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Immune reconstitution inflammatory syndrome (IRIS) is the paradoxical worsening or unmasking of an infection or neoplasm in HIV-1-infected patients shortly after antiretroviral therapy (ART) initiation. New insights into the pathogenesis of IRIS may help identify biomarkers that could be useful in predicting or diagnosing IRIS.Studies of immunopathogenesis have shown a signification activation of both innate and adaptive immune responses with elevation of plasma or serum chemokines and cytokines. Markers of inflammation such as C-reactive protein, interferon-inducible protein 10 or interferon γ may be helpful as predictors of IRIS events. In addition, tuberculosis (TB)-associated IRIS is associated with a prominent Th1 response that can be heightened even prior to ART initiation in cases of unmasking TB, and may assist in early diagnosis. Large prospective studies are needed to elucidate the predictive and diagnostic value of IRIS biomarkers and advance them to the clinic.Reversal of immunosuppression by ART leads to exaggerated pathogen-specific immune responses (known as IRIS) that appear to be primed prior to therapy. Inflammatory markers, chemokines and cytokines that signify innate and adaptive immune activation are biomarkers that could prove of clinical value after appropriate validation.

Following antiretroviral therapy, a significant proportion of HIV+ patients with mycobacterial coinfections develop a paradoxical, poorly understood inflammatory disease termed immune reconstitution inflammatory syndrome (IRIS). Here, we show that Mycobacterium avium–infected T cell–deficient mice injected with CD4 T cells also develop an immune reconstitution disease (IRD) manifesting as weight loss, impaired lung function, and rapid mortality. This form of IRD requires Ag recognition and interferonγ production by the donor CD4 T cells and correlates with marked alterations in blood and tissue CD11b+ myeloid cells. Interestingly, disease is associated with impaired, rather than augmented, T-cell expansion and function and is not strictly dependent on lymphopenia-induced T-cell proliferation. Instead, our findings suggest that mycobacterial-associated IRIS results from a heightened sensitivity of infected lymphopenic hosts to the detrimental effects of Ag-driven CD4 T-cell responses.

Background: Immune reconstitution inflammatory syndrome (IRIS) is reported widely in patients initiating antiretroviral therapy (ART). However, few studies are prospective, and no study has evaluated the impact of the timing of ART when allocated randomly during an acute opportunistic infection (OI). Methodology/Principal Findings: A5164 randomized 282 subjects with AIDS-related OIs (tuberculosis excluded), to early or deferred ART. IRIS was identified prospectively using pre-defined criteria. We evaluated associations between IRIS and baseline variables in subjects with follow-up on ART using Wilcoxon and Fisher’s exact tests, logistic regression, and Cox models with time-varying covariates. Twenty of 262 (7.6%) subjects developed IRIS after a median of 33 days on ART. Subjects with fungal infections (other than pneumocystis) developed IRIS somewhat more frequently (OR = 2.7; 95% CI: 1.02, 7.2; p-value = 0.06 (using Fisher’s exact test)). In Cox models, lower baseline and higher on-treatment CD4+ T-cell counts and percentage were associated with IRIS. Additionally, higher baseline and lower on-treatment HIV RNA levels were associated with IRIS. Corticosteroids during OI management and the timing of ART were not associated with the development of IRIS. Implications: In patients with advanced immunosuppression and non-tuberculous OIs, the presence of a fungal infection, lower CD4+ T-cell counts and higher HIV RNA levels at baseline, and higher CD4+ T-cell counts and lower HIV RNA levels on treatment are associated with IRIS. Early initiation of ART does not increase the incidence of IRIS, and concern about IRIS should not prompt deferral of ART. Trial Registration: ClinicalTrials.gov NCT00055120

Biomarkers could be useful in evaluating immune reconstitution inflammatory syndrome (IRIS). A cohort of 45 HIV-1-infected, antiretroviral treatment (ART)-naive patients with baseline CD4 T cell counts

Purpose of review HIV and pathogenic simian immunodeficiency virus infection are characterized by chronic immune activation. This review addresses the factors that influence immune activation and may thus determine the rate of disease progression during the asymptomatic period of HIV. Recent findings Immune activation stems from foreign antigen stimulation, including HIV, microbial products and coinfections and compensatory homeostatic mechanisms. Continuous immune stimulation creates a permissive environment for further viral replication, while temporarily allowing successful replenishment of the T-cell pool. Type I interferon, microbial translocation, activated (but ineffective) effector T cells, unruly regulatory T cells and inadequate T helper 17 cells all play important roles in the cycle of activation, functional exhaustion and T-cell death that leads to immunodeficiency. Summary The asymptomatic chronic phase of HIV infection is a dynamic balance between host and virus, the outcome of which determines an individual's course of disease. Evaluation of the factors that determine the immunologic threshold of disease progression could assist in designing therapeutic strategies, including individualized timing of ART.

