Impact of Delaying Antiretroviral Treatment during Primary HIV Infection on Telomere Length

2021 ◽  
Author(s):  
Marieke Raffenberg ◽  
Tanja Engel ◽  
Isabella C Schoepf ◽  
Neeltje A Kootstra ◽  
Peter Reiss ◽  
...  
Keyword(s):  
Hiv Infection ◽  
Telomere Length ◽  
Antiretroviral Treatment ◽  
Mononuclear Cells ◽  
Multivariable Analysis ◽  
Limited Effect ◽  
Peripheral Blood Mononuclear ◽  
Primary Hiv Infection ◽  
Hiv Seroconversion ◽  
Chronic Hiv Infection

Abstract Background Telomere length (TL) shortens during aging, HIV-seroconversion and untreated chronic HIV infection. It is unknown whether early antiretroviral therapy (ART) start is associated with less TL shortening during primary HIV infection (PHI). Methods We measured TL in peripheral blood mononuclear cells by quantitative PCR in participants of the Zurich PHI Study with samples available for >6 years. We obtained uni-/multivariable estimates from mixed-effects models and evaluated the association of delaying ART start or interrupting ART with baseline and longitudinal TL. Results In 105 participants with PHI (median age 36 years, 9% women), median ART delay was 25, 42, and 60 days, respectively, in the 1 st (shortest), 2 nd, and 3 rd (longest) ART delay tertile. First ART delay tertile was associated with longer baseline TL (p for trend=0.034), and longer TL over 6 years, but only with continuous ART (p<0.001), not if ART was interrupted >12 months (p=0.408). In multivariable analysis, participants in the 2 nd and 3 rd ART delay tertile had 17.6% (5.4-29.7%; p=0.004) and 21.5% (9.4-33.5%; p<0.001) shorter TL, after adjustment for age, with limited effect modification by clinical variables. Discussion In PHI, delaying ART start for even a matter of weeks was associated with significant and sustained TL shortening.

scholarly journals Loss of CXCR4 on non-classical monocytes in participants of the Women’s Interagency HIV Study (WIHS) with subclinical atherosclerosis

2018 ◽  
Vol 115 (6) ◽  
pp. 1029-1040 ◽  
Author(s):  
Karin A L Mueller ◽  
David B Hanna ◽  
Erik Ehinger ◽  
Xiaonan Xue ◽  
Livia Baas ◽  
...  
Keyword(s):  
Hiv Infection ◽  
Mononuclear Cells ◽  
Smoking Status ◽  
Subclinical Atherosclerosis ◽  
Cxcr4 Expression ◽  
Monocyte Subset ◽  
Surface Markers ◽  
Peripheral Blood Mononuclear ◽  
Cell Counts ◽  
Classical Monocytes

AbstractAimsTo test whether human immunodeficiency virus (HIV) infection and subclinical cardiovascular disease (sCVD) are associated with expression of CXCR4 and other surface markers on classical, intermediate, and non-classical monocytes in women.Methods and resultssCVD was defined as presence of atherosclerotic lesions in the carotid artery in 92 participants of the Women’s Interagency HIV Study (WIHS). Participants were stratified into four sets (n = 23 each) by HIV and sCVD status (HIV−/sCVD−, HIV−/sCVD+, HIV+/sCVD−, and HIV+/sCVD+) matched by age, race/ethnicity, and smoking status. Three subsets of monocytes were determined from archived peripheral blood mononuclear cells. Flow cytometry was used to count and phenotype surface markers. We tested for differences by HIV and sCVD status accounting for multiple comparisons. We found no differences in monocyte subset size among the four groups. Expression of seven surface markers differed significantly across the three monocyte subsets. CXCR4 expression [median fluorescence intensity (MFI)] in non-classical monocytes was highest among HIV−/CVD− [628, interquartile range (IQR) (295–1389)], followed by HIV+/CVD− [486, IQR (248–699)], HIV−/CVD+ (398, IQR (89–901)), and lowest in HIV+/CVD+ women [226, IQR (73–519)), P = 0.006 in ANOVA. After accounting for multiple comparison (Tukey) the difference between HIV−/CVD− vs. HIV+/CVD+ remained significant with P = 0.005 (HIV−/CVD− vs. HIV+/CVD− P = 0.04, HIV−/CVD− vs. HIV−/CVD+ P = 0.06, HIV+/CVD+ vs. HIV+/CVD− P = 0.88, HIV+/CVD+ vs. HIV−/CVD+ P = 0.81, HIV+/CVD− vs. HIV−/CVD+, P = 0.99). All pairwise comparisons with HIV−/CVD− were individually significant (P = 0.050 vs. HIV−/CVD+, P = 0.028 vs. HIV+/CVD−, P = 0.009 vs. HIV+/CVD+). CXCR4 expression on non-classical monocytes was significantly higher in CVD− (501.5, IQR (249.5–887.3)) vs. CVD+ (297, IQR (81.75–626.8) individuals (P = 0.028, n = 46 per group). CXCR4 expression on non-classical monocytes significantly correlated with cardiovascular and HIV−related risk factors including systolic blood pressure, platelet and T cell counts along with duration of antiretroviral therapy (P < 0.05). In regression analyses, adjusted for education level, study site, and injection drug use, presence of HIV infection and sCVD remained significantly associated with lower CXCR4 expression on non-classical monocytes (P = 0.003), but did not differ in classical or intermediate monocytes.ConclusionCXCR4 expression in non-classical monocytes was significantly lower among women with both HIV infection and sCVD, suggesting a potential atheroprotective role of CXCR4 in non-classical monocytes.

scholarly journals Impact of Aging and HIV Infection on the Function of the C-Type Lectin Receptor MINCLE in Monocytes

2018 ◽  
Vol 74 (6) ◽  
pp. 794-801 ◽  
Author(s):  
Heidi J Zapata ◽  
Peter H Van Ness ◽  
Stefan Avey ◽  
Barbara Siconolfi ◽  
Heather G Allore ◽  
...  
Keyword(s):  
Hiv Infection ◽  
Mononuclear Cells ◽  
Innate Immune ◽  
Synthetic Analog ◽  
Peripheral Blood Mononuclear ◽  
Lectin Receptor ◽  
Cord Factor ◽  
Factor Α ◽  
Insight Into ◽  
Necrosis Factor

AbstractBoth aging and HIV infection are associated with an enhanced pro-inflammatory environment that contributes to impaired immune responses and is mediated in part by innate immune pattern-recognition receptors. MINCLE is a C-type lectin receptor that recognizes trehalose-6,6ʹ-dimycolate or “cord factor,” the most abundant glycolipid in Mycobacterium tuberculosis. Here, we evaluated MINCLE function in monocytes in a cohort of HIV-infected and uninfected young (21–35 years) and older adults (≥60 years) via stimulation of peripheral blood mononuclear cells with trehalose-6,6-dibehenate, a synthetic analog of trehalose-6,6ʹ-dimycolate and measurement of cytokine production (interleukin [IL]-10, IL-12, IL-6, tumor necrosis factor-α) by multicolor flow cytometry. Our studies show an age- and HIV-associated increase in cytokine multifunctionality of monocytes both at the population and single cell level that was dominated by IL-12, IL-10, and IL-6. These findings provide insight into the host response to M. tuberculosis and possible sources for the pro-inflammatory environment seen in aging and HