Tryptophan metabolism and its relationship with central nervous system toxicity in people living with HIV switching from efavirenz to dolutegravir.

The mechanisms underlying central nervous system (CNS) toxicities in antiretroviral-treated persons living with HIV (PLWH) remain elusive. We investigated the associations between markers of tryptophan metabolism and measurements of CNS toxicity in PLWH. In a prospective study, virologically suppressed PLWH receiving efavirenz-containing antiretroviral regimens with ongoing CNS toxicity were switched to dolutegravir-containing regimens and followed up for 12 weeks. Plasma tryptophan and kynurenine concentrations and the kynurenine/tryptophan ratio were calculated. Ten CNS toxicities were graded according to the ACTG adverse events scale. Scores ranged from 0 (none) to 3 (severe) and were summed, giving a total from 0 to 30. Paired-samples t tests and linear mixed model analyses were conducted to assess changes in, and relationships between, laboratory and clinical parameters. Mean kynurenine plasma concentration increased from baseline to week 12 (2.15 to 2.50 µmol/L, p = 0.041). No significant changes were observed for tryptophan (54.74 to 56.42 µmol/L, p = 1.000) or kynurenine/tryptophan ratio (40.37 to 41.08 µmol/L, p = 0.276). Mean CNS toxicity score decreased from 10.00 to 4.63 (p < 0.001). Plasma kynurenine concentration correlated with CNS toxicity score: for every 1 µmol/L increase in kynurenine concentration observed, a 1.7 point decrease was observed in CNS toxicity score (p < 0.038). A similar trend was observed for the kynurenine/tryptophan ratio: for every 1 µmol/mmol increase observed in kynurenine/tryptophan ratio, a 0.1 point decrease was observed in CNS toxicity score (p = 0.054). Switching from efavirenz to dolutegravir was associated with increases in plasma kynurenine concentration and improvements in CNS toxicity scores. Underlying mechanisms explaining the rise in kynurenine concentrations need to be established.

HIV-1 and HIV-2 differentially mature plasmacytoid dendritic cells into IFN-producing cells or APCs.

HIV-1 causes a progressive impairment of immune function. HIV-2 is a naturally attenuated form of HIV, and HIV-2 patients display a slow-progressing disease. The leading hypothesis for the difference in disease phenotype between HIV-1 and HIV-2 is that more efficient T cell-mediated immunity allows for immune-mediated control of HIV-2 infection, similar to that observed in the minority of HIV-1-infected long-term nonprogressors. Understanding how HIV-1 and HIV-2 differentially influence the immune function may highlight critical mechanisms determining disease outcome. We investigated the effects of exposing primary human peripheral blood cells to HIV-1 or HIV-2 in vitro. HIV-2 induced a gene expression profile distinct from HIV-1, characterized by reduced type I IFN, despite similar upregulation of IFN-stimulated genes and viral restriction factors. HIV-2 favored plasmacytoid dendritic cell (pDC) differentiation into cells with an APC phenotype rather than IFN-α-producing cells. HIV-2, but not HIV-1, inhibited IFN-α production in response to CpG-A. The balance between pDC maturation into IFN-α-producing cells or development of an APC phenotype differentiates the early response against HIV-1 and HIV-2. We propose that divergent paths of pDC differentiation driven by HIV-1 and HIV-2 cause the observed differences in pathogenicity between the two viruses.

Ig-like transcript 7, but not bone marrow stromal cell antigen 2 (also known as HM1.24, tetherin, or CD317), modulates plasmacytoid dendritic cell function in primary human blood leukocytes.