Intermittent administration of interleukin-2 (IL-2) to human immunodeficiency virus (HIV)- infected patients on antiretroviral therapy (ART) is capable of inducing significant increases in CD4 T cell counts as a result of increased T cell survival and decreased cell turnover. However, its role in the setting of ART interruptions (STI) is less well characterized. We sought to compare the effect of continuous (C) versus intermittent (P) ART on CD4 responses in patients undergoing IL-2 therapy.CD4 cell responses were compared in 25 patients who underwent IL-2 therapy during periods of continuous ART (n = 90 cycles) as well as during STI (n = 45 cycles). During STI, patients resumed ART for only 10 days surrounding each IL-2 cycle.C cycles resulted in a significantly greater CD4 gain than P cycles (Delta156 cells/microL, 95% CI = 68-243). In multivariate analyses, baseline CD4/CD25 expression and treatment arm remained strong predictors of CD4 gain while CD8/CD38+, CD8/DR+, and CD4 Ki67+ phenotype were not predictive.Continuous ART was associated with a statistically significantly greater CD4 cell response to IL-2 therapy than was intermittent ART. These observations may have important implications for the appropriate integration of IL-2 therapy into STI strategies.

IL-15 is a member of the gamma chain-dependent cytokines and known to affect innate and CD8(+) adaptive immune responses. Despite a growing interest in the use of IL-15 as an immunotherapeutic agent, the broad spectrum of immunoregulatory functions exerted by IL-15 has not been fully elucidated. Here, we demonstrate that IL-15 increases expression of CD25 and forkhead box transcription factor P3 (FOXP3), a master transcriptional regulator of regulatory T cells, in human peripheral CD4(+)CD25(-) T cells in the absence of antigenic stimulation. Comparisons involving IL-2 and IL-7 revealed that the induction of CD25(hi) and FOXP3 expression was most prominent with IL-15 and IL-2. More modest effects were seen with IL-7. Despite levels of FOXP3 expression comparable to that of conventional regulatory T cells, cytokine-induced CD4(+)CD25(hi)FOXP3(+) cells exerted only weak suppressor activity. Thus, the current study has demonstrated that IL-15 acts as a potent inducer of CD4(+)CD25(hi)FOXP3(+) cells in the periphery, and suggests a potential role for IL-15 in blunting immune activation. This study has provided further insights into the pleiotropic nature of IL-15 beyond the regulation of CD8(+) T cells.

Background. Intermittent interleukin (IL)-2 administration to human immunodeficiency virus (HIV)-infected patients leads to CD4 + T cell expansions. The factors potentially affecting these expansions were investigated in the present study. Methods. A matched (for baseline CD4 + T cell count) case-control study was designed. Nonresponders (NRs) were defined as patients with a ≤10% increase in CD4+ T cell count 2 months after the third IL-2 cycle (week 24), compared with that at baseline (week 0). Control subjects experienced a ≥50% increase in CD4 + T cell count at week 24. Immunophenotype, Ki67 and forkhead box protein P3 (FoxP3) expression, and T cell receptor excision circle (TREC) measurements in T cells were evaluated at weeks 0 and 24 in both groups. Results. Control subjects and NRs did not differ significantly at baseline in age, viral load, CD4+ T cell count, nadir CD4 + T cell count, or CD8 + T cell count. At week 0, NRs had lower TREC levels per 1 X 10 6 T cells and higher levels of T cell proliferation and activation than did control subjects. At week 24, both groups experienced decreases in T cell proliferation and increases in CD25 and FoxP3 expression on CD4 + T cells, with TREC levels per 1 X 10 6 CD4 + T cells decreasing significantly only in control subjects. Conclusions. Increased immune activation can adversely affect CD4+ T cell expansions after IL-2 administration. Despite the lack of expansion, other evidence of IL-2-induced biological activity was observed.

