Telmisartan increases vascular reparative capacity in older HIV-infected adults: a pilot study.

BackgroundEndothelial progenitor cells (EPCs) are bone marrow-derived cells that contribute to vascular repair. EPCs may be reduced in HIV-infected (HIV+) persons, contributing to cardiovascular disease (CVD). Telmisartan is an angiotensin receptor blocker that increases EPCs in HIV-uninfected adults.ObjectiveTo assess telmisartan's effects on EPC number and immunophenotype in older HIV + adults at risk for CVD.MethodsHIV + persons ≥50 years old with HIV-1 RNA < 50 copies/mL on suppressive antiretroviral therapy and ≥1 CVD risk factor participated in a prospective, open-label, pilot study of oral telmisartan 80 mg daily for 12 weeks. Using CD34 and CD133 as markers of early maturity and KDR as a marker of endothelial lineage commitment, EPCs were quantified via flow cytometry and defined as viable CD3-/CD33-/CD19-/glycophorin- cells of four immunophenotypes: CD133+/KDR+, CD34+/KDR+, CD34+/CD133+, or CD34+/KDR+/CD133+. The primary endpoint was a 12-week change in EPC subsets (NCT01578772).ResultsSeventeen participants (88% men, median age 60 years and peripheral CD4+ T lymphocyte count 625 cells/mm3) enrolled and completed the study. After 6 and 12 weeks of telmisartan, frequencies of all EPC immunophenotypes were higher than baseline (all p < 0.10 except week 12 CD133+/KDR+ EPC, p = 0.13). Participants with lower baseline EPC levels had the largest gains. Additionally, the percentage of CD34+ cells with endothelial commitment (KDR+) increased.ConclusionsOur data suggest that telmisartan use is associated with an increase in circulating EPCs in older HIV + individuals with CVD risk factors. Further controlled studies are needed to assess whether EPC increases translate to a reduction in CVD risk in this population

Low Levels of Endothelial Progenitor Cells and Their Association with Systemic Inflammation and Monocyte Activation in Older HIV-Infected Men

Endothelial progenitor cells (EPCs) repair damaged vascular endothelium, and low circulating EPC levels have been associated with cardiovascular disease (CVD). CD34+/KDR+ EPCs are commonly reported in the literature and CD34+/CD133+/KDR+ EPCs are rare in circulation but highly specific for endothelial lineage. HIV-infected (HIV+) adults have chronic inflammation and increased CVD risk, but the relationship between CVD, vascular inflammation, and EPCs in HIV remains unclear. In a pilot study, EPCs were measured in 57 HIV+ men [≥50 years old, HIV-1 RNA <50 copies/ml on antiretroviral therapy (ART)] by real-time flow cytometry using cellular immaturity (CD34 and/or CD133) and endothelial commitment (KDR) markers. Fasting inflammatory biomarker levels were measured by ELISA. Median age was 57 years; CD4+ T lymphocyte count was 570 cells/mm3. Prevalent CVD risk factors included 16% diabetes, 28% hypertension, 53% dyslipidemia, and 33% smoking. Median (interquartile range) EPC values were CD34+/KDR+ 0.1 (0.0-0.9) cells/105 peripheral blood mononuclear cells (PBMCs) and CD34+/CD133+/KDR+ 0.1 (0.0-0.9) cells/105 PBMCs. We observed a high prevalence of undetectable CD34+/KDR+ (40%) and CD34+/CD133+/KDR+ EPCs (44%). Men with undetectable EPCs were more likely to have ≥2 CVD risk factors, lower interleukin-6 (IL-6), and higher sCD163 levels. In these older HIV+ men on suppressive ART, CD34+/KDR+ and CD34+/CD133+/KDR+ EPC levels were low and often undetectable. Undetectable EPC levels were associated with greater CVD risk factor burden, lower IL-6 (consistent with decreased EPC production stimulus), and higher sCD163 (consistent with monocyte activation and prior CVD associations) levels, suggesting a potential relationship between EPCs and atherosclerotic burden in this population

Genetic Diversity within Alphaherpesviruses: Characterization of a Novel Variant of Herpes Simplex Virus 2.

International audienceVery low levels of variability have been reported for the herpes simplex virus 2 (HSV-2) genome. We recently described a new genetic variant of HSV-2 (HSV-2v) characterized by a much higher degree of variability for the UL30 gene (DNA polymerase) than observed for the HG52 reference strain. Retrospective screening of 505 clinical isolates of HSV-2 by a specific real-time PCR assay targeting the UL30 gene led to the identification of 13 additional HSV-2v isolates, resulting in an overall prevalence of 2.8%. Phylogenetic analyses on the basis of microsatellite markers and gene sequences showed clear differences between HSV-2v and classical HSV-2. Thirteen of the 14 patients infected with HSV-2v originated from West or Central Africa, and 9 of these patients were coinfected with HIV. These results raise questions about the origin of this new virus. Preliminary results suggest that HSV-2v may have acquired genomic segments from chimpanzee alphaherpesvirus (ChHV) by recombination.This article deals with the highly topical question of the origin of this new HSV-2 variant identified in patients with HIV coinfection originating mostly from West or Central Africa. HSV-2v clearly differed from classical HSV-2 isolates in phylogenetic analyses and may be linked to simian ChHV. This new HSV-2 variant highlights the possible occurrence of recombination between human and simian herpesviruses under natural conditions, potentially presenting greater challenges for the future

Telmisartan to reduce cardiovascular risk in older HIV-infected adults: a pilot study.

