Elevated sCD163 in plasma but not cerebrospinal fluid is a marker of neurocognitive impairment in HIV infection.
TL;DR: These findings are consistent with persistent monocyte/macrophage activation in neurophysiologically impaired HIV-infected individuals despite virally suppressive ART and the value of sCD163, as a plasma marker of neurocognitive impairment.
Abstract: Objective
Here we evaluated whether neurocognitive disorders in HIV-infected individuals on effective antiretroviral therapy (ART) are associated with persistent monocyte activation as indexed by levels of soluble CD163 (sCD163), shed by monocyte/macrophages.
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TL;DR: It is suggested that adjunctive therapies — treatments targeting CNS inflammation and other metabolic processes, including glutamate homeostasis, lipid and energy metabolism — are needed to reverse or improve HAND-related neurological dysfunction.
Abstract: In the past two decades, several advancements have improved the care of HIV-infected individuals. Most importantly, the development and deployment of combination antiretroviral therapy (CART) has resulted in a dramatic decline in the rate of deaths from AIDS, so that people living with HIV today have nearly normal life expectancies if treated with CART. The term HIV-associated neurocognitive disorder (HAND) has been used to describe the spectrum of neurocognitive dysfunction associated with HIV infection. HIV can enter the CNS during early stages of infection, and persistent CNS HIV infection and inflammation probably contribute to the development of HAND. The brain can subsequently serve as a sanctuary for ongoing HIV replication, even when systemic viral suppression has been achieved. HAND can remain in patients treated with CART, and its effects on survival, quality of life and everyday functioning make it an important unresolved issue. In this Review, we describe the epidemiology of HAND, the evolving concepts of its neuropathogenesis, novel insights from animal models, and new approaches to treatment. We also discuss how inflammation is sustained in chronic HIV infection. Moreover, we suggest that adjunctive therapies--treatments targeting CNS inflammation and other metabolic processes, including glutamate homeostasis, lipid and energy metabolism--are needed to reverse or improve HAND-related neurological dysfunction.
662 citations
TL;DR: The manifestations of HIV-associated neurocognitive disorder in the era of effective HIV therapy is described, diagnosis and treatment recommendations are outlined, and the research questions that remain are explored.
Abstract: Neurological involvement in HIV is often associated with cognitive impairment. Although severe and progressive neurocognitive impairment has become rare in HIV clinics in the era of potent antiretroviral therapy, most patients with HIV worldwide have poor outcomes on formal neurocognitive tests. In this Review, we describe the manifestations of HIV-associated neurocognitive disorder in the era of effective HIV therapy, outline diagnosis and treatment recommendations, and explore the research questions that remain. Although comorbid disorders, such as hepatitis C infection or epilepsy, might cause some impairment, their prevalence is insufficient to explain the frequency with which it is encountered. HIV disease markers, such as viral load and CD4 cell counts, are not strongly associated with ongoing impairment on treatment, whereas cardiovascular disease markers and inflammatory markers are. New cerebrospinal fluid and neuroimaging biomarkers are needed to detect and follow impairment. Ongoing research efforts to optimise HIV therapy within the CNS, and potentially to intervene in downstream mechanisms of neurotoxicity, remain important avenues for future investigation. Ultimately, the full control of virus in the brain is a necessary step in the goal of HIV eradication.
470 citations
TL;DR: Gut epithelial barrier dysfunction, innate immune activation, inflammation, and coagulation-but not T-cell activation, senescence, and exhaustion-independently predict mortality in individuals with treated HIV infection with a history of AIDS and are viable targets for interventions.
Abstract: Background. While inflammation predicts mortality in treated human immunodeficiency virus (HIV) infection, the prognostic significance of gut barrier dysfunction and phenotypic T-cell markers remains unclear.
