HIV-associated Immune Activation Research Articles

Mechanisms and efficacy of small molecule latency-promoting agents to inhibit HIV reactivation ex vivo.

Drugs that inhibit HIV transcription and/or reactivation of latent HIV have been proposed as a strategy to reduce HIV-associated immune activation or to achieve a functional cure, yet comparative studies are lacking. We evaluated 26 drugs, including drugs previously reported to inhibit HIV transcription (inhibitors of Tat-dependent HIV transcription, Rev, HSF-1/PTEF-b, HSP90, Jak/Stat, or SIRT1/Tat deacetylation) and other agents that were not tested before (inhibitors of PKC, NF-κB, SP-1, or histone acetyltransferase; NR2F1 agonists), elongation (inhibitors of CDK9/ PTEF-b), completion (inhibitors of PolyA-polymerase), or splicing (inhibitors of human splice factors). To investigate if those drugs would vary in their ability to affect different blocks to HIV transcription, we measured levels of initiated, elongated, midtranscribed, completed, and multiply spliced HIV RNA in PBMCs from antiretroviral therapy-suppressed individuals following ex vivo treatment with each drug and subsequent T cell activation. We identified new drugs that prevent HIV reactivation, including CDK and splicing inhibitors. While some drugs inhibited 1 or 2 steps, other drugs (CDK inhibitors, splicing inhibitors, tanespimycin, and triptolide) inhibited multiple stages of HIV transcription and blocked the production of supernatant viral RNA. These drugs and targets deserve further study in strategies aimed at reducing HIV-associated immune activation or achieving a functional cure.

Differential susceptibility of cells infected with defective and intact HIV proviruses to killing by obatoclax and other small molecules.

Some drugs that augment cell-intrinsic defenses or modulate cell death/survival pathways have been reported to selectively kill cells infected with HIV or Simian Immunodeficiency Virus (SIV), but comparative studies are lacking. We hypothesized that these drugs may differ in their ability to kill cells infected with intact and defective proviruses. To investigate this hypothesis, drugs were tested ex vivo on peripheral blood mononuclear cells (PBMC) from nine antiretroviral therapy (ART)-suppressed individuals. We tested drugs currently in clinical use or human trials, including auranofin (p53 modulator), interferon alpha2A, interferon gamma, acitretin (RIG-I inducer), GS-9620/vesatolimod (TLR7 agonist), nivolumab (PD-1 blocker), obatoclax (Bcl-2 inhibitor), birinapant [inhibitor of apoptosis proteins (IAP) inhibitor], bortezomib (proteasome inhibitor), and INK128/sapanisertib [mammalian target of rapamycin mTOR] [c]1/2 inhibitor). After 6 days of treatment, we measured cell counts/viabilities and quantified levels of total, intact, and defective HIV DNA by droplet digital PCR (Intact Proviral DNA Assay). Obatoclax reduced intact HIV DNA [median = 27-30% of dimethyl sulfoxide control (DMSO)] but not defective or total HIV DNA. Other drugs showed no statistically significant effects. Obatoclax and other Bcl-2 inhibitors deserve further study in combination therapies aimed at reducing the intact HIV reservoir in order to achieve a functional cure and/or reduce HIV-associated immune activation.

HIV-1-Host Interaction in Gut-Associated Lymphoid Tissue (GALT): Effects on Local Environment and Comorbidities.

HIV-1 replication in the gastrointestinal (GI) tract causes severe CD4+ T-cell depletion and disruption of the protective epithelial barrier in the intestinal mucosa, causing microbial translocation, the main driver of inflammation and immune activation, even in people living with HIV (PLWH) taking antiretroviral drug therapy. The higher levels of HIV DNA in the gut compared to the blood highlight the importance of the gut as a viral reservoir. CD4+ T-cell subsets in the gut differ in phenotypic characteristics and differentiation status from the ones in other tissues or in peripheral blood, and little is still known about the mechanisms by which the persistence of HIV is maintained at this anatomical site. This review aims to describe the interaction with key subsets of CD4+ T cells in the intestinal mucosa targeted by HIV-1 and the role of gut microbiome and its metabolites in HIV-associated systemic inflammation and immune activation that are crucial in the pathogenesis of HIV infection and related comorbidities.