The Ig-like transcript (ILT) 7 is a surface molecule selectively expressed by human plasmacytoid dendritic cells (pDCs). ILT7 cross-linking suppresses pDC activation and type I IFN (IFN-I) secretion following TLR7/9 engagement. The bone marrow stromal cell Ag 2 (BST2, aka HM1.24, tetherin, or CD317) is expressed by different cell types upon exposure to IFN-I and is a natural ligand for ILT7. In this study, we show that ILT7 expression decreased spontaneously in pDCs upon in vitro culture, which correlates with pDC differentiation measured as increased side scatter properties and CCR7 expression. TLR7/9 ligands, as well as HIV, induced BST2 upregulation on all tested cell types except T cells, which required TCR stimulation to respond to TLR9L-induced IFN-I. IFN-γ, IL-4, IL-10, and TNF-α had only marginal effects on BST2 expression in blood leukocytes compared with TLR9L. Preincubation with ILT7 cross-linking Ab inhibited IFN-I production in PBMCs treated with TLR7/9L or HIV, whereas BST2 blockade did not affect IFN-I responses even when BST2 upregulation was further boosted with TCR agonists or immunoregulatory cytokines. Our data indicate that BST2-mediated ILT7 cross-linking may act as a homeostatic regulatory mechanism on immature circulating pDC, rather than a negative feedback for activated mature pDCs that have downregulated ILT7.

Antibodies to gp120 and PD-1 expression on virus-specific CD8+ T cells in protection from simian AIDS.

We compared the relative efficacies against simian immunodeficiency virus (SIV) challenge of three vaccine regimens that elicited similar frequencies of SIV-specific CD4(+) and CD8(+) T-cell responses but differed in the level of antibody responses to the gp120 envelope protein. All macaques were primed with DNA plasmids expressing SIV gag, pol, env, and Retanef genes and were boosted with recombinant modified vaccinia Ankara virus (MVA) expressing the same genes, either once (1 × MVA) or twice (2 × MVA), or were boosted once with MVA followed by a single boost with replication-competent adenovirus (Ad) type 5 host range mutant (Ad5 h) expressing SIV gag and nef genes but not Retanef or env (1 × MVA/Ad5). While two of the vaccine regimens (1 × MVA and 1 × MVA/Ad5) protected from high levels of SIV replication only during the acute phase of infection, the 2 × MVA regimen, with the highest anti-SIV gp120 titers, protected during the acute phase and transiently during the chronic phase of infection. Mamu-A*01 macaques of this third group exhibited persistent Gag CD8(+)CM9(+) effector memory T cells with low expression of surface Programmed death-1 (PD-1) receptor and high levels of expression of genes associated with major histocompatibility complex class I (MHC-I) and MHC-II antigen. The fact that control of SIV replication was associated with both high titers of antibodies to the SIV envelope protein and durable effector SIV-specific CD8(+) T cells suggests the hypothesis that the presence of antibodies at the time of challenge may increase innate immune recruiting activity by enhancing antigen uptake and may result in improvement of the quality and potency of secondary SIV-specific CD8(+) T-cell responses.

Fatal pancreatitis in simian immunodeficiency virus SIV(mac251)-infected macaques treated with 2',3'-dideoxyinosine and stavudine following cytotoxic-T-lymphocyte-associated antigen 4 and indoleamine 2,3-dioxygenase blockade.

Human immunodeficiency virus (HIV) infection is associated with immune activation, CD4⁺-T-cell loss, and a progressive decline of immune functions. Antiretroviral therapy (ART) only partially reverses HIV-associated immune dysfunction, suggesting that approaches that target immune activation and improve virus-specific immune responses may be needed. We performed a preclinical study in rhesus macaques infected with the pathogenic simian immunodeficiency virus SIV(mac251) and treated with ART. We tested whether vaccination administered together with cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4) blockade and treatment with the indoleamine 2,3-dioxygenase (IDO) inhibitor 1-methyl-D-tryptophan (D-1mT), decreased immune activation and improved vaccine efficacy. The treatment did not augment vaccine immunogenicity; rather, it dramatically increased ART-related toxicity, causing all treated animals to succumb to acute pancreatitis and hyperglycemic coma. The onset of fulminant diabetes was associated with severe lymphocyte infiltration of the pancreas and complete loss of the islets of Langerhans. Thus, caution should be used when considering approaches aimed at targeting immune activation during ART.

Overactivation of plasmacytoid dendritic cells inhibits antiviral T-cell responses: a model for HIV immunopathogenesis.