Methods. We assessed immunologic predictors of mortality in a case-control study within the Longitudinal Study of the Ocular Complications of AIDS (LSOCA), using conditional logistic regression. Sixty-four case patients who died within 12 months of treatment-mediated viral suppression were each matched to 2 control individuals (total number of controls, 128) by duration of antiretroviral therapy–mediated viral suppression, nadir CD4+ T-cell count, age, sex, and prior cytomegalovirus (CMV) retinitis. A similar secondary analysis was conducted in the SCOPE cohort, which had participants with less advanced immunodeficiency.
Results. Plasma gut epithelial barrier integrity markers (intestinal fatty acid binding protein and zonulin-1 levels), soluble CD14 level, kynurenine/tryptophan ratio, soluble tumor necrosis factor receptor 1 level, high-sensitivity C-reactive protein level, and D-dimer level all strongly predicted mortality, even after adjustment for proximal CD4+ T-cell count (all P ≤ .001). A higher percentage of CD38+HLA-DR+ cells in the CD8+ T-cell population was a predictor of mortality before (P = .031) but not after (P = .10) adjustment for proximal CD4+ T-cell count. Frequencies of senescent (defined as CD28−CD57+ cells), exhausted (defined as PD1+ cells), naive, and CMV-specific T cells did not predict mortality.
Conclusions. Gut epithelial barrier dysfunction, innate immune activation, inflammation, and coagulation—but not T-cell activation, senescence, and exhaustion—independently predict mortality in individuals with treated HIV infection with a history of AIDS and are viable targets for interventions.
399 citations
TL;DR: While immune activation, inflammation, and coagulopathy are characteristic of untreated HIV infection and improve with drug-induced control of HIV replication, the drivers of RIDS in treated HIV infection are incompletely understood and it is not entirely clear how these two phenomena are linked.
Abstract: Antiretroviral therapy has revolutionized the course of HIV infection, improving immune function and decreasing dramatically the mortality and morbidity due to the opportunistic complications of the disease Nonetheless, even with sustained suppression of HIV replication, many HIV-infected persons experience a syndrome characterized by increased T cell activation and evidence of heightened inflammation and coagulation This residual immune dysregulation syndrome or RIDS is more common in persons who fail to increase circulating CD4+ T cells to normal levels and in several epidemiologic studies it has been associated with increased morbidity and mortality These morbid and fatal events are not the typical opportunistic infections and malignancies seen in the early AIDS era but rather comprise a spectrum of cardiovascular events, liver disease, metabolic disorders, kidney disease, bone disease, and a spectrum of malignant complications distinguishable from the opportunistic malignancies that characterized the earlier days of the AIDS epidemic While immune activation, inflammation, and coagulopathy are characteristic of untreated HIV infection and improve with drug-induced control of HIV replication, the drivers of RIDS in treated HIV infection are incompletely understood And while inflammation, immune activation, and coagulopathy are more common in treated persons who fail to restore circulating CD4+ T cells, it is not entirely clear how these two phenomena are linked
289 citations
Cites background from "Elevated sCD163 in plasma but not c..."
...Increased peripheral blood markers of monocyte activation (i.e., sCD14 and sCD163) and inflammation are also associated with HIV-associated neurocognitive dysfunction during ART-mediated viral suppression (Burdo et al., 2013; Letendre et al., 2012; Lyons et al., 2011)....
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TL;DR: The pathogenesis of HAND is multifaceted, and mounting evidence indicates that immune cells play a major role, and HIV-1 induces a neuroinflammatory response that is likely to be a major contributor to the cognitive and behavior changes seen in HIV infection.
