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1.  Elevated Interleukin 8 and T-Helper 1 and T-Helper 17 Cytokine Levels Prior to Antiretroviral Therapy in Participants Who Developed Immune Reconstitution Inflammatory Syndrome During ACTG A5164 
The Journal of Infectious Diseases  2012;206(11):1715-1723.
Background. Immune reconstitution inflammatory syndrome (IRIS) reflects an aberrant immune response that can develop in human immunodeficiency virus–infected patients initiating antiretroviral therapy (ART). Its pathogenesis remains unclear.
Methods. We performed a nested case-control study using specimens from ACTG A5164. We compared plasma biomarkers and T-cell subsets in 19 IRIS and 39 control participants at study entry, ART initiation, and IRIS and used conditional logistic regression to develop IRIS predictive models. We evaluated the effect of corticosteroids on biomarker levels.
Results. Eleven and 8 participants developed paradoxical and unmasking IRIS, respectively, none while still receiving corticosteroids. Compared to controls, cases displayed elevations at study entry in interleukin (IL) 8, T-helper (Th) 1 (IL-2, interferon [IFN]-γ, tumor necrosis factor [TNF]) and Th17 (IL-17) cytokine levels that persisted through ART initiation and IRIS. In logistic regression, baseline higher IFN-γ and TNF were strong predictors of IRIS. Participants who received corticosteroids and later developed IRIS had marked increases in IL-6, IL-8, and IFN-γ at the time of IRIS. T-cell activation markers did not differ in cases and controls prior to ART but were increased in cases at the time of IRIS.
Conclusions. Increased IL-8, Th1, and Th17 cytokine levels in IRIS patients precede ART initiation and could help identify patient populations at higher risk for IRIS.
doi:10.1093/infdis/jis604
PMCID: PMC3488199  PMID: 23002445
2.  Host Gene Expression Changes Correlating With Anti–HIV-1 Effects in Human Subjects After Treatment With Peginterferon Alfa-2a 
The Journal of Infectious Diseases  2012;205(9):1443-1447.
We investigated whether interferon-inducible genes (IFIGs) with known anti–human immunodeficiency virus (HIV) activity in vitro were associated with in vivo virological response in HIV infection. Nine untreated HIV-1–infected volunteers were treated for 12 weeks with peginterferon alfa-2a. A subset of IFIGs (23 of 47) increased compared with baseline through 6 weeks beyond therapy, and 10 of the 23 IFIGs significantly inversely correlated (r = −0.7; P < .05) with virological response. The strength of peginterferon alfa-2a–induced IFIG response significantly correlated with declines in HIV load during treatment (r2 = 0.87, p = .003). This study links HIV virological response to a specific IFIG subset, a potential prognostic indicator in peginterferon alfa-2a–treated patients with HIV infection.
doi:10.1093/infdis/jis211
PMCID: PMC3324397  PMID: 22454462
3.  Replication Capacity in Relation to Immunologic and Virologic Outcomes in HIV-1 infected, Treatment-Naïve Subjects 
Objectives
To evaluate the association between baseline (BL) replication capacity (RC) [RCBL] and immunologic/virologic parameters (at BL and after 48 weeks on therapy) in HIV-1 infected subjects initiating antiretroviral therapy.
Methods
RCBL was determined using a modified Monogram PhenoSense HIV drug susceptibility assay on plasma HIV-1 from 321 treatment-naïve subjects from ACTG384. Univariate and multivariable analyses were performed to determine the association of RCBL with BL and on-therapy virologic and immunologic outcomes.
Results
Higher RCBL was associated with lower baseline CD4 (CD4BL) (r=−0.23, p<0.0001), higher baseline HIV-1 (RNABL) (r=0.25, p<0.0001), higher CD4BL activation percent (r=0.23, p<0.0001) and lower CD4BL memory count (r=−0.21, p=0.0002).
In a multivariable model, week 48 CD4 increase (ΔCD448) was associated with lower CD4BL memory count and higher CD4BL naive percent (p=0.004, p=0.015, respectively). The interaction between CD4BL and RCBL was significant (p=0.018), with a positive association between RCBL and ΔCD448 in subjects with higher CD4BL, and a negative association at lower absCD4BL.