A delicate balance between immunostimulatory and immunosuppressive signals mediated by dendritic cells (DCs) and other antigen-presenting cells (APCs) regulates the strength and efficacy of antiviral T-cell responses. HIV is a potent activator of plasmacytoid DCs (pDCs), and chronic pDC activation by HIV promotes the pathogenesis of AIDS. Cholesterol is pivotal in maintaining HIV envelope integrity and allowing HIV-cell interaction. By depleting envelope-associated cholesterol to different degrees, we generated virions with reduced ability to activate pDCs. We found that APC activation was dissociated from the induction of type I IFN-α/ß and indoleamine-2,3-dioxygenase (IDO)-mediated immunosuppression in vitro. Extensive cholesterol withdrawal, resulting in partial protein and RNA loss from the virions, rendered HIV a more powerful recall immunogen for stimulating memory CD8 T-cell responses in HIV-exposed, uninfected individuals. These enhanced responses were dependent on the inability of cholesterol-depleted HIV to induce IFN-α/ß.

The Educational Impact of Web-Based, Faculty-Led Continuing Medical Education Programs in Type 2 Diabetes: A Survey Study to Analyze Changes in Knowledge, Competence, and Performance of Health Care Professionals.

BACKGROUND: The treatment landscape for type 2 diabetes (T2D) is continually evolving; therefore, ongoing education of health care professionals (HCPs) is essential. There is growing interest in measuring the impact of educational activities, such as through use of the Moore framework; however, data on the benefits of continuing medical education (CME) in the management of T2D remain limited. OBJECTIVE: This study aimed to evaluate HCP satisfaction; measure improvements in knowledge, competence, and performance following short, case-based, multidisciplinary web-based CME activities; and identify the remaining educational gaps. METHODS: Two faculty-led, CME-accredited, web-based educational activities on T2D and obesity, touchIN CONVERSATION and touch MultiDisciplinary Team, were developed and made available on a free-to-access medical education website. Each activity comprised 3 videos lasting 10 to 15 minutes, which addressed learning objectives developed based on a review of published literature and faculty feedback. Participant satisfaction (Moore level 2) was evaluated using a postactivity questionnaire. For both activities, changes in knowledge and competence (Moore levels 3 and 4) were assessed using questionnaires completed by representative HCPs before or after participation in the activities. A second set of HCPs completed a questionnaire before and after engaging in activities that assessed changes in self-reported performance (Moore level 5). RESULTS: Each activity was viewed by approximately 6000 participants within 6 months. The participants expressed high levels of satisfaction (>80%) with both activities. Statistically significant improvements from baseline in knowledge and competence were reported following participation in touchIN CONVERSATION (mean score, SD before vs after activity: 4.36, 1.40 vs 5.42, 1.37; P<.001), with the proportion of learners answering at least six of 7 questions correctly, increasing from 22% (11/50) to 60% (30/50). A nonsignificant improvement in knowledge and competence was observed following participation in touch MultiDisciplinary Team (mean score, SD 4.36, 1.24 vs 4.58, 1.07; P=.35); however, baseline knowledge and competence were relatively high, where 80% of the respondents (40/50) answered at least four of 6 questions correctly. A significant improvement in HCP self-reported performance was observed in a combined analysis of both activities (mean score, SD 2.65, 1.32 vs 3.15, 1.26; P=.03), with the proportion of learners selecting the answer representing the best clinical option for all 4 questions increasing from 32% (11/34) to 59% (20/34) after the activity. Several unmet educational needs were self-reported or identified from the analysis of incorrectly answered questions, including setting individualized glycemic targets and the potential benefits of sodium-glucose cotransporter 2 inhibitor therapies. CONCLUSIONS: Short, case-based, web-based CME activities designed for HCPs to fit their clinical schedules achieved improvements in knowledge, competence, and self-reported performance in T2D management. Ongoing educational needs identified included setting individualized glycemic targets and the potential benefits of sodium-glucose cotransporter 2 inhibitor therapies.

Combined effect of antiretroviral therapy and blockade of IDO in SIV-infected rhesus macaques.