BackgroundHIV-infected persons are at increased cardiovascular disease (CVD) risk, but traditional CVD therapies are understudied in this population. Telmisartan is an angiotensin receptor blocker (ARB) and peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist that improves endothelial function and cardiovascular mortality in HIV-uninfected populations. We assessed the effects of telmisartan on endothelial function in older HIV-infected persons at risk for CVD in a small pilot study.MethodsHIV-infected individuals≥50 years old on suppressive antiretroviral therapy (ART) with ≥1 traditional CVD risk factor received open-label telmisartan 80 mg daily for 6 weeks. Brachial artery flow-mediated dilation (FMD) measured endothelial function. The primary endpoint was 6-week change in maximum relative FMD.ResultsSeventeen participants enrolled; 16 completed all evaluations (88% men, 65% non-White, median age 60 years, CD4+T lymphocyte count 625 cells/mm3). Antiretroviral therapy included 71% protease inhibitor (PI), 29% non-nucleoside reverse transcriptase inhibitor (NNRTI), 29% integrase inhibitor, 65% tenofovir, and 29% abacavir. Cardiovascular disease risk factor prevalence included 76% hyperlipidemia, 65% hypertension, 18% smoking, and 12% diabetes mellitus. After 6 weeks, statistically significant blood pressure changes were observed (systolic-16.0 mmHg, diastolic-6.0 mmHg) without significant changes in FMD. In subset analyses, FMD increased more among abacavir-treated, PI-treated, and non-smoking participants.ConclusionsNo significant FMD changes were observed after 6 weeks of telmisartan therapy; however, abacavir- and PI-treated participants and non-smokers showed greater FMD increases. Additional studies are needed to explore the effects of telmisartan on endothelial function among HIV-infected individuals with traditional CVD and/or ART-specific risk factors

Long-term follow-up of HIV-infected patients once diagnosed with acyclovir-resistant herpes simplex virus infection

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Circulating LOXL2 Levels Reflect Severity of Intestinal Fibrosis and GALT CD4+ T Lymphocyte Depletion in Treated HIV Infection.

BackgroundIncomplete immune reconstitution may occur despite successful antiretroviral therapy (ART). Gut-associated lymphoid tissue (GALT) fibrosis may contribute via local CD4+ T lymphocyte depletion, intestinal barrier disruption, microbial translocation, and immune activation.MethodsIn a cross-sectional analysis, we measured circulating fibrosis biomarker levels on cryopreserved plasma from adult HIV-infected (HIV+) SCOPE study participants on suppressive ART who also had fibrosis quantification on recto-sigmoid biopsies. Relationships among biomarker levels, clinical and demographic variables, GALT lymphoid aggregate (LA) collagen deposition, and LA CD4+ T lymphocyte density were analyzed using simple regression. Biomarker levels were also compared to levels in HIV+ viremic SCOPE participants and a convenience sample of HIV-uninfected (HIV-) samples.ResultsHIV+ aviremic participants (n = 39) were 92% male and 41% non-white, with median age 48 years, CD4+ T lymphocyte count 277 cells/mm3, and 17 years since HIV diagnosis. Most biomarkers were lower in HIV- (n = 36) vs HIV+ aviremic individuals, although CXCL4 levels were higher. HIV+ viremic individuals (N = 18) had higher median TGF-β3, CIC-C1Q, and TIMP-1 (P < 0.05) and lower LOXL2 levels (P = 0.08) than HIV+ aviremic individuals. Only higher LOXL2 levels correlated with more GALT collagen deposition (R = 0.44, P= 0.008) and lower LA CD4+ T lymphocyte density (R = -0.32, P = 0.05) among aviremic individuals.ConclusionsCirculating LOXL2 levels may be a noninvasive measure of intestinal fibrosis and GALT CD4+ T lymphocyte depletion in treated HIV infection. LOXL2 crosslinks elastin and collagen, and elevated LOXL2 levels occur in pathologic states, making LOXL2 inhibition a potential interventional target for intestinal fibrosis and its sequelae

No difference in HIV-1 integrase resistance between CSF and blood compartments Short title: HIV-1 integrase resistance in compartments