Coronary heart disease in patients with human immunodeficiency virus infection

According to the World Health Organization, more than 38 million people are carriers of the human immunodeficiency virus (HIV). The relative risk of cardiovascular events in patients with HIV infection is 1.52 times higher than those without it. An HIV-positive status is associated with a 50% increased risk of acute myocardial infarction. The mechanisms of CVD development caused by HIV activity are not fully understood, and the contribution of traditional risk factors cannot fully explain such a high potential for coronary heart disease (CHD) in patients with HIV infection. Data suggest that HIV-associated chronic inflammation and immune system activation may lead to progressive endothelial dysfunction and vascular damage. The pathogenesis of atherosclerosis and, consequently, CHD in HIV infection is extremely versatile and poorly studied. The key mechanisms in HIV-associated CHD include the effect of HIV proteins on immunocompetent cells and vascular endothelium, immunodeficiency, translocation of microorganisms from the gut, and chronic inflammation with platelet activation. Despite considerable progress in understanding HIV-associated cardiovascular disease, many unresolved questions remain. Even with effective viral suppression, inflammation and immune dysregulation appear to increase the risk of cardiovascular complications. The lack of large-scale clinical studies on the prevention and treatment of cardiovascular disease in HIV is very important. Nevertheless, some important features should be considered in the management of patients with HIV infection.

Elevated Foxp3+ double-negative T cells are associated with disease progression during HIV infection.

Persistent immune activation, which occurs during the whole course of HIV infection, plays a pivotal role in CD4+ T cells depletion and AIDS progression. Furthermore, immune activation is a key factor that leads to impaired immune reconstitution after long-term effective antiretroviral therapy (ART), and is even responsible for the increased risk of developing non-AIDS co-morbidities. Therefore, it’s imperative to identify an effective intervention targeting HIV-associated immune activation to improve disease management. Double negative T cells (DNT) were reported to provide immunosuppression during HIV infection, but the related mechanisms remained puzzled. Foxp3 endows Tregs with potent suppressive function to maintain immune homeostasis. However, whether DNT cells expressed Foxp3 and the accurate function of these cells urgently needed to be investigated. Here, we found that Foxp3+ DNT cells accumulated in untreated people living with HIV (PLWH) with CD4+ T cell count less than 200 cells/µl. Moreover, the frequency of Foxp3+ DNT cells was negatively correlated with CD4+ T cell count and CD4/CD8 ratio, and positively correlated with immune activation and systemic inflammation in PLWH. Of note, Foxp3+ DNT cells might exert suppressive regulation by increased expression of CD39, CD25, or vigorous proliferation (high levels of GITR and ki67) in ART-naive PLWH. Our study underlined the importance of Foxp3+ DNT cells in the HIV disease progression, and suggest that Foxp3+ DNT may be a potential target for clinical intervention for the control of immune activation during HIV infection.

Inflammation, HIV, and Immune Quiescence: Leveraging on Immunomodulatory Products to Reduce HIV Susceptibility

The relationship between inflammation and HIV has been a focus of research over the last decade. In HIV-infected individuals, increased HIV-associated immune activation significantly correlated to disease progression. While genital inflammation (GI) has been shown to significantly increase the risk of HIV acquisition and transmission, immune correlates for reduced risk remain limited. In certain HIV-exposed seronegative individuals, an immune quiescent phenotype characterized reduced risk. Immune quiescence is defined by specific, targeted, highly regulated immune responses that hinder overt inflammation or immune activation. Targeted management of inflammation, therefore, is a plausible strategy to mitigate HIV risk and slow disease progression. Nonsteroidal anti-inflammatory drugs (NSAIDs) such as hydroxychloroquine and aspirin have shown encouraging preliminary results in low-risk women by reducing systemic and genital immune activation. A topical NSAID, containing ibuprofen, is effective in treating vulvovaginal inflammation. Additionally, the glucocorticoids (GCs), prednisolone, and dexamethasone are used to treat HIV-associated immune activation. Collectively, these data inform on immune-modulating drugs to reduce HIV risk. However, the prolonged use of these pharmaceutical drugs is associated with adverse effects, both systemically and to a lesser extent topically. Natural products with their reduced side effects coupled with anti-inflammatory properties render them viable options. Lactic acid (LA) has immunomodulatory properties. LA regulates the genital microbiome by facilitating the growth of Lactobacillus species, while simultaneously limiting bacterial species that cause microbial dysbiosis and GI.Glycerol monolaurate, besides being anti-inflammatory, also inhibited SIV infections in rhesus macaques. The proposed pharmaceutical and natural products could be used in combination with either antiretrovirals for treatment or preexposure prophylaxis for HIV prevention. This review provides a summary on the associations between inflammation, HIV risk, and disease progression. Furthermore, we use the knowledge from immune quiescence to exploit the use of pharmaceutical and natural products as strategic interventions to manage inflammation, toward mitigating HIV infections.

