically HIV+patients treated with recombinant interleukin-7. Paper presented at the in the Program and Abstracts from the 19th Conference on Retroviruses and Opportunistic Infections, Seattle, WA, Abstract # 94. Silverberg, 2009, HIV infection and the risk of cancers with and without a known infectious cause, AIDS, 23, 2337, 10.1097/QAD.0b013e3283319184 Silvestri, 2007, Understanding the benign nature of SIV infection in natural hosts, The Journal of Clinical Investigation, 117, 3148, 10.1172/JCI33034 Smurzynski, 2010, Relationship between CD4+ T-cell counts/HIV-1 RNA plasma viral load and AIDS-defining events among persons followed in the ACTG longitudinal linked randomized trials study, Journal of Acquired Immune Deficiency Syndromes, 55, 117, 10.1097/QAI.0b013e3181e8c129 Stacey, 2009, Induction of a striking systemic cytokine cascade prior to peak viremia in acute human immunodeficiency virus type 1 infection, in contrast to more modest and delayed responses in acute hepatitis B and C virus infections, Journal of Virology, 83, 3719, 10.1128/JVI.01844-08 Stewart, 2010, CD36 ligands promote sterile inflammation through assembly of a toll-like receptor 4 and 6 heterodimer, Nature Immunology, 11, 155, 10.1038/ni.1836 Sullivan, 2000, Epidemiology of thrombosis in HIV-infected individuals. The adult/adolescent spectrum of HIV disease project, AIDS, 14, 321, 10.1097/00002030-200002180-00015 Tenorio, A., Zheng, E., Bosch, R., Deeks, S. G., Rodriguez, B., Krishnan, S., et al. (2013). Soluble markers of inflammation & coagulation, but not T-cell activation, predict non-AIDS-defining events during suppressive antiretroviral therapy. Paper presented at the in the Program and Abstracts of the 20th Conference on Retroviruses and Opportunistic Infections, 2013, Atlanta, GA, Abstract #790. The Antiretroviral Therapy Cohort Collaboration, 2008, Life expectancy of individuals on combination antiretroviral therapy in high-income countries: A collaborative analysis of 14 cohort studies, The Lancet, 372, 293, 10.1016/S0140-6736(08)61113-7 Tien, 2010, Inflammation and mortality in HIV-infected adults: Analysis of the FRAM study cohort, Journal of Acquired Immune Deficiency Syndromes, 55, 316, 10.1097/QAI.0b013e3181e66216 Tincati, 2009, Early initiation of highly active antiretroviral therapy fails to reverse immunovirological abnormalities in gut-associated lymphoid tissue induced by acute HIV infection, Antiviral Therapy, 14, 321, 10.1177/135965350901400310 Tindall, 1988, Characterization of the acute clinical illness associated with human immunodeficiency virus infection, Archives of Internal Medicine, 148, 945, 10.1001/archinte.1988.00380040185026 Triant, 2008, Fracture prevalence among human immunodeficiency virus (HIV)-infected versus non-HIV-infected patients in a large U.S. healthcare system, The Journal of Clinical Endocrinology and Metabolism, 93, 3499, 10.1210/jc.2008-0828 Triant, 2007, Increased acute myocardial infarction rates and cardiovascular risk factors among patients with human immunodeficiency virus disease, The Journal of Clinical Endocrinology and Metabolism, 92, 2506, 10.1210/jc.2006-2190 Triant, 2009, Association of C-reactive protein and HIV infection with acute myocardial infarction, Journal of Acquired Immune Deficiency Syndromes, 51, 268, 10.1097/QAI.0b013e3181a9992c Triant, 2010, Association of immunologic and virologic factors with myocardial infarction rates in a US healthcare system, Journal of Acquired Immune Deficiency Syndromes, 55, 615, 10.1097/QAI.0b013e3181f4b752 Tseng, 2012, Sudden cardiac death in patients with human immunodeficiency virus infection, Journal of the American College of Cardiology, 59, 1891, 10.1016/j.jacc.2012.02.024 van Sighem, 2010, Life expectancy of recently diagnosed asymptomatic HIV-infected patients approaches that of uninfected individuals, AIDS, 24, 1527, 10.1097/QAD.0b013e32833a3946 Veazey, 1998, Gastrointestinal tract as a major site of CD4+ T cell depletion and viral replication in SIV infection, Science, 280, 427, 10.1126/science.280.5362.427 Volpato, 2001, Cardiovascular disease, interleukin-6, and risk of mortality in older women: The women’s health and aging study, Circulation, 103, 947, 10.1161/01.CIR.103.7.947 Wikby, 2006, The immune risk phenotype is associated with IL-6 in the terminal decline stage: Findings from the Swedish NONA immune longitudinal study of very late life functioning, Mechanisms of Ageing and Development, 127, 695, 10.1016/j.mad.2006.04.003 Yong, 2011, Low CD4 count is associated with an increased risk of fragility fracture in HIV-infected patients, Journal of Acquired Immune Deficiency Syndromes, 57, 205, 10.1097/QAI.0b013e31821ecf4c Young, 2012, CD4 cell count and the risk of AIDS or death in HIV-Infected adults on combination antiretroviral therapy with a suppressed viral load: A longitudinal cohort study from COHERE, PLoS Medicine, 9, e1001194, 10.1371/journal.pmed.1001194 Yukl, 2010, Differences in HIV burden and immune activation within the gut of HIV-positive patients receiving suppressive antiretroviral therapy, Journal of Infectious Diseases, 202, 1553, 10.1086/656722 Zeng, 2011, Cumulative mechanisms of lymphoid tissue fibrosis and T cell depletion in HIV-1 and SIV infections, The Journal of Clinical Investigation, 121, 998, 10.1172/JCI45157 Zonios, 2008, Idiopathic CD4+ lymphocytopenia: Natural history and prognostic factors, Blood, 112, 287, 10.1182/blood-2007-12-127878 Zuckerman, 2004, Higher concentration of HIV RNA in rectal mucosa secretions than in blood and seminal plasma, among men who have sex with men, independent of antiretroviral therapy, Journal of Infectious Diseases, 190, 156, 10.1086/421246