Abstract: Individuals living with HIV who are optimally treated with combination antiretroviral therapy (cART) can now lead an extended life. In spite of this remarkable survival benefit from viral suppression achieved by cART in peripheral blood, the rate of mild to moderate cognitive impairment remains high. A cognitive decline that includes impairments in attention, learning and executive function is accompanied by increased rates of mood disorders that together adversely impact the daily life of those with chronic HIV infection. The evidence is clear that cells in the brain are infected with HIV that has crossed the blood-brain barrier both as cell-free virus and within infected monocytes and T cells. Viral proteins that circulate in blood can induce brain endothelial cells to release cytokines, invoking another source of neuroinflammation. The difficulty of efficient delivery of cART to the central nervous system (CNS) contributes to elevated viral load in the CNS, resulting in a persistent HIV-associated neurocognitive disorders (HAND). The pathogenesis of HAND is multifaceted, and mounting evidence indicates that immune cells play a major role. HIV-infected monocytes and T cells not only infect brain resident cells upon migration into the CNS but also produce proinflammatory cytokines such as TNF and IL-1s, which in turn, further activate microglia and astrocytes. These activated brain resident cells, along with perivascular macrophages, are the main contributors to neuroinflammation in HIV infection and release neurotoxic factors such as excitatory amino acids and inflammatory mediators, resulting in neuronal dysfunction and death. Cytokines, which are elevated in the blood of patients with HIV infection, may also contribute to brain inflammation by entering the brain from the blood. Host factors such as aging and co-morbid conditions such as cytomegalovirus co-infection and vascular pathology are important factors that affect the HIV-host immune interactions in HAND pathogenesis. By these diverse mechanisms, HIV-1 induces a neuroinflammatory response that is likely to be a major contributor to the cognitive and behavior changes seen in HIV infection.
276 citations
References
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TL;DR: It is shown that increased lipopolysaccharide is bioactive in vivo and correlates with measures of innate and adaptive immune activation, which establish a mechanism for chronic immune activation in the context of a compromised gastrointestinal mucosal surface and provide new directions for therapeutic interventions that modify the consequences of acute HIV infection.
Abstract: Chronic activation of the immune system is a hallmark of progressive HIV infection and better predicts disease outcome than plasma viral load, yet its etiology remains obscure. Here we show that circulating microbial products, probably derived from the gastrointestinal tract, are a cause of HIV-related systemic immune activation. Circulating lipopolysaccharide, which we used as an indicator of microbial translocation, was significantly increased in chronically HIV-infected individuals and in simian immunodeficiency virus (SIV)-infected rhesus macaques (P
3,049 citations
University of Düsseldorf1, University of Pittsburgh2, University of New South Wales3, Icahn School of Medicine at Mount Sinai4, University of California, San Diego5, Washington University in St. Louis6, Children's Memorial Hospital7, University of Miami8, University of Gothenburg9, National Institutes of Health10, Columbia University11, University of Washington12, Johns Hopkins University13, University of California, San Francisco14, University of North Carolina at Chapel Hill15, University of Hawaii at Manoa16, University of Puerto Rico17
TL;DR: This report reviews the collective experience with HIV-associated neurocognitive disorders (HAND), particularly since the advent of highly active antiretroviral treatment, and their definitional criteria; discusses the impact of comorbidities; and suggests inclusion of the term asymptomatic neuroc cognitive impairment to categorize individuals with subclinical impairment.
Abstract: In 1991, the AIDS Task Force of the American Academy of Neurology published nomenclature and research case definitions to guide the diagnosis of neurologic manifestations of HIV-1 infection. Now, 16 years later, the National Institute of Mental Health and the National Institute of Neurological Diseases and Stroke have charged a working group to critically review the adequacy and utility of these definitional criteria and to identify aspects that require updating. This report represents a majority view, and unanimity was not reached on all points. It reviews our collective experience with HIV-associated neurocognitive disorders (HAND), particularly since the advent of highly active antiretroviral treatment, and their definitional criteria; discusses the impact of comorbidities; and suggests inclusion of the term asymptomatic neurocognitive impairment to categorize individuals with subclinical impairment. An algorithm is proposed to assist in standardized diagnostic classification of HAND.
2,292 citations
"Elevated sCD163 in plasma but not c..." refers methods in this paper
...A recent study (CHARTER) [23] used the Frascati criteria [27] to diagnostically classify 1555 HIV-infected individuals at six university clinics across the United States....