Increased activity of IDO, which catalyzes the degradation of Trp into kynurenine (Kyn), is observed during HIV/SIV infection, and it may contribute to the persistence of HIV/SIV by suppressing antiviral T cell responses. We administered the IDO inhibitor 1-methyl-d-tryptophan (d-1mT) for 13 days to SIV-infected rhesus macaques receiving antiretroviral therapy (ART). d-1mT treatment increased the plasma levels of Trp, without reducing the levels of Kyn, suggesting only a partial effect on IDO enzymatic activity. Surprisingly, d-1mT significantly reduced the virus levels in plasma and lymph nodes of ART-treated animals with incomplete responsiveness to ART. In SIV-infected animals that were not receiving ART, d-1mT was ineffective in reducing the plasma viral load and had only a marginal effect on the plasma Kyn/Trp ratio. Increased IDO and TGF-beta mRNA expression in lymph nodes of ART-treated macaques after d-1mT treatment suggested that compensatory counterregulatory mechanisms were activated by d-1mT, which may account for the lack of effect on plasma Kyn. Finally, d-1mT did not interfere with the ART-induced T cell dynamics in lymph nodes (increased frequency of total CD4 T cells, increase of CD8 T cells expressing the antiapoptotic molecule Bcl2, and reduction of regulatory T cells). Thus, d-1mT appeared to synergize with ART in inhibiting viral replication and did not interfere with the beneficial immunologic effects of ART. Further studies are required to elucidate the immunologic or virologic mechanism by which d-1mT inhibited SIV replication in vivo.

Cerebral function parameters in people with HIV switching integrase inhibitors: a randomized controlled trial.

Background: Different antiretroviral therapies (ARTs) may have differing effects on central nervous system (CNS) function. We assessed CNS pharmacodynamic effects of switching integrase inhibitors in people-with-HIV (PWH).Methods: PWH on tenofovir-DF/emtricitabine plus raltegravir 400 mg twice daily with suppressed plasma HIV RNA and without overt neuropsychiatric symptoms were randomly allocated on a 1:2 basis to remain on raltegravir or switch to dolutegravir 50 mg once daily for 120 days. Pharmacodynamic parameters assessed included cognitive function (z-score of 7 domains), patient-reported outcome measures (PROMs; PHQ-9 and Beck's depression questionnaires), cerebral metabolite ratios measured by proton magnetic resonance spectroscopy (H1-MRS) and plasma and cerebrospinal fluid (CSF) HIV RNA. Pharmacokinetic parameters were also assessed in plasma and CSF. Changes and factors associated with changes in pharmacodynamics parameters were assessed.Results:In 20 subjects (19 male, 14 white ethnicity, median age 43 years (IQR: 11.5) and CD4 + count 717 (SD: 298) cells/µL), over 120 days there were no statistically significant changes in cognitive function [mean z-score difference (95%CI) -0.004 (-0.38/0.37); p = 0.98], PROMs [PHQ-9 median score change: 0 in control arm, -0.5 switch arm (p = 0.57); Beck's depression questionnaire: -1.5 control arm, -1.0 switch arm (p = 0.38)], nor cerebral metabolite ratios between study arms. CSF HIV RNA was <5 copies/mL at baseline and day 120 in all subjects. Geometric mean pre-dose CSF dolutegravir concentration was 7.6 ng/mL (95% CI: 5.2-11.1).Conclusions:Switching integrase inhibitor in virologically suppressed PWH without overt neuropsychiatric symptoms resulted in no significant changes in an extensive panel of CNS pharmacodynamics parameters.

PDL-1 upregulation on monocytes and T cells by HIV via type I interferon: restricted expression of type I interferon receptor by CCR5-expressing leukocytes.

The programmed death (PD)-1 interacts with its ligand (PDL-1) delivering a negative signal to T cells. During human immunodeficiency virus (HIV)-1 infection PD-1 and PDL-1 expressions are increased. Here we show that monocytes and CCR5(+) T cells of HIV-uninfected donors upregulated PDL-1 upon in vitro exposure to HIV. HIV-induced PDL-1 required interferon (IFN)-alpha, but not IFN-gamma, production. Inhibition of endocytosis, required for HIV-induced IFN-alpha production, prevented PDL-1 upregulation. IFN-alpha-inducing Toll-like receptor (TLR) agonists increased PDL-1 on monocytes and CCR5(+) T cells. CD80 and CD86 were also increased on monocytes and CCR5(+) T cells after HIV exposure, but only CD80 was IFN-alpha-dependent. IFN-alpha-receptor subunit 2 (IFNAR2), was expressed only by CCR5(+) T cells and monocytes, explaining why these leukocytes responded to HIV-induced IFN-alpha. Finally, T cell proliferation was improved by PDL-1 blockade in HIV-treated PBMC. In the setting of HIV infection, IFN-alpha may negatively affect T cell responses by inducing PDL-1.