HIV-Related Immune Activation and Inflammation: Current Understanding and Strategies.

Although antiretroviral therapy effectively controls human immunodeficiency virus (HIV) replication, a residual chronic immune activation/inflammation persists throughout the disease. This aberrant immune activation and inflammation are considered an accelerator of non-AIDS-related events and one of the driving forces of CD4+ T cell depletion. Unfortunately, HIV-associated immune activation is driven by various factors, while the mechanism of excessive inflammation has not been formally clarified. To date, several clinical interventions or treatment candidates undergoing clinical trials have been proposed to combat this systemic immune activation/inflammation. However, these strategies revealed limited results, or their nonspecific anti-inflammatory properties are similar to previous interventions. Here, we reviewed recent learnings of immune activation and persisting inflammation associated with HIV infection, as well as the current directions to overcome it. Of note, a more profound understanding of the specific mechanisms for aberrant inflammation is still imperative for identifying an effective clinical intervention strategy.

The Adenosine Pathway and Human Immunodeficiency Virus-Associated Inflammation.

Human immunodeficiency virus (HIV) is associated with an increased risk of age-associated comorbidities and mortality compared to people without HIV. This has been attributed to HIV-associated chronic inflammation and immune activation despite viral suppression. The adenosine pathway is an established mechanism by which the body regulates persistent inflammation to limit tissue damage associated with inflammatory conditions. However, HIV infection is associated with derangements in the adenosine pathway that limits its ability to control HIV-associated inflammation. This article reviews the function of purinergic signaling and the role of the adenosine signaling pathway in HIV-associated chronic inflammation. This review also discusses the beneficial and potential detrimental effects of pharmacotherapeutic strategies targeting this pathway among people with HIV.

Tissue-specific transcriptional profiling of plasmacytoid dendritic cells reveals a hyperactivated state in chronic SIV infection.

HIV associated immune activation (IA) is associated with increased morbidity in people living with HIV (PLWH) on antiretroviral therapy, and remains a barrier for strategies aimed at reducing the HIV reservoir. The underlying mechanisms of IA have not been definitively elucidated, however, persistent production of Type I IFNs and expression of ISGs is considered to be one of the primary factors. Plasmacytoid DCs (pDCs) are a major producer of Type I IFN during viral infections, and are highly immunomodulatory in acute HIV and SIV infection, however their role in chronic HIV/SIV infection has not been firmly established. Here, we performed a detailed transcriptomic characterization of pDCs in chronic SIV infection in rhesus macaques, and in sooty mangabeys, a natural host non-human primate (NHP) species that undergoes non-pathogenic SIV infection. We also investigated the immunostimulatory capacity of lymph node homing pDCs in chronic SIV infection by contrasting gene expression of pDCs isolated from lymph nodes with those from blood. We observed that pDCs in LNs, but not blood, produced high levels of IFNα transcripts, and upregulated gene expression programs consistent with T cell activation and exhaustion. We apply a novel strategy to catalogue uncharacterized surface molecules on pDCs, and identified the lymphoid exhaustion markers TIGIT and LAIR1 as highly expressed in SIV infection. pDCs from SIV-infected sooty mangabeys lacked the activation profile of ISG signatures observed in infected macaques. These data demonstrate that pDCs are a primary producer of Type I IFN in chronic SIV infection. Further, this study demonstrated that pDCs trafficking to LNs persist in a highly activated state well into chronic infection. Collectively, these data identify pDCs as a highly immunomodulatory cell population in chronic SIV infection, and a putative therapeutic target to reduce immune activation.