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...This algorithm conforms to the Frascati criteria for diagnosing HAND [27], which requires at least mild impairment in at least two of the seven ability domains....
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TL;DR: It is shown that circulating microbial products, probably derived from the gastrointestinal tract, are a cause of HIV-related systemic immune activation and increased lipopolysaccharide is bioactive in vivo and correlates with measures of innate and adaptive immune activation.
Abstract: Chronic activation of the immune system is a hallmark of progressive HIV infection and better predicts disease outcome than plasma viral load, yet its etiology remains obscure. Here, we show that circulating microbial products, likely derived from the gastrointestinal tract, are a primary cause of HIV-related systemic immune activation. Circulating lipopolysaccharide, an indicator of microbial translocation, is significantly increased in chronically HIV-infected individuals and SIV-infected rhesus macaques. We show that monocytes are chronically stimulated in vivo by increased lipopolysaccharide, which also correlates with measures of innate and adaptive immune activation. Effective antiretroviral therapy appears to reduce microbial translocation. Furthermore, in non-pathogenic SIV infection of sooty mangabeys, microbial translocation does not seem to occur. These data establish a mechanism for chronic immune activation in the context of a compromised gastrointestinal mucosal surface and provide novel directions for therapeutic interventions that modify the consequences of acute HIV infection.
1,984 citations
TL;DR: The intestine appears to be a major target for SIV replication and the major site of CD4+ T cell loss in early SIV infection.
Abstract: Human and simian immunodeficiency virus (HIV and SIV) replicate optimally in activated memory CD4(+) T cells, a cell type that is abundant in the intestine. SIV infection of rhesus monkeys resulted in profound and selective depletion of CD4+ T cells in the intestine within days of infection, before any such changes in peripheral lymphoid tissues. The loss of CD4+ T cells in the intestine occurred coincident with productive infection of large numbers of mononuclear cells at this site. The intestine appears to be a major target for SIV replication and the major site of CD4+ T cell loss in early SIV infection.
1,436 citations
TL;DR: In this article, the authors used comparable methods of subject screening and assessments to classify neurocognitive impairment (NCI) in large groups of HIV + and HIV − participants from the pre-CART era (1988-1995, N = 857) and CART era(2000-2007; N = 937).
Abstract: Combination antiretroviral therapy (CART) has greatly reduced medical morbidity and mortality with HIV infection, but high rates of HIV-associated neurocognitive disorders (HAND) continue to be reported. Because large HIV-infected (HIV+) and uninfected (HIV−) groups have not been studied with similar methods in the pre-CART and CART eras, it is unclear whether CART has changed the prevalence, nature, and clinical correlates of HAND. We used comparable methods of subject screening and assessments to classify neurocognitive impairment (NCI) in large groups of HIV + and HIV − participants from the pre-CART era (1988–1995; N = 857) and CART era (2000–2007; N = 937). Impairment rate increased with successive disease stages (CDC stages A, B, and C) in both eras: 25%, 42%, and 52% in pre-CART era and 36%, 40%, and 45% in CART era. In the medically asymptomatic stage (CDC-A), NCI was significantly more common in the CART era. Low nadir CD4 predicted NCI in both eras, whereas degree of current immunosuppression, estimated duration of infection, and viral suppression in CSF (on treatment) were related to impairment only pre-CART. Pattern of NCI also differed: pre-CART had more impairment in motor skills, cognitive speed, and verbal fluency, whereas CART era involved more memory (learning) and executive function impairment. High rates of mild NCI persist at all stages of HIV infection, despite improved viral suppression and immune reconstitution with CART. The consistent association of NCI with nadir CD4 across eras suggests that earlier treatment to prevent severe immunosuppression may also help prevent HAND. Clinical trials targeting HAND prevention should specifically examine timing of ART initiation.
1,325 citations