BACKGROUND The interleukin-7 (IL-7)/IL-7 receptor alpha (IL-7Ralpha) system is an important regulator of T-cell homeostasis. We evaluated the IL-7/IL-7Ralpha system in a large cohort of HIV-infected patients, including a subset treated with intermittent IL-2. METHODS IL-7 serum levels and CD127 (IL-7Ralpha) expression on T cells were evaluated in a cross-sectional study of 36 healthy volunteers, 151 HIV-infected patients, and 83 HIV-infected patients who had received IL-2 therapy. Multivariate regression models were used to determine predictors of CD127 expression. RESULTS HIV-infected patients had higher IL-7 levels compared with healthy volunteers (P = 0.022) and IL-2-treated patients (P = 0.012). CD127 expression was significantly lower on CD4 and CD8 T cells of HIV-infected patients compared with healthy volunteers (P = 0.008 and P < 0.001, respectively), and CD127 median fluorescence intensity was lowest on CD4 T cells in IL-2-treated patients (P < 0.001 compared with HIV-infected patients). The proportion of naive and effector memory/effector T cells were significant predictors of CD127 expression on T cells. IL-2 immunotherapy led to the expansion of a CD25/CD127-low subset of CD4 T cells. CONCLUSIONS CD127 expression on T cells remains low in HIV-infected patients despite antiretroviral therapy, reflecting persistent aberration in the subset composition of the T-cell pool.

Both naïve CD4+and naïve CD8+T cells are depleted in individuals with human immunodeficiency virus type 1 (HIV-1) infection by unknown mechanisms. Analysis of their dynamics prior to and after highly active antiretroviral therapy (HAART) could reveal possible mechanisms of depletion. Twenty patients were evaluated with immunophenotyping, intracellular Ki67 staining, T-cell receptor excision circle (TREC) quantitation in sorted CD4 and CD8 cells, and thymic computed tomography scans prior to and ∼6 and ∼18 months after initiation of HAART. Naïve T-cell proliferation decreased significantly during the first 6 months of therapy (P< 0.01) followed by a slower decline. Thymic indices did not change significantly over time. At baseline, naïve CD4+T-cell numbers were lower than naive CD8+T-cell numbers; after HAART, a greater increase in naïve CD4+T cells than naïve CD8+T cells was observed. A greater relative change (n-fold) in the number of TREC+T cells/μl than in naïve T-cell counts was observed at 6 months for both CD4+(median relative change [n-fold] of 2.2 and 1.7, respectively;P< 0.01) and CD8+T cell pools (1.4 and 1.2;P< 0.01). A more pronounced decrease in the proliferation than the disappearance rate of naïve T cells after HAART was observed in a second group of six HIV-1-infected patients studied by in vivo pulse labeling with bromodeoxyuridine. These observations are consistent with a mathematical model where the HIV-1-induced increase in proliferation of naïve T cells is mostly explained by a faster recruitment into memory cells.

Introduction Idiopathic CD4+ Lymphocytopenia (ICL) is a rare, likely heterogeneous syndrome characterized by persistent CD4+ lymphopenia ( Methods We analyzed bone marrow core biopsies of 12 ICL patients in a phase I/IIA NIH clinical trial designed to evaluate recombinant human Interleukin-7 (rhIL-7) as a potential therapy for ICL . Subjects received 3 injections of rhIL-7 over two 24-week periods. Bone marrow biopsies were performed at week 1 and week 24 to analyze numbers of T-cells and T-cell precursors at baseline and post rhIL-7 therapy. Peripheral blood T-cell counts were assessed in parallel. Double chromogenic immunohistochemical staining using anti-terminal deoxynucleotidyl transferase (TdT) and anti-CD3 antibodies was performed on fixed, paraffin-embedded samples using an automated stainer (Ventana). Single CD3-positive T-cells and double-positive TdT/CD3 precursor T-cells were counted in at least ten consecutive fields under a light microscope and results expressed as mean positive cell number per field before and after treatment with rhIL-7. Similar staining procedure using TdT and CD79a was performed to evaluate precursor B-cells in the same patient cohort. In addition, bone marrow biopsies from 10 healthy control subjects were analyzed in parallel. Results Compared to healthy controls, ICL patients showed no significant differences in the number of bone marrow precursor T-cells (p=0.069) but had lower levels of mature T-cells (p Conclusion Novel histological technique for double chromogenic staining allows for the visualization of T-cell precursors in bone marrow biopsies. Our study revealed no evidence that lymphopenia in ICL patients is associated with lack of T-cell precursors in bone marrow, suggesting downstream defects in T-cell differentiation, proliferation or survival. Administration of rhIL-7 was associated with an increase in peripheral blood T-cells and increase in bone marrow precursor T-cells, while B-cell lineage cells remained unchanged. Disclosures No relevant conflicts of interest to declare.

Decreases in the detection of CD127 expression on T cells of human immunodeficiency virus-infected patients by flow cytometry can occur by delayed processing or by peripheral blood mononuclear cell isolation and cryopreservation. These observations should be considered in the interpretation of functional studies and the planning of multicenter clinical trials.

To evaluate the relationship between T cell turnover, immune activation, and CD4 recovery in HIV infection, 32 antiretroviral-naive HIV-1-infected patients were studied before and after initiation of highly active antiretroviral therapy (HAART). Elevated CD4 and CD8 T cell turnover (measured by Ki67) in HIV infection decreased with HAART in blood and lymphoid tissue. Increased peripheral CD4 T cell turnover was strongly associated with immune activation even after viral suppression to less than 50 copies/mL (R = 0.8; p

Cytomegalovirus retinitis successfully treated with ganciclovir implant in a patient with blood ganciclovir resistance and ocular ganciclovir sensitivity

The long-term immunologic effects of intermittent interleukin 2 (IL-2) therapy were evaluated in a cross-sectional study by comparing 3 groups: HIV-seronegative volunteers, HIV-infected (HIV(+)) patients receiving highly active antiretroviral therapy (HAART), and HIV(+) patients receiving HAART and intermittent IL-2. Whole-blood immunophenotyping was performed to study expression of the IL-2 receptor chains on T lymphocytes and natural killer cells and to further characterize CD4(+)/CD25(+) T cells. Increased CD25 expression, especially in CD4(+) T cells but also in CD8(+) T cells, without increases in expression of the beta and gamma chains of the IL-2 receptor was detected in the IL-2 group. Up to 79% of naive CD4(+) T cells (median, 61%) from patients in the IL-2 group expressed CD25, and the number of naive CD4(+)/CD25(+) T cells correlated positively with both the total and naive CD4(+) T-cell counts. A discrete population of CD45 double intermediate RA(+)/RO(+) CD4(+) cells was also preferentially expanded in the IL-2 group, and the number of these cells strongly correlated with the total CD4(+) count. Despite increases in CD25 expression, T lymphocytes from patients treated with IL-2 did not have increased expression of early (CD69) or late (CD95) activation markers or evidence of recent proliferation (Ki67). Both CD4(+)/CD25(+) and CD4(+)/CD25(-) cells from IL-2-treated HIV(+) patients proliferated in response to mitogens, specific antigens, and T-cell-receptor-mediated stimuli. Thus, intermittent administration of IL-2 in HIV(+) patients leads to preferential expansion of a unique subset of CD4(+) T cells that may represent a critical population in T-cell homeostasis.

Intermittent interleukin-2 (IL-2) therapy has been shown to increase the number of CD4+ T cells, preferentially cells with a naive phenotype, in patients with HIV infection. For this report we investigated the mechanism underlying this expansion by studying the relative roles of peripheral expansion and thymic output. In a cohort of six patients receiving IL-2 over a period of 1 year, the mean number of naive CD4+ T cells increased from 139 to 387 cells per μl while levels of T cell receptor rearrangement excision circles (TRECs) declined from 47,946 to 26,510 copies per 106naive T cells, thus making it unlikely that the CD4+ T cell count increases were secondary to increase in thymic output. To examine directly the impact of IL-2 on peripheral expansion, peripheral blood mature, naive CD4+ T cells were labeledex vivowith 5-bromodeoxyuridine as well as stained directly for Ki67. These studies revealed a 7-fold increase in the percentage of 5-bromodeoxyuridine-positive cells and a 20–40-fold increase in Ki67 staining in the naive CD4+ T cell pool in the setting of IL-2 administration. This degree of increase in mature CD4+ T cell turnover induced by IL-2 does not compromise the future replicative potential of these cells, because longitudinal measurements of telomere length went from 6,981 to 7,153 bp after 1 year of IL-2 therapy. These data strongly suggest that much of the increase in CD4+ cells associated with IL-2 treatment is caused by peripheral expansion of existing naive CD4+ T cells rather than increased thymic output and that these increases occur without compromising the potential of these cells for further cell division.