Preservation of Gastrointestinal Mucosal Barrier Function and Microbiome in Patients With Controlled HIV Infection.

BackgroundDespite successful ART in people living with HIV infection (PLHIV) they experience increased morbidity and mortality compared with HIV-negative controls. A dominant paradigm is that gut-associated lymphatic tissue (GALT) destruction at the time of primary HIV infection leads to loss of gut integrity, pathological microbial translocation across the compromised gastrointestinal barrier and, consequently, systemic inflammation. We aimed to identify and measure specific changes in the gastrointestinal barrier that might allow bacterial translocation, and their persistence despite initiation of antiretroviral therapy (ART).MethodWe conducted a cross-sectional study of the gastrointestinal (GIT) barrier in PLHIV and HIV-uninfected controls (HUC). The GIT barrier was assessed as follows: in vivo mucosal imaging using confocal endomicroscopy (CEM); the immunophenotype of GIT and circulating lymphocytes; the gut microbiome; and plasma inflammation markers Tumour Necrosis Factor-α (TNF-α) and Interleukin-6 (IL-6); and the microbial translocation marker sCD14.ResultsA cohort of PLHIV who initiated ART early, during primary HIV infection (PHI), n=5), and late (chronic HIV infection (CHI), n=7) infection were evaluated for the differential effects of the stage of ART initiation on the GIT barrier compared with HUC (n=6). We observed a significant decrease in the CD4 T-cell count of CHI patients in the left colon (p=0.03) and a trend to a decrease in the terminal ileum (p=0.13). We did not find evidence of increased epithelial permeability by CEM. No significant differences were found in microbial translocation or inflammatory markers in plasma. In gut biopsies, CD8 T-cells, including resident intraepithelial CD103+ cells, did not show any significant elevation of activation in PLHIV, compared to HUC. The majority of residual circulating activated CD38+HLA-DR+ CD8 T-cells did not exhibit gut-homing integrins α4ß7, suggesting that they did not originate in GALT. A significant reduction in the evenness of species distribution in the microbiome of CHI subjects (p=0.016) was observed, with significantly higher relative abundance of the genus Spirochaeta in PHI subjects (p=0.042).ConclusionThese data suggest that substantial, non-specific increases in epithelial permeability may not be the most important mechanism of HIV-associated immune activation in well-controlled HIV-positive patients on antiretroviral therapy. Changes in gut microbiota warrant further study.

Soluble CD163 Identifies Those at Risk for Increased Hepatic Inflammation & Fibrosis.

BackgroundLiver disease remains a significant cause of morbidity and mortality in HIV-infected persons. Soluble CD163 is a marker of Kupffer cell activation that is highly associated with development of hepatic fibrosis. The relative contributions of HIV-associated systemic immune activation vs other etiologies of injury are poorly characterized.MethodsWe utilized subjects in the Miami Adult Studies on HIV (MASH) cohort to evaluate 464 participants including 361 people with HIV (PWH) and 103 hepatitis C virus (HCV)/HIV-uninfected controls. Subjects underwent testing for hepatic fibrosis using both magnetic resonance elastography and the Enhanced Liver Fibrosis Index. Steatosis was evaluated by magnetic resonance imaging–derived proton density fat fraction. Immune activation markers and cytokines were quantitated using Luminex methodologies.ResultsParticipants with HIV with or without HCV coinfection had higher levels of sCD163 than uninfected controls (P < .05). Soluble sCD163 was highly associated with elevated alanine aminotransferase, a key marker of inflammation/injury and with hepatic fibrosis. Hepatic steatosis was also associated with a cytokine pattern suggestive of Kupffer cell activation but was not associated with an increase in sCD14 or sCD27.ConclusionsInjury and resultant hepatic fibrosis occur by distinct though overlapping mechanistic pathways. In PWH, sCD163 is highly associated with both injury and fibrosis, suggesting that persistent systemic immune activation is a major contributor to long-term outcomes, adding to damage caused by alcohol, steatosis, and other hepatotoxic drug effects.