Differential effect of type I and type II interferons on neopterin production and amino acid metabolism in human astrocyte-derived cells.

Intrathecal production of neopterin, a pteridine produced by interferon (IFN)-gamma-stimulated monocyte-derived macrophages, is associated with neurological disorders and infections. We investigated whether IFN-alpha/beta, IFN-gamma, or human immunodeficiency virus (HIV) induce neopterin production by human astroglioma cells. IFN-alpha/beta and IFN-gamma, but not HIV, induced neopterin. Interestingly, IFN-gamma, but not IFN-alpha/beta, increased expression and activity of the tryptophan-catabolizing enzyme indoleamine (2,3)-dioxygenase. In contrast, IFN-alpha/beta, but not IFN-gamma, reduced the uptake of three aromatic amino acids in U87MG and U138 astroglioma cells. Thus type I and type II IFN stimulate astrocyte-derived cells to produce neopterin and exert differential effects on amino acid metabolism.

How does indoleamine 2,3-dioxygenase contribute to HIV-mediated immune dysregulation.

Infection with the human immunodeficiency virus type 1 (HIV) results in a chronic infection that progressively cripples the host immune defenses. HIV infection is associated with increased tryptophan (trp) catabolism by the cytokine-inducible enzyme indoleamine 2,3-dioxygenase (IDO). IDO has powerful immune suppressive activity, which could contribute to the immune dysfunction observed in HIV-infected patients. In this review we discuss the immune mechanisms that could mediate the HIV-induced increase of IDO activity (such as IFN-gamma, IFN-alpha, CTLA-4/B7 and direct viral exposure). We then consider the current knowledge of IDO-mediated immune suppressive mechanisms with regard to different cell types (CD4(+) T cells, CD8(+) T cells, natural killer cells, B cells and regulatory T cells), from the perspective of their potential consequences for the HIV-infected host. HIV-induced, IDO-mediated trp catabolism may contribute to the perpetuation of HIV infection into its chronic phase by dampening efficient immune anti-viral responses. Therapeutic approaches aimed at manipulating this powerful immune suppressive mechanism might be considered in the setting of HIV infection.

Do regulatory T-cells play a role in AIDS pathogenesis?

The impairment of adaptive immune responses to HIV and abnormalities in the immune regulatory function mechanisms during HIV infection have been regarded as key issues in AIDS pathogenesis since the early years of the pandemic. However, the multiple mechanisms underlying this impairment are still not fully understood. New emerging information shows that alterations in the number and/or function of regulatory T-cells may contribute to HIV pathogenesis. Thus, pharmacologic manipulation of regulatory T-cells as well as blocking the activity of other immunomodulatory molecules, such as indoleamine 2,3-dioxygenase, glucocorticoid-induced tumor necrosis factor receptor and PD1, might provide a valuable approach to redirect the immune system towards an efficient antiviral response.

Changes in T Cell and Dendritic Cell Phenotype from Mid to Late Pregnancy Are Indicative of a Shift from Immune Tolerance to Immune Activation.

During pregnancy, the mother allows the immunologically distinct fetoplacental unit to develop and grow. Opinions are divided as to whether this represents a state of fetal-specific tolerance or of a generalized suppression of the maternal immune system. We hypothesized that antigen-specific T cell responses are modulated by an inhibitory T cell phenotype and modified dendritic cell (DC) phenotype in a gestation-dependent manner. We analyzed changes in surface markers of peripheral blood T cells, ex vivo antigen-specific T cell responses, indoleamine 2,3-dioxygenase (IDO) activity (kynurenine/tryptophan ratio, KTR), plasma neopterin concentration, and the in vitro expression of progesterone-induced blocking factor (PIBF) in response to peripheral blood mononuclear cell culture with progesterone. We found that mid gestation is characterized by reduced antigen-specific T cell responses associated with (1) predominance of effector memory over other T cell subsets; (2) upregulation of inhibitory markers (programmed death ligand 1); (3) heightened response to progesterone (PIBF); and (4) reduced proportions of myeloid DC and concurrent IDO activity (KTR). Conversely, antigen-specific T cell responses normalized in late pregnancy and were associated with increased markers of T cell activation (CD38, neopterin). However, these changes occur with a simultaneous upregulation of immune suppressive mechanisms including apoptosis (CD95), coinhibition (TIM-3), and immune regulation (IL-10) through the course of pregnancy. Together, our data suggest that immune tolerance dominates in the second trimester and that it is gradually reversed in the third trimester in association with immune activation as the end of pregnancy approaches.