In this issue of Blood , Allers and colleagues describe the long-term follow-up of their previously reported HIV+ patient who was treated with allogeneic CCR5Δ32/Δ32 stem cell transplantation (SCT) for relapsed acute myeloid leukemia (AML).[1][1],[2][2] The patient has since remained off

Idiopathic CD4 lymphocytopenia (ICL) is a syndrome of unknown etiology characterized by low peripheral CD4 T cell counts and susceptibility to opportunistic infections. One hypothesis for its etiology is trapping of T cells in effector sites. 11 ICL patients and 16 healthy controls (HC) underwent colonic biopsies for CD3, CD4, and CD8 T cell enumeration by flow cytometry (FC) and immunohistochemistry (IHC) in lamia propria (LP). Mucosal IL17+ CD4 T cells were assessed after PMA/ionomycin stimulation. Plasma levels of LPS (for microbial translocation), I-FABP (for gut epithelial integrity), sCD14 (for monocyte activation), D-dimer (for coagulation) and CRP, IL-6 and TNFalpha (for inflammation) were tested in 33 ICL patients and 44 HC. ICL patients had fewer CD3 (2.84-fold, P=0.0080), CD4 (3.04-fold, P=0.013) and CD8 (2.28-fold, P=0.043) T cells in the colonic mucosa compared to HC by FC and fewer CD3 (2.31-fold, P=0.036) and CD4 (3.81-fold, P=0.0003) T cells in LP by IHC. The proportion of IL-17+ CD4 T cells was higher in ICL compared to HC (6.04 vs 3.35%, P=0.013). Levels of sCD14 levels were slightly higher in ICL than in HC (1.42 vs 1.21 µg/ml, P=0.003). Levels of LPS, I-FABP, IL-6, TNFalpha, D-Dimer, and CRP levels were not significantly different between ICL and HC (all P>0.05). These data suggest that colonic mucosal lymphopenia accompanies peripheral T cell lymphopenia in ICL, albeit with preserved gut epithelial integrity and a lack of systemic inflammation.

Patients with Idiopathic CD4 Lymphocytopenia (ICL) have low circulating CD4 T-cell counts and develop opportunistic diseases and papillomavirus-related dysplasia. The etiology of ICL is unknown but the low numbers of CD4 T-cells could be explained by decreased thymic production, increased cell death, and/or increased migration or retention of the T cells in secondary lymphoid organs or tissues. To distinguish between these three possibilities we set up a humanized mouse model by transferring either peripheral blood mononuclear cells (PBMC), or Hematopoietic Stem Cells (HSC) from ICL patients or healthy controls (HC) into immune-compromised mice. First, we transferred HC cells into three different strains of mice to identify the most efficient and reproducible host for the human cells. We found that NOD-RAGKO-γcKO (NRG) mice represented the best model, as one to four weeks after transferring PBMC into NRG mice, we reproducibly found human T cells in blood, spleen, lymph node and bone marrow with no graft versus host disease. We next transferred PBMC from either HC or ICL patients into NRG mice to compare survival, expansion, phenotype and migration properties of the human cells. Preliminary results show that mice that received ICL cells developed lymphocytopenia comparable to ICL patients. These data encourage further use of this humanized mouse model to identify the etiology and pathogenesis of ICL and perhaps other human immune-deficiencies that affect T-cell homeostasis.

OBJECTIVE AND DESIGN In an attempt to determine the mechanisms underlying the CD4 T cell expansions in patients receiving intermittent interleukin (IL)-2, a cohort of 10 HIV infected patients were studied during a 5-day cycle of IL-2 to measure rates of apoptosis, the expression of activation markers in CD4 and CD8 T cell subsets and the serum levels of proinflammatory cytokines. All patients were receiving highly active antiretroviral therapy. METHODS Peripheral blood mononuclear cells were tested pre- and at the completion of IL-2 treatment with annexin V/7-AAD for the measurement of apoptosis. Phenotypic analyses of T lymphocytes were performed in parallel. Serum levels of interferon (IFN)gamma, granulocyte-macrophage colony stimulating factor, IL-6 and tumor necrosis factor (TNF)alpha were tested by enzyme-linked immunosorbent assay. RESULTS IL-2 increased the spontaneous apoptosis rates of CD4 and CD8 T lymphocytes (P = 0.003). Expression of HLA-DR, CD38 and CD95 increased on both CD4 and CD8 T lymphocytes whereas CD25 induction was observed exclusively on CD4 T cells. Significant increases of serum IL-6 and TNFalpha levels were noted in all patients whereas viral loads remained unchanged. CONCLUSION Administration of IL-2 for 5 days in HIV infected patients leads to enhanced apoptosis of both CD4 and CD8 T cells despite an eventual increase of the CD4 T cell count. A profound activation state with induction of activation markers on T cells and high levels of TNFalpha and IL-6 accompanies the increased apoptosis during the IL-2 cycle. These data suggest that the CD4 expansions seen in the context of intermittent IL-2 therapy are the net result of increases in both cell proliferation and cell death.

In this issue of Blood , Scott-Algara and colleagues describe decreased surface expression with intracellular accumulation of CXCR4 in CD4+ T cells of 6 patients with ICL.[1][1] This was associated with decreased migratory responses to CXCL12 and was restored by both in vitro and in vivo IL-2. In

Expression of the alpha chain of the interleukin 2 receptor on T lymphocytes is restricted, increasing in the setting of activation, particularly after antigenic stimulation via the TCR. The effects of IL-2 in vitro on the expression of CD25 and proliferation as well as the cytokine induction in CD25-depleted T cells were studied. CD25-depleted and PBMC of healthy donors were cultured for 7 days with 0, 10, or 100 IU/ml of IL-2. Phenotypic analysis and measurement of cytokines in the culture supernatants were performed. IL-2 led to a dose-dependent induction of the IL-2R alpha chain on both CD4 and CD8 T lymphocytes. In the CD25-depleted cultures, IL-2 treatment (100 IU/ml) increased the percentage of CD4 T cells expressing CD25 by 30.6% (P = 0.05) and of CD8 T cells by 48.2% (P = 0.01) on day 7 compared to no treatment. In the PBMC cultures the increase on day 7 was 36.4% for CD4 (P = 0.01) and 50.8% (P = 0.025) for CD8 T lymphocytes. The patterns of cytokine induction in the CD25-depleted and control cultures were similar with increases of IFN-gamma, GM-CSF, IL-16, TNF alpha, and soluble IL-2 receptor in the IL-2-containing cultures. CFSE experiments demonstrated the proliferative capacity of both CD25-positive and -negative T cells. Interleukin 2 alone can lead to a dose-dependent induction of the alpha chain of its receptor on resting CD4 and CD8 T lymphocytes. IL-2 as a sole stimulant is also associated with generation of a cytokine milieu that includes IFN-gamma, GM-CSF, IL-16, and TNF alpha.

TPS10595 Background: Kaposi sarcoma (KS) is a multicentric angioproliferative tumor seen most frequently in people with HIV. It is caused by the gammaherpesvirus Kaposi-sarcoma associated herpesvirus (KSHV, or human herpesvirus 8) and is remarkable for its tendency to progress or regress based on host immune factors. Pomalidomide is an orally available third generation thalidomide derivative with immunomodulatory and antiangiogenic properties that may address unmet clinical needs in KS. Methods: The primary objective is to assess the safety, tolerability and pharmacokinetics of pomalidomide in subjects with KS, whether HIV associated or not, and to explore its antitumor effect at the tolerable dose once determined. This is the first assessment of this agent in patients with HIV and/or KS. Subjects with confirmed KS and no symptomatic pulmonary or visceral KS are eligible. Those with HIV must be compliant with HAART; have achieved an HIV viral load

Background: The incidence, manifestations, outcome and clinical predictors of paradoxical TB-IRIS in patients with HIV and culture confirmed pulmonary tuberculosis (PTB) in India have not been studied prospectively. Methods: HIV+ patients with culture confirmed PTB started on anti-tuberculosis therapy (ATT) were followed prospectively after anti-retroviral therapy (ART) initiation. Established criteria for IRIS diagnosis were used including decline in plasma HIV RNA at IRIS event. Pre-ART plasma levels of interleukin (IL)-6 and C-reactive protein (CRP) were measured. Univariate and multivariate logistic regression models were used to evaluate associations between baseline variables and IRIS. Results: Of 57 patients enrolled, 48 had complete follow up data. Median ATT-ART interval was 28 days (interquartile range, IQR 14–47). IRIS events occurred in 26 patients (54.2%) at a median of 11 days (IQR: 7–16) after ART initiation. Corticosteroids were required for treatment of most IRIS events that resolved within a median of 13 days (IQR: 9–23). Two patients died due to CNS TB-IRIS. Lower CD4 + T-cell counts, higher plasma HIV RNA levels, lower CD4/CD8 ratio, lower hemoglobin, shorter ATT to ART interval, extra-pulmonary or miliary TB and higher plasma IL-6 and CRP levels at baseline were associated with paradoxical TB-IRIS in the univariate analysis. Shorter ATT to ART interval, lower hemoglobin and higher IL-6 and CRP levels remained significant in the multivariate analysis. Conclusion: Paradoxical TB–IRIS frequently complicates HIV-TB therapy in India. IL-6 and CRP may assist in predicting IRIS events and serve as potential targets for immune interventions.

Despite the major advances in the management of HIV infection, HIV-infected patients still have greater morbidity and mortality than the general population. Serious non-AIDS events (SNAEs), including non-AIDS malignancies, cardiovascular events, renal and hepatic disease, bone disorders and neurocognitive impairment, have become the major causes of morbidity and mortality in the antiretroviral therapy (ART) era. SNAEs occur at the rate of 1 to 2 per 100 person-years of follow-up. The pathogenesis of SNAEs is multifactorial and includes the direct effect of HIV and associated immunodeficiency, underlying co-infections and co-morbidities, immune activation with associated inflammation and coagulopathy as well as ART toxicities. A number of novel strategies such as ART intensification, treatment of co-infection, the use of anti-inflammatory drugs and agents that reduce microbial translocation are currently being examined for their potential effects in reducing immune activation and SNAEs. However, currently, initiation of ART before advanced immunodeficiency, smoking cessation, optimisation of cardiovascular risk factors and treatment of HCV infection are most strongly linked with reduced risk of SNAEs or mortality. Clinicians should therefore focus their attention on addressing these issues prior to the availability of further data.

Idiopathic CD4 lymphocytopenia (ICL) is a presumed heterogenous syndrome with key element low CD4 T-cell counts (below 300/mm3) without evidence of HIV infection or other known immunodeficiency. The etiology, pathogenesis, and management of ICL remain poorly understood and inadequately defined. The clinical presentation can range from serious opportunistic infections to incidentally diagnosed asymptomatic individuals. Cryptococcal and non-tuberculous mycobacterial infections and progressive multifocal leukoencephalopathy are the most significant presenting infections, although the spectrum of opportunistic diseases can be similar to that in patients with lymphopenia and HIV infection. Malignancy is common and related to opportunistic pathogens with an oncogenic potential. Autoimmune diseases are also seen in ICL with an increased incidence. The etiology of ICL is unknown. Mechanisms implicated in CD4 reduction may include decreased production, increased destruction, and tissue sequestration. New distinct genetic defects have been identified in certain patients with ICL, supporting the hypothesis of the lack of a common etiology in this syndrome. The management of ICL is focused on the treatment of opportunistic infections, appropriate prophylactic antibiotics, and close monitoring. In selected patients with life-threatening infections or profound immunodeficiency, strategies to increase T-cell counts or enhance immune function could be considered and have included interleukin-2, interferon-gamma, interleukin-7, and hematopoietic stem cell transplantation. The prognosis is influenced by the accompanying opportunistic infections and may be affected by publication bias of severe cases with unfavorable outcomes. As newer laboratory investigation techniques are being developed and targeted experimental treatments become available, our comprehension and prognosis of this rare syndrome could be significantly improved.

The authors regret that a typographical error in the above-referenced article incorrectly lists the units for C-reactive protein (CRP) as “mg/L” rather than “mg/dL” in the Abstract, the Results section under the subheading “Biomarkers in IRIS patients at baseline (pre-ART),” and in Figures 1a, 2b, and 2d. CRP units are correctly given as “mg/dL” in the Methods section. Clarification of this error does not alter any aspect of the data analysis or conclusions of the article.

The persistence and roles of memory T cells with effector capability have been questioned. We analyzed human memory CD4+ T cells from peripheral blood defined by their expression of chemokine receptors CCR5 and CCR2, the principal subsets being CCR5−CCR2−, CCR5+CCR2−, and CCR5+CCR2+. CCR2+ cells co-expressed the most chemokine receptor types (up to six) and migrated to the greatest number of chemokines, followed by CCR5+CCR2− cells. Numbers of T cell receptor gene excision circles were CCR5−CCR2− > CCR5+CCR2− > CCR5+CCR2+. The CCR2+ cells were those most readily activated through TCR but showed reduced proliferative potential, were enriched in cells responding to a remote immunogen, secreted high levels of effector cytokines, and were resistant to apoptosis. By contrast, the CCR5+CCR2− population was enriched in recently activated/cycling cells and Treg, and was more susceptible to apoptosis. The data suggest that patterns of CCR5 and CCR2 expression separate effector- vs. memory-cell enriched CD4+ subsets, and that CCR2 marks highly differentiated, long-lived memory cells with effector capabilities. The data also suggest co-ordination among a memory cell’s position on a unidirectional pathway of differentiation, ability to be recruited into tissue, and threshold for activation/effector function, with the most chemokine-responsive cells being best equipped as first responders in a recall response.