Characterization of CD31 expression in CD4+ and CD8+T cell subpopulations in chronic untreated HIV infection

BackgroundThe platelet endothelial cell adhesion molecule-1 (PECAM-1) or CD31 has been involved in regulation of T-cell tolerance, activation, survival and homing in mice cells. However, there is limited knowledge about the expression pattern and role of this molecule in human T cells, particularly in conditions of chronic immune activation. ObjectivesWe explored CD31 expression in T cell differentiation subsets of individuals with untreated HIV infection and in non-HIV-infected controls. We also assessed phenotypic differences between CD31+ and CD31- subsets in memory and terminally differentiated (TEMRA) CD4+ and CD8 + T cells. MethodsForty-one individuals with untreated HIV infection and 34 non-HIV-infected controls were included in the study. We compared the expression of CD31 in CD4+ and CD8 + T cells across stages of differentiation in the two study groups by flow cytometry. We also analyzed the expression of CD57 (a marker of senescence), Ki67 (a marker of cycling cells), PD-1 (a marker of exhaustion), and CD38/HLA-DR (a marker of immune activation) on memory and TEMRA CD31+ and CD31- T cells. ResultsCD31 expression was significantly higher in CD8 + T cells than in CD4 + T cells, measured as frequency, absolute numbers and median fluorescence intensity (MFI), in both study groups (p < 0.0001 in all cases). Intermediate differentiation subsets of CD4+ and CD8 + T cells expressed higher levels of CD31 in the context of HIV infection (p < 0.001 in all cases). CD31 expression frequency decreased with cellular differentiation of CD4+ and CD8 + T cells in both groups, but this decrease was steeper in individuals without HIV infection (CD4+: p < 0.001 and CD8+: p < 0.0001). As expected, memory and TEMRA CD4+ and CD8 + T cells expressed significantly higher levels of CD57, PD-1, Ki67 and CD38/HLA-DR in HIV-infected compared to non-HIV-infected individuals (p < 0.01 in all cases). CD31 expression was associated with lower activation of memory (but not TEMRA) CD4 + T cells in non-HIV-infected persons, an effect not observed in the HIV-infected group. CD31 expression on memory CD8 + T cells of HIV-infected individuals was associated higher levels of PD-1 (p = 0.0019) and CD38/HLADR (p = 0.0345), and higher PD-1 expression on CD8 + TEMRA (p = 0.0024), an effect not observed in non-HIV-infected individuals. ConclusionIn the context of HIV-associated chronic immune activation, specifically on memory CD8 + T cells, CD31 expression was associated with higher PD-1 and CD38/HLA-DR co-expression, suggesting that CD31 expression may result from an insufficient attempt to contain T cell exhaustion and activation. CD31-targeted therapies may contribute to modulate these cellular responses.

Inflammation, HIV, and Immune Quiescence: Leveraging on Immunomodulatory Products to Reduce HIV Susceptibility.

The relationship between inflammation and HIV has been a focus of research over the last decade. In HIV-infected individuals, increased HIV-associated immune activation significantly correlated to disease progression. While genital inflammation (GI) has been shown to significantly increase the risk of HIV acquisition and transmission, immune correlates for reduced risk remain limited. In certain HIV-exposed seronegative individuals, an immune quiescent phenotype characterized reduced risk. Immune quiescence is defined by specific, targeted, highly regulated immune responses that hinder overt inflammation or immune activation. Targeted management of inflammation, therefore, is a plausible strategy to mitigate HIV risk and slow disease progression. Nonsteroidal anti-inflammatory drugs (NSAIDs) such as hydroxychloroquine and aspirin have shown encouraging preliminary results in low-risk women by reducing systemic and genital immune activation. A topical NSAID, containing ibuprofen, is effective in treating vulvovaginal inflammation. Additionally, the glucocorticoids (GCs), prednisolone, and dexamethasone are used to treat HIV-associated immune activation. Collectively, these data inform on immune-modulating drugs to reduce HIV risk. However, the prolonged use of these pharmaceutical drugs is associated with adverse effects, both systemically and to a lesser extent topically. Natural products with their reduced side effects coupled with anti-inflammatory properties render them viable options. Lactic acid (LA) has immunomodulatory properties. LA regulates the genital microbiome by facilitating the growth of Lactobacillus species, while simultaneously limiting bacterial species that cause microbial dysbiosis and GI. Glycerol monolaurate, besides being anti-inflammatory, also inhibited SIV infections in rhesus macaques. The proposed pharmaceutical and natural products could be used in combination with either antiretrovirals for treatment or preexposure prophylaxis for HIV prevention. This review provides a summary on the associations between inflammation, HIV risk, and disease progression. Furthermore, we use the knowledge from immune quiescence to exploit the use of pharmaceutical and natural products as strategic interventions to manage inflammation, toward mitigating HIV infections.