Enrichment of HLA Types and Single-Nucleotide Polymorphism Associated With Non-progression in a Strictly Defined Cohort of HIV-1 Controllers.

HIV-1 controllers (HIC) are extremely rare patients with the ability to control viral replication, maintain unchanging CD4 T-cell count, and evade disease progression for extensive periods of time, in the absence of antiretroviral therapy. In order to establish the representation of key genetic correlates of atypical disease progression within a cohort of HIV-1+ individuals who control viral replication, we examine four-digit resolution HLA type and single-nucleotide polymorphisms (SNP) previously identified to be correlated to non-progressive infection, in strictly defined HIC. Clinical histories were examined to identify patients exhibiting HIC status. Genomic DNA was extracted, and high definition HLA typing and genome-wide SNP analysis was performed. Data were compared with frequencies of SNP in European long-term non-progressors (LTNP) and primary infection cohorts. HLA-B alleles associated with atypical disease progression were at very high frequencies in the group of five HIC studied. All four HIC of European ancestry were HLA-B*57+ and half were also HLA-B*27+. All HIC, including one of self-reported African ethnicity, had the HLA-Cw*0602 allele, and the HLA-DQ9 allele was present only in HIC of European ancestry. A median 95% of the top 19 SNP known to be associated with LTNP status was observed in European HIC (range 78-100%); 17/19 of the SNP considered mapped to chromosome 6 in the HLA region, whereas 2/19 mapped to chromosome 8. The HIC investigated here demonstrated high enrichment of HLA types and SNP previously associated with long-term non-progression. These findings suggest that the extreme non-progressive phenotype considered here is associated with a genetic signature characterized by a single-genetic unit centered around the HLA-B*57 haplotype and the possible additive effect of HLA-B*27.

Immune Responses in the Central Nervous System Are Anatomically Segregated in a Non-Human Primate Model of Human Immunodeficiency Virus Infection.

The human immunodeficiency virus (HIV) accesses the central nervous system (CNS) early during infection, leading to HIV-associated cognitive impairment and establishment of a viral reservoir. Here, we describe a dichotomy in inflammatory responses in different CNS regions in simian immunodeficiency virus (SIV)-infected macaques, a model for HIV infection. We found increased expression of inflammatory genes and perivascular leukocyte infiltration in the midbrain of SIV-infected macaques. Conversely, the frontal lobe showed downregulation of inflammatory genes associated with interferon-γ and interleukin-6 pathways, and absence of perivascular cuffing. These immunologic alterations were not accompanied by differences in SIV transcriptional activity within the tissue. Altered expression of genes associated with neurotoxicity was observed in both midbrain and frontal lobe. The segregation of inflammatory responses to specific regions of the CNS may both account for HIV-associated neurological symptoms and constitute a critical hurdle for HIV eradication by shielding the CNS viral reservoir from antiviral immunity.

Ribonucleases in HIV type 1 inhibition: effect of recombinant RNases on infection of primary T cells and immune activation-induced RNase gene and protein expression.

Ribonucleases (RNases) have therapeutic potential against cancer and viral diseases and have been reported to inhibit replication of the human immunodeficiency virus type 1 (HIV-1) in chronically infected cell lines. The ribonuclease eosinophil-derived neurotoxin (EDN) is responsible for the anti-HIV-1 activity of a soluble factor produced in response to human alloantigens (ASF). Four recombinant RNases (EDN; a four amino acid extension of the N-terminus EDN, -4EDN; RNase A; and angiogenin) were tested for inhibition of HIV-1 replication in PHA blasts. All RNases showed anti-HIV-1 activity, irrespective of whether the RNases were added before, during, or 2 h after infection. Polyclonal antibodies against the four RNases blocked the antiviral activity. ASF inhibited HIV-1 replication in vitro if added up to 4 h after infection. We demonstrated that allostimulation induced EDN, RNase A, and angiogenin mRNA expression in peripheral blood mononuclear cells (PBMCs), although only EDN protein was detected. We identified monocytes and dendritic cells, but not macrophages or T cells, as EDN-producing cells. These findings raise the possibilities that multiple naturally occurring RNases may contribute to protection against HIV-1 infection and could be considered for utilization in HIV-1 therapy.