IL-15 is a member of the cytokine family that utilizes a common γ chain. While initially characterized as a T cell growth factor, predominantly involved in CD8+ T cell proliferation and survival, IL-15 is a pleiotropic cytokine that can affect both innate and adaptive immune responses. In the present study, we demonstrate that IL-15 increases expression of the alpha chain of the IL-2 receptor (CD25) and foxP3, a master control gene for the development and function of regulatory T cells, in human peripheral CD4+CD25− T cells without a need for additional antigenic stimulation signals. Side-by-side comparisons involving two other γc-cytokines: IL-2 and IL-7 revealed that the induction of CD25high and foxP3 expression was most prominent with IL-15 (median-fold increase: 46 and 53, respectively for CD25high and foxP3, p=0.0005) and IL-2 (32 and 42, p=0.0004). More modest effects were seen with IL-7 (18 and 12, p=0.0105). Despite levels of foxP3 expression comparable to that of conventional Tregs, these cytokine-induced CD4+CD25+foxP3+ cells exerted only weak suppressor activity. The current study has uncovered an unexpected function of IL-15 in the induction of CD4+CD25+foxP3+ cells from human peripheral T cells, thus helped to delineate and provided further insights into the pleiotropic nature of IL-15 beyond the regulation of CD8+ T cells. Funded in part by NCI Contract N01-CO-12400.

To determine the immunological profile most important for IRIS prediction, we evaluated 20 baseline plasma biomarkers in Acquired Immunodeficiency Syndrome (AIDS) patients initiating antiretroviral therapy (ART). Patients were enrolled in a randomized, placebo-controlled ART initiation trial in South Africa and Mexico to test whether maraviroc could prevent IRIS. Participants were classified prospectively as having IRIS within 6months of ART initiation. Twenty plasma biomarkers were measured at study enrollment for 267 participants. Biomarkers were tested for predicting IRIS with adjustment for covariates chosen through forward stepwise selection. Sixty-two participants developed IRIS and of these 19 were tuberculosis (TB)-IRIS. Baseline levels of vitamin D and higher d-dimer, interferon gamma (IFNγ), and sCD14 were independently associated with risk of IRIS in multivariate analyses. TB-IRIS cases exhibited a distinct biosignature from IRIS related to other pathogens, with increased levels of C-reactive protein (CRP), sCD14, IFNγ, and lower levels of Hb that could be captured by a composite risk score. Elevated markers of Type 1 T helper (Th1) response, monocyte activation, coagulation and low vitamin D were independently associated with IRIS risk. Interventions that decrease immune activation and increase vitamin D levels warrant further study.

Background Appendicitis occurs with increased frequency in HIV infected compared to HIV uninfected persons. CMV-related appendicitis specifically presents with typical appendicitis symptoms including surgical abdomen, fever and leukocytosis and may have a more severe course with higher mortality than other types of infective appendicitis. We report the first case of CMV appendicitis as a manifestation of Immune Reconstitution Inflammatory Syndrome (IRIS). Case presentation The patient was a 38 year old woman with a recent diagnosis of HIV infection who complained of right lower quadrant pain, anorexia, nausea and fevers two weeks after initiating antiretroviral therapy. Acute appendicitis was suspected and the patient underwent an appendectomy. Pathologic examination of the resected appendiceal tissue demonstrated inflammation with perforation and cytopathic changes typical of CMV that were positive for CMV by immunostain. This presentation of CMV abruptly after antiretroviral therapy initiation with a pronounced cellular infiltration of the tissue, is consistent with CMV-IRIS presenting as appendicitis. Conclusions Appendicitis can be a rare manifestation of CMV-IRIS in HIV-infected patients who start antiretroviral therapy. Evaluation of appendiceal tissue for cytopathic changes and CMV should be considered in acute appendicitis in HIV infected persons.