International audienceBackground: Little is known about the HIV-1 integrase resistance in CNS. This study aimed to evaluate integrase resistance in CSF, as a marker of CNS, and compare it to the HIV resistance in plasma. Methods: The HIV integrase was sequenced both in plasma and CSF for 59 HIV-1 patients. The clinical and biological data were collected from clinical routine care. Results: Among the 59 HIV-1 patients, 32 (54.2%) were under antiretroviral (ARV) treatment. The median (IQR) HIV-1 RNA in viremic patients was 5.32 (3.85-5.80) and 3.59 (2.16-4.50) versus 4.79 (3.56-5.25) and 3.80 (2.68-4.33) in CSF log10 copies/mL for ARV naïve and treated patients, respectively. The patients were mainly infected with non-B subtypes (72.2%) with the most prevalent recombinant form CRF02_AG (42.4%). The HIV-1 integrase sequences presented resistance mutations for 9/27 (33.3%) and 8/32 (25.0%) in CSF for ARV naïve (L74I n=3, L74I/M n=1, T97A n=1, E157Q n=4) and treated (L74I n=6, L74M n=1, 1 T97A n=1, 1 N155H n=1) patients, respectively. Integrase resistance mutations in CSF were similar to that in plasma, except for 1/59 patients. Conclusions: This work shows similar integrase resistance profiles in CNS and plasma in a population of HIV-1 viremic patients

Circulating LOXL2 Levels Reflect Severity of Intestinal Fibrosis and GALT CD4+ T Lymphocyte Depletion in Treated HIV Infection

Background: Incomplete immune reconstitution may occur despite successful antiretroviral therapy (ART). Gut-associated lymphoid tissue (GALT) fibrosis may contribute via local CD4+ T lymphocyte depletion, intestinal barrier disruption, microbial translocation, and immune activation. Methods: In a cross-sectional analysis, we measured circulating fibrosis biomarker levels on cryopreserved plasma from adult HIV-infected (HIV+) SCOPE study participants on suppressive ART who also had fibrosis quantification on recto-sigmoid biopsies. Relationships among biomarker levels, clinical and demographic variables, GALT lymphoid aggregate (LA) collagen deposition, and LA CD4+ T lymphocyte density were analyzed using simple regression. Biomarker levels were also compared to levels in HIV+ viremic SCOPE participants and a convenience sample of HIV-uninfected (HIV-) samples. Results: HIV+ aviremic participants (n=39) were 92% male and 41% non-white, with median age 48 years, CD4+ T lymphocyte count 277 cells/mm3, and 17 years since HIV diagnosis. Most biomarkers were lower in HIV− (n=36) vs HIV+ aviremic individuals, although CXCL4 levels were higher. HIV+ viremic individuals (N=18) had higher median TGF-ß3, CIC-C1Q, and TIMP-1 (P<0.05) and lower LOXL2 levels (P=0.08) than HIV+ aviremic individuals. Only higher LOXL2 levels correlated with more GALT collagen deposition (R=0.44, P=0.007) and lower LA CD4+ T lymphocyte density (R=−0.32, P=0.05) among aviremic individuals. Conclusions: Circulating LOXL2 levels may be a noninvasive measure of intestinal fibrosis and GALT CD4+T lymphocyte depletion in treated HIV infection. LOXL2 crosslinks elastin and collagen, and elevated LOXL2 levels occur in pathologic states, making LOXL2 inhibition a potential interventional target for intestinal fibrosis and its sequelae

More HIV-1 RNA detected and quantified with the Cobas 6800 system in patients on antiretroviral therapy

International audienceAbstract Background Target-detected (TD) results or low-level viraemia (LLV) can be observed in HIV-1 patients on ART, which regularly raises questions. Objectives We describe here the impact on HIV-1 RNA quantification of switching from the COBAS AmpliPrep/COBAS TaqMan (CAP/CTM) to the Cobas 6800 system (C6800), based on analyses of viraemia close to the lower limit of quantification (LLoQ). Patients and methods We retrospectively selected two groups of patients: 200 individuals whose viral loads (VLs) were consistently &lt;50 copies/mL with CAP/CTM for at least 3 years before switching to C6800 (group 1), and 35 other patients with confirmed LLV when C6800 was in use (group 2). In both groups, we compared several consecutive VL results performed before and after the change of quantification assay. Analyses were performed with McNemar’s paired tests or Fisher’s exact tests. Results In group 1, the frequency of TD results (below or above the LLoQ) increased significantly after the switch to C6800 for patients with &lt;25% of results being TD for VLs performed with CAP/CTM (P &lt; 0.0001). Significantly more patients had at least one VL ≥20 or ≥50 copies/mL with C6800, in both group 1 (37.0% versus 18.5%; P &lt; 0.0001 and 6.5% versus 0%; P = 0.0009, respectively) and group 2 (100% versus 66%; P = 0.0015 and 97% versus 40%; P &lt; 0.0001, respectively). Conclusions C6800 revealed residual or low-level HIV-1 RNA that was not detected with CAP/CTM, resulting in twice as many patients being found to have a VL ≥20 copies/mL. Physicians and patients should be aware of possible differences in results between assays, and it is crucial to specify the quantitative assay used in studies