Tryptophan Metabolism and Its Relationship with Depression and Cognitive Impairment Among HIV-infected Individuals.

OBJECTIVE: Cognitive impairment (CI) and major depressive disorder (MDD) remain prevalent in treated HIV-1 disease; however, the pathogenesis remains elusive. A possible contributing mechanism is immune-mediated degradation of tryptophan (TRP) via the kynurenine (KYN) pathway, resulting in decreased production of serotonin and accumulation of TRP degradation products. We explored the association of these biochemical pathways and their relationship with CI and MDD in HIV-positive (HIV+) individuals. METHODS: In a cross-sectional analysis, concentrations of neopterin (NEO), tumor necrosis factor-alpha, TRP, KYN, KYN/TRP ratio, phenylalanine (PHE), tyrosine (TYR), PHE/TYR ratio, and nitrite were assessed in the cerebrospinal fluid (CSF) and plasma of HIV+ (n = 91) and HIV-negative (HIV-) individuals (n = 66). CI and MDD were assessed via a comprehensive neuropsychological test battery. A Global Deficit Score ≥0.5 was defined as CI. Nonparametric statistical analyses included Kruskal-Wallis and Mann-Whitney U tests, and multivariate logistic regression. RESULTS: Following Bonferroni correction, NEO concentrations were found to be greater in CSF and TRP concentration was found to be lower in the plasma of HIV+ versus HIV- individuals, including a subgroup of aviremic (defined as HIV-1 RNA <50 cps/mL) HIV+ participants receiving antiretroviral therapy (n = 44). There was a nonsignificant trend toward higher KYN/TRP ratios in plasma in the HIV+ group (P = 0.027; Bonferroni corrected α = 0.0027). In a logistic regression model, lower KYN/TRP ratios in plasma were associated with CI and MDD in the overall HIV+ group (P = 0.038 and P = 0.063, respectively) and the aviremic subgroup (P = 0.066 and P = 0.027, respectively), though this observation was not statistically significant following Bonferroni correction (Bonferroni corrected α = 0.0031). CONCLUSIONS: We observed a trend toward lower KYN/TRP ratios in aviremic HIV+ patients with CI and MDD.

Neuroinflammation in treated HIV-positive individuals: A TSPO PET study.

OBJECTIVE: To explore the effects of microglial activation on brain function and structure, and its relationship with peripheral inflammatory markers, in treated, HIV-positive individuals, using in vivo [(11)C]PBR28 PET (to measure the 18 kDa translocator protein [TSPO]). METHODS: Cognitively healthy HIV-positive individuals on suppressive antiretroviral therapy and HIV-negative individuals (controls) underwent brain [(11)C]PBR28 PET and MRI. HIV-positive patients completed neuropsychological testing and CSF testing for chemokines. The concentration of bacterial ribosomal 16sDNA in plasma was measured as a marker of microbial translocation. RESULTS: HIV-positive individuals showed global increases in TSPO expression compared to controls (corrected p < 0.01), with significant regional increases in the parietal (p = 0.001) and occipital (p = 0.046) lobes and in the globus pallidus (p = 0.035). TSPO binding in the hippocampus, amygdala, and thalamus were associated with poorer global cognitive performance in tasks assessing verbal and visual memory (p < 0.05). Increased TSPO binding was associated with increased brain white matter diffusion MRI mean diffusivity in HIV-positive individuals, a lower CD4/CD8 ratio, and both high pretreatment HIV RNA and plasma concentration ribosomal 16s DNA (p < 0.05). CONCLUSIONS: Cognitively healthy HIV-positive individuals show evidence for a chronically activated brain innate immune response and elevated blood markers of microbial translocation despite effective control of plasma viremia. Increased brain inflammation is associated with poorer cognitive performance and white matter microstructural pathology, suggesting a possible role in cognitive impairments found in some HIV-positive patients despite effective treatment.