Conclusions
At baseline, higher RC was significantly associated with higher HIV-1 RNA, higher CD4 cell activation, lower CD4 cell count, and lower CD4 memory cell count. These factors may interact, directly or indirectly, to modify the extent to which CD4 recovery occurs in patients starting antiretroviral therapy at different baseline CD4 counts.
doi:10.1097/QAI.0b013e3181938faf
PMCID: PMC3482469  PMID: 19194319
HIV; replication capacity; viral fitness; pathogenesis; immune reconstitution; activation; memory
4.  Randomized pilot trial of a synbiotic dietary supplement in chronic HIV-1 infection 
Background
Infection with HIV-1 results in marked immunologic insults and structural damage to the intestinal mucosa, including compromised barrier function. While the development of highly active antiretroviral therapy (HAART) has been a major advancement in the treatment of HIV-1 infection, the need for novel complementary interventions to help restore intestinal structural and functional integrity remains unmet. Known properties of pre-, pro-, and synbiotics suggest that they may be useful tools in achieving this goal.
Methods
This was a 4-week parallel, placebo-controlled, randomized pilot trial in HIV-infected women on antiretroviral therapy. A synbiotic formulation (Synbiotic 2000®) containing 4 strains of probiotic bacteria (1010 each) plus 4 nondigestible, fermentable dietary fibers (2.5 g each) was provided each day, versus a fiber-only placebo formulation. The primary outcome was bacterial translocation. Secondary outcomes included the levels of supplemented bacteria in stool, the activation phenotype of peripheral T-cells and monocytes, and plasma levels of C-reactive protein and soluble CD14.
Results
Microbial translocation, as measured by plasma bacterial 16S ribosomal DNA concentration, was not altered by synbiotic treatment. In contrast, the synbiotic formulation resulted in significantly elevated levels of supplemented probiotic bacterial strains in stool, including L. plantarum and P. pentosaceus, with the colonization of these two species being positively correlated with each other. T-cell activation phenotype of peripheral blood lymphocytes showed modest changes in response to synbiotic exposure, with HLA-DR expression slightly elevated on a minor population of CD4+ T-cells which lack expression of HLA-DR or PD-1. In addition, CD38 expression on CD8+ T-cells was slightly lower in the fiber-only group. Plasma levels of soluble CD14 and C-reactive protein were unaffected by synbiotic treatment in this study.
Conclusions
Synbiotic treatment for 4 weeks can successfully augment the levels of probiotic species in the gut during chronic HIV-1 infection. Associated changes in microbial translocation appear to be absent, and markers of systemic immune activation appear largely unchanged. These findings may help inform future studies aimed at testing pre- and probiotic approaches to improve gut function and mucosal immunity in chronic HIV-1 infection.
Trial registration
Clinical Trials.gov: NCT00688311
doi:10.1186/1472-6882-12-84
PMCID: PMC3414771  PMID: 22747752
Human immunodeficiency virus-1 (HIV-1); synbiotics; probiotics; prebiotics; microbial translocation; immune activation; highly active antiretroviral therapy (HAART); combined antiretroviral therapy (CART); complementary therapy.
5.  HIV-1 viruses detected during episodic blips following IL-7 administration are similar to the viruses present before and after IL-7 therapy 
AIDS (London, England)  2011;25(2):159-164.
Background
Administration of recombinant human (rh) interleukin (IL)-7 leads to CD4 and CD8 T cell expansions in HIV-infected individuals, demonstrating promising capacity for immune reconstitution. However, a proportion of patients treated with rhIL-7 experience transient increases in plasma HIV-RNA (“blips”), possibly reflecting “purging” of a quiescent reservoir that provides a barrier to viral eradication.
Objective
To identify the sources of HIV detected during transient viremic episodes following IL-7 administration, viral quasispecies were analyzed in a total of 281 primary sequences derived from 7 patients who experienced the episodic blips following IL-7 therapy.
Method
The C2-V3 region of the HIV-1 env gene were sequenced from HIV-1 RNA in plasma and HIV DNA from peripheral blood mononuclear cells (PBMCs) obtained at baseline (day 0 of rhIL-7 therapy), during the episode of viral blips (day 4), and at a time when levels of plasma HIV-RNA had returned to less than 50 copies/ml (day 28).
Results
The HIV sequences detected during transient viremia following IL-7 administration were closely related to those of the plasma viruses present before and after cytokine administration. All virus quasispecies detected during blips were also present in proviral sequences in PBMCs.
Conclusion
The low level viremia induced by IL-7 likely reflects predominantly transient induction or release of virus from a pre-existing pool rather than activation of silent quasispecies.
doi:10.1097/QAD.0b013e328340a270
PMCID: PMC3074174  PMID: 21124203
HIV-1; quasispecies; IL-7; transient HIV viremia; virus reservoir
6.  Safety, Tolerability and Mechanisms of Antiretroviral Activity of Peginterferon alfa-2a in HIV-1-Mono-infected Subjects: A Phase II Clinical Trial 
The Journal of infectious diseases  2010;201(11):1686-1696.
Background
The antiviral activity of pegylated interferon-alpha-2a has not been studied in untreated HIV-1-infected subjects without chronic hepatitis C virus (HCV) infection.
Methods
Untreated HIV-1-infected volunteers without HCV received weekly pegylated interferon alfa-2a (180 μg) for twelve weeks. Changes in HIV-1 RNA (pVL), CD4+ T-cell counts, pharmacokinetics, pharmacodynamic measurements of 2’,5’ oligoadenylate synthetase (OAS) activity, and induction of interferon inducible genes (IFIG) were measured. Nonparametric statistical analysis was performed.
Results
Eleven subjects completed 12 weeks of therapy. Median pVL decline and change in CD4 T-cell counts at week 12 were 0.61 log10 cp/mL [90% CI:0.20,1.18] and −44 (− 95, 85) cells/mm3, respectively. There was no correlation between pVL declines and concurrent pegylated interferon plasma concentrations. However, subjects with larger increases in OAS exhibited greater decreases in pVL at weeks 1 and 2 (estimated Spearman correlations -0.75 [-0.93,-0.28]) and -0.61 [-0.87,-0.09], respectively). Subjects with higher baseline IFIG levels had smaller week 12 declines in pVL (0.66[0.06,0.91]), while those with larger IFIG induction exhibited larger declines in pVL (-0.74 [-0.93,-0.21]).
Conclusion
Pegylated interferon alfa-2a was well tolerated and had significant anti-HIV-1 activity in HIV-1-monoinfected patients. The anti-HIV-1 effect correlated with OAS protein (weeks 1 and 2) and IFIG induction (week 12), but not with pegylated interferon concentrations.
doi:10.1086/652420
PMCID: PMC2946345  PMID: 20420510
7.  Incomplete Reconstitution of T Cell Subsets on Combination Antiretroviral Therapy in the AIDS Clinical Trials Group Protocol 384 
Background
Initiation of combination antiretroviral therapy (ART) results in higher total CD4 cell counts, a surrogate for immune reconstitution. Whether the baseline CD4 cell count affects reconstitution of immune cell subsets has not been well characterized.
Methods
Using data from 978 patients (621 with comprehensive immunological assessments) from the AIDS [Acquired Immunodeficiency Syndrome] Clinical Trials Group protocol 384, a randomized trial of initial ART, we compared reconstitution of CD4+, CD4+ naive and memory, CD4+ activation, CD8+, CD8+ activation, B, and natural killer cells among patients in different baseline CD4+ strata. Reference ranges for T cell populations in control patients negative for human immunodeficiency virus (HIV) infection were calculated using data from AIDS Clinical Trials Group protocol A5113.
Results
Patients in the lower baseline CD4+ strata did not achieve total CD4+ cell counts similar to those of patients in the higher strata during 144 weeks of ART, although CD4+ cell count increases were similar. Ratios of CD4+ naive-memory cell counts and CD4+:CD8+ cell counts remained significantly reduced in patients with lower baseline CD4+ cell counts (≤350 cells/mm3). These immune imbalances were most notable for those initiating ART with a baseline CD4+ cell count ≤200 cells/mm3, even after adjustment for baseline plasma HIV RNA levels.
Conclusions
After nearly 3 years of ART, T cell subsets in patients with baseline CD4+ cell counts >350 cells/mm3 achieved or approached the reference range those of control individuals without HIV infection. In contrast, patients who began ART with ≤350 CD4+ cells/mm3 generally did not regain normal CD4+ naive-memory cell ratios. These results support current guidelines to start ART at a threshold of 350 cells/mm3 and suggest that there may be immunological benefits associated with initiating therapy at even higher CD4+ cell counts.
doi:10.1086/595888
PMCID: PMC2676920  PMID: 19123865
8.  Quantitative 3D Video Microscopy of HIV Transfer Across T Cell Virological Synapses 
Science (New York, N.Y.)  2009;323(5922):1743-1747.
The spread of HIV between immune cells is greatly enhanced by cell-cell adhesions called virological synapses, although the underlying mechanisms have been unclear. With use of an infectious, fluorescent clone of HIV, we tracked the movement of Gag in live CD4 T cells and captured the direct translocation of HIV across the virological synapse. Quantitative, high-speed three-dimensional (3D) video microscopy revealed the rapid formation of micrometer-sized “buttons” containing oligomerized viral Gag protein. Electron microscopy showed that these buttons were packed with budding viral crescents. Viral transfer events were observed to form virus-laden internal compartments within target cells. Continuous time-lapse monitoring showed preferential infection through synapses. Thus, HIV dissemination may be enhanced by virological synapse-mediated cell adhesion coupled to viral endocytosis.
doi:10.1126/science.1167525
PMCID: PMC2756521  PMID: 19325119
9.  Multifunctional Human Immunodeficiency Virus (HIV) Gag-Specific CD8+ T-Cell Responses in Rectal Mucosa and Peripheral Blood Mononuclear Cells during Chronic HIV Type 1 Infection▿  
Journal of Virology  2007;81(11):5460-5471.
The intestinal tract is a lymphocyte-rich site that undergoes severe depletion of memory CD4+ T cells within days of simian immunodeficiency virus or human immunodeficiency virus type 1 (HIV-1) infection. An ensuing influx of virus-specific CD8+ T cells, which persist throughout the chronic phase of infection, has also been documented in the gastrointestinal tract. However, little is known of the functionality of these effector cells or their relationship to the disease course. In this study, we measured CD8+ T-cell responses to HIV-1 peptides in paired rectal and blood samples from chronically infected patients. In both blood and rectum, there was an immunodominant CD8+ T-cell response to HIV Gag compared to Pol and Env (P < 0.01). In contrast, cytomegalovirus pp65 peptides elicited gamma interferon (IFN-γ) secretion strongly in peripheral blood mononuclear cells (PBMC) but weakly in rectal CD8+ T cells (P = 0.015). Upon stimulation with HIV peptides, CD8+ T cells from both sites were capable of mounting complex responses including degranulation (CD107 expression) and IFN-γ and tumor necrosis factor alpha (TNF-α) production. In rectal tissue, CD107 release was frequently coupled with production of IFN-γ or TNF-α. In patients not on antiretroviral therapy, the magnitude of Gag-specific responses, as a percentage of CD8+ T cells, was greater in the rectal mucosa than in PBMC (P = 0.054); however, the breakdown of responding cells into specific functional categories was similar in both sites. These findings demonstrate that rectal CD8+ T cells are capable of robust and varied HIV-1-specific responses and therefore likely play an active role in eliminating infected cells during chronic infection.
doi:10.1128/JVI.02535-06
PMCID: PMC1900284  PMID: 17344302
10.  Oral serum-derived bovine immunoglobulin improves duodenal immune reconstitution and absorption function in patients with HIV enteropathy 
AIDS (London, England)  2013;27(14):2207-2217.
Objectives:
To examine the impact of serum-derived bovine immunoglobulin, an oral medical food known to neutralize bacterial antigen and reduce intestinal inflammation, on restoration of mucosal immunity and gastrointestinal function in individuals with HIV enteropathy.
Design:
Open-label trial with intensive 8-week phase of bovine serum immunoglobulin (SBI) 2.5 g twice daily with a 4-week washout period and an optional 9-month extension study.
Methods:
HIV enteropathy was defined as chronic gastrointestinal symptoms including frequent loose or watery stools despite no identifiable, reversible cause. Upper endoscopy for tissue immunofluorescent antibody assay and disaccharide gut permeability/absorption studies were performed before and after 8 weeks of SBI to test mucosal immunity and gastrointestinal function. Blood was collected for markers of microbial translocation, inflammation, and collagen kinetics. A validated gastrointestinal questionnaire assessed changes in symptoms.
Results:
All eight participants experienced profound improvement in symptoms with reduced bowel movements/day (P = 0.008) and improvements in stool consistency (P = 0.008). Gut permeability was normal before and after the intervention, but d-xylose absorption increased in seven of eight participants. Mucosal CD4+ lymphocyte densities increased by a median of 139.5 cells/mm2 from 213 to 322 cells/mm2 (P = 0.016). Intestinal-fatty acid binding protein (I-FABP), a marker of enterocyte damage, initially rose in seven of eight participants after 8 weeks (P = 0.039), and then fell below baseline in four of five who continued receiving SBI (P = 0.12). Baseline serum I-FABP levels were negatively correlated with subsequent rise in mucosal CD4+ lymphocyte densities (r = −0.74, P = 0.046).
Conclusion:
SBI significantly increases intestinal mucosal CD4+ lymphocyte counts, improves duodenal function, and showed evidence of promoting intestinal repair in the setting of HIV enteropathy.
doi:10.1097/QAD.0b013e328362e54c
PMCID: PMC3754419  PMID: 23660579
bovine immunoglobulin; d-xylose absorption; gastrointestinal associated lymphoid tissue; gut permeability; HIV enteropathy; immune reconstitution; immunohistochemistry; intestinal fatty acid binding protein; monocyte chemotaxis protein-1
11.  Molecular Characterization of Stool Microbiota in HIV-Infected Subjects by Panbacterial and Order-Level 16S Ribosomal DNA (rDNA) Quantification and Correlations with Immune Activation 
Background
The relationship between gut microbial community composition at the higher-taxonomic order-level and local and systemic immunologic abnormalities in HIV disease may provide insight into how bacterial translocation impacts HIV disease.
Methods
Antiretroviral (ART)-naive HIV patients underwent upper endoscopy before and nine months after starting ART. Duodenal tissue was paraffin-embedded for immunohistochemical analysis (IHC) and digested for FACS for T-cell subsets and immune activation (CD38+/HLA-DR+) enumeration. Stool samples were provided from patients and controls for comparison. Metagenomic microbial DNA was extracted from feces for optimized 16S ribosomal RNA gene (rDNA) real-time qPCR assays designed to quantify panbacterial loads and the relative abundances of proinflammatory Enterobacteriales order, and the dominant Bacteroidales and Clostridiales orders.
Results
Samples from 10 HIV-subjects prior to initiating, and from 6 subjects receiving, ART were available for analysis. There was a trend for a greater proportion of Enterobacteriales in HIV-positive subjects compared to controls (p=0.099). There were significant negative correlations between total bacterial load and duodenal CD4+ and CD8+ T-cell activation levels (r= −0.74, p= 0.004 and r= −0.67, p=0.013, respectively). The proportions of Enterobacteriales and Bacteroidales were significantly correlated with duodenal CD4+ T-cell depletion and peripheral CD8+ T-cell activation, respectively.
Conclusions
These data represent the first report of quantitative molecular and cellular correlations between total/universal and order-level gut bacterial populations and GALT levels of immune activation in HIV-infected subjects. The correlations between lower overall 16S rDNA levels and tissue immune activation suggest that the gut microbiome may contribute to immune activation and influence HIV progression.
doi:10.1097/QAI.0b013e31821a603c
PMCID: PMC3153564  PMID: 21436711
HIV infection; 16S rDNA; gastrointestinal-associated lymphoid tissue; stool; duodenal tissue; peripheral blood mononuclear cells; CD8+ T-cell; CD4+ T-lymphocyte; microbes
12.  Low sensitivity of T-cell based detection of tuberculosis among HIV co-infected Tanzanian inpatients 
East African medical journal  2008;85(9):442-449.
OBJECTIVE
To evaluate the performance of QuantiFERON-TB GOLD (QFTG) in a resource-poor setting among patients with and without HIV infection.
DESIGN
Cross-sectional study
SETTING
Two hospitals in Northern Tanzania
PARTICIPANTS
Adult male and female inpatients.
INTERVENTION
All patients were screened for HIV infection and underwent tuberculin skin test (TST) and QFTG.
RESULTS
Eighty-three subjects were enrolled, and 29 (35%) of 83 were HIV-infected. QFTG yielded indeterminate results in 12 (22%; 95%CI 12%–34%) of 54 HIV-uninfected and 13 (45%; 95%CI 26%–64%) of 29 HIV-infected subjects (p=0.0323). Among those with smear-positive pulmonary tuberculosis, TST was positive in 40 (100%; 95%CI 91%–100%) of 40 HIV-uninfected subjects compared with 7 (54%; 95%CI 25%–81%) of 13 HIV-infected subjects (p<0.0001), and QFTG was positive in 28(70%; 95%CI 53%–83%) of 40 HIV-uninfected subjects compared with 3(23%; 95%CI 5%–54%) of 13 HIV-infected subjects (p=0.0029). Among medical inpatients at risk for latent tuberculosis infection, TST was positive in 7(50%) of 14 HIV-uninfected patients and 3(19%) of 16 HIV-infected patients (p=0.0701) and QFTG was positive among 2(14%) of 14 HIV-uninfected patients and 3(19%) of 16 HIV-infected patients (p=0.7437).
CONCLUSIONS
The presence of HIV co-infection was associated with a significant reduction in sensitivity of both the TST (p<0.0001) and QFTG (p=0.0029) for the diagnosis of active M.tuberculosis infection. The high proportion of indeterminate QFTG and lack of sensitivity, particularly among HIV-infected patients, may limit its applicability in settings like Tanzania. Larger studies in resource-poor settings are required.
PMCID: PMC3168735  PMID: 19537417
HIV; Tuberculosis; Diagnosis; Blood test; Interferon/TypeII

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