Optimizing ethambutol dosing among HIV/tuberculosis co-infected patients: a population pharmacokinetic modelling and simulation study.

Reduced ethambutol serum concentrations are commonly observed among TB patients co-infected with HIV and may lead to treatment failure. To perform a population pharmacokinetic study of ethambutol in HIV/TB patients, and to evaluate an intensified ethambutol weight-based dosing strategy to support pharmacokinetic target attainment. We conducted a prospective study of ethambutol pharmacokinetics among HIV/TB patients administered first-line TB treatment in Botswana, with study visits before and after initiation of ART. Clinical and disease status markers, including HIV-associated systemic immune activation and gut dysfunction biomarkers, were evaluated as covariates of ethambutol pharmacokinetic parameters in non-linear mixed effects analysis. Monte Carlo simulations were performed to compare pharmacokinetic target attainment under standard and intensified weight-based ethambutol dosing strategies. We studied 40 HIV/TB patients prior to initiation of ART, of whom 24 returned for a second visit a median of 33 days following ART initiation. Ethambutol serum concentrations were best explained by a two-compartment model with first-order elimination, with a significant improvement in oral bioavailability following ART initiation. In Monte Carlo simulations, a supplementary ethambutol dose of 400 mg daily led to >2-fold improvements in pharmacokinetic target attainment probabilities in lung tissue, both before and after ART initiation. Low serum ethambutol concentrations were commonly observed among HIV/TB patients in Botswana, and the oral bioavailability of ethambutol increased following ART initiation. Supplementary ethambutol dosing among HIV/TB patients may provide a strategy to optimize anti-TB treatment regimens in this high-risk population.

Fungal Translocation Is Associated with Immune Activation and Systemic Inflammation in Treated HIV.

The mechanisms causing HIV-associated immune activation remain incompletely understood. Alteration of intestinal integrity with subsequent translocation of bacterial products appears to play an important role; however, little is known about the impact of fungal translocation. We assessed the effect of fungal translocation and its association with immune activation in people living with HIV (PLWH) compared with uninfected controls. We measured serum levels of β-D-glucan (BDG) and anti-Saccharomyces cerevisiae antibodies (ASCA) immunoglobulin G (IgG) and immunoglobulin A (IgA) and markers of systemic inflammation and immune activation in virally suppressed PLWH on antiretroviral therapy (ART) and uninfected controls. T-test and Mann-Whitney tests were used to compare markers by HIV status and correlation and regression analyses were used to assess associations of fungal translocation markers with markers of inflammation. One hundred seventy-six participants were included (128 HIV+ and 48 HIV-); 72% male, 65% African American, median age was 50 years, and CD4 was 710 cells/cm3. Levels of BDG tended to be lower in HIV+ when compared with controls (p = .05). No significant difference in levels of ASCA IgG and IgA was seen between groups (p > .75). There was a significant correlation between BDG and several markers of inflammation and immune activation in PLWH, not seen in uninfected controls. In contrast, no correlations were seen between levels of ASCA IgG and IgA with inflammatory markers. PLWH on ART do not have higher levels of BDG or ASCA when compared with uninfected controls, however, the association found between BDG and several inflammation markers suggests a potential role of fungal translocation in the heightened immune activation seen in treated HIV.

KIR and HLA-C Genetic Polymorphisms Influence Plasma IP-10 Concentration in Antiretroviral Therapy-Naive HIV-Infected Adult Zimbabweans.

Past studies on the relationship between Killer cell Immunoglobulin-like Receptor (KIR) and Human Leukocyte Antigen (HLA) genetic variation and chronic immune activation (CIA) in HIV infection are not uniformly consistent. Moreover, interferon-γ-induced protein 10 (IP-10) is a soluble biomarker of immune activation, with high plasma concentrations predicting accelerated disease progression in HIV infection. Thus, we investigated the association of KIR and HLA-C genetic polymorphisms with plasma IP-10 concentration in 183 treatment-naive chronically HIV-infected adults of Bantu origin from Zimbabwe. KIR genetic variation was determined using allele-specific primer PCR while HLA-C typing was characterized by sequencing. Plasma IP-10 was quantified using enzyme-linked immunosorbent assay. The KIR2DL3 gene was significantly associated with CIA as observed from IP-10 concentrations among KIR2DL3 carriers (265.20 pg/mL, IQR: 179.99-385.19) compared with KIR2DL3 noncarriers (183.56 pg/mL; IQR: 110.98-230.81; p = 0.001) and among KIR2DL3+HLA-C2 carriers (226.23 pg/mL, IQR: 187.96-394.73) compared with KIR2DL3+HLA-C2 noncarriers (212.86 pg/mL, IQR: 160.15-344.99; p = 0.017), respectively. Similarly, IP-10 concentrations were significantly higher (p = 0.030) in the KIR3DS1 carriers (313.86 pg/mL, IQR: 230.05-469.20) compared with KIR3DS1 noncarriers (246.01 pg/mL, IQR: 169.58-373.32). Thus, KIR and HLA-C could be playing important roles in HIV-associated immune activation. The elevation of IP-10 in KIR2DL3 and KIR2DL3+C2 could potentially be explained by increased IFN-γ secretion from activated NK cell activation due to the absence of KIR2DL3's cognate C1 ligand. To the best of our knowledge, this is the first study on a potential link between KIR and HLA-C genetic determinants and plasma IP-10 concentration in this population sample. Future studies are called for in other world populations for biomarkers of disease progression and mechanisms of IP-10 variability in HIV infection.

Heavy Cannabis Use Associated With Reduction in Activated and Inflammatory Immune Cell Frequencies in Antiretroviral Therapy-Treated Human Immunodeficiency Virus-Infected Individuals.

Cannabis is a widely used drug in the United States, and the frequency of cannabis use in the human immunodeficiency virus (HIV)-infected population is disproportionately high. Previous human and macaque studies suggest that cannabis may have an impact on plasma viral load; however, the relationship between cannabis use and HIV-associated systemic inflammation and immune activation has not been well defined. The impact of cannabis use on peripheral immune cell frequency, activation, and function was assessed in 198 HIV-infected, antiretroviral-treated individuals by flow cytometry. Individuals were categorized into heavy, medium, or occasional cannabis users or noncannabis users based on the amount of the cannabis metabolite 11-nor-carboxy-tetrahydrocannabinol (THC-COOH) detected in plasma by mass spectrometry. Heavy cannabis users had decreased frequencies of human leukocyte antigen (HLA)-DR+CD38+CD4+ and CD8+ T-cell frequencies, compared to frequencies of these cells in non-cannabis-using individuals. Heavy cannabis users had decreased frequencies of intermediate and nonclassical monocyte subsets, as well as decreased frequencies of interleukin 23- and tumor necrosis factor-α-producing antigen-presenting cells. While the clinical implications are unclear, our findings suggest that cannabis use is associated with a potentially beneficial reduction in systemic inflammation and immune activation in the context of antiretroviral-treated HIV infection.

Pyrazinamide clearance is impaired among HIV/tuberculosis patients with high levels of systemic immune activation.

Pyrazinamide is the main driver of sterilizing effect in the standard regimen in adults and older children, and this effect is concentration-dependent. Tuberculosis patients co-infected with human immunodeficiency virus (HIV) have an increased risk for poor tuberculosis treatment outcomes and adverse drug events. We sought to determine whether measures of systemic immune activation were related to pyrazinamide pharmacokinetics among HIV/tuberculosis patients. We conducted a prospective cohort study of pyrazinamide pharmacokinetics in HIV/tuberculosis patients in Gaborone, Botswana. Patients underwent intensive pharmacokinetic sampling before and after the initiation of antiretroviral therapy, which can increase immune activation in HIV/tuberculosis. Compartmental pharmacokinetic modeling was performed to determine whether variability in systemic immune activation was related to variability in pyrazinamide pharmacokinetic parameters. Forty HIV/tuberculosis patients completed the first pharmacokinetic sampling visit, and 24 patients returned for a second visit following antiretroviral therapy initiation. The pyrazinamide plasma concentration-versus-time data were best explained by a one-compartment model with first-order elimination, and a combined additive and proportional residual error model. Pyrazinamide clearance was higher in men than women. Expression of CD38 and HLA- DR on CD8+T cells, a measure of HIV-associated immune activation, was inversely related to pyrazinamide clearance, with increasing immune activation associated with decreasing pyrazinamide clearance. Future studies should verify this finding in larger numbers of tuberculosis patients with and without HIV co-infection.

Immune activation and HIV-specific T cell responses are modulated by a cyclooxygenase-2 inhibitor in untreated HIV-infected individuals: An exploratory clinical trial.

Pathologically elevated immune activation and inflammation contribute to HIV disease progression and immunodeficiency, potentially mediated by elevated levels of prostaglandin E2, which suppress HIV-specific T cell responses. We have previously shown that a high dose of the cyclooxygenase-2 inhibitor celecoxib can reduce HIV-associated immune activation and improve IgG responses to T cell-dependent vaccines. In this follow-up study, we included 56 HIV-infected adults, 28 antiretroviral therapy (ART)-naïve and 28 on ART with undetectable plasma viremia but CD4 counts below 500 cells/μL. Patients in each of the two study groups were randomized to receive 90 mg qd of the cyclooxygenase-2 inhibitor etoricoxib for six months, two weeks or to a control arm, respectively. T cell activation status, HIV Gag-specific T cell responses and plasma inflammatory markers, tryptophan metabolism and thrombin generation were analyzed at baseline and after four months. In addition, patients received tetanus toxoid, conjugated pneumococcal and seasonal influenza vaccines, to which IgG responses were determined after four weeks. In ART-naïve patients, etoricoxib reduced the density of the activation marker CD38 in multiple CD8+ T cell subsets, improved Gag-specific T cell responses, and reduced in vitro plasma thrombin generation, while no effects were seen on plasma markers of inflammation or tryptophan metabolism. No significant immunological effects of etoricoxib were observed in ART-treated patients. Patients receiving long-term etoricoxib treatment had poorer tetanus toxoid and conjugated pneumococcal vaccine responses than those receiving short-course etoricoxib. Cyclooxygenase-2 inhibitors may attenuate harmful immune activation in HIV-infected patients without access to ART.

HIV as a Cause of Immune Activation and Immunosenescence.

Systemic immune activation has emerged as an essential component of the immunopathogenesis of HIV. It not only leads to faster disease progression, but also to accelerated decline of overall immune competence. HIV-associated immune activation is characterized by an increase in proinflammatory mediators, dysfunctional T regulatory cells, and a pattern of T-cell-senescent phenotypes similar to those seen in the elderly. These changes predispose HIV-infected persons to comorbid conditions that have been linked to immunosenescence and inflamm-ageing, such as atherosclerosis and cardiovascular disease, neurodegeneration, and cancer. In the antiretroviral treatment era, development of such non-AIDS-defining, age-related comorbidities is a major cause of morbidity and mortality. Treatment strategies aimed at curtailing persistent immune activation and inflammation may help prevent the development of these conditions. At present, the most effective strategy appears to be early antiretroviral treatment initiation. No other treatment interventions have been found effective in large-scale clinical trials, and no adjunctive treatment is currently recommended in international HIV treatment guidelines. This article reviews the role of systemic immune activation in the immunopathogenesis of HIV infection, its causes and the clinical implications linked to immunosenescence in adults, and the therapeutic interventions that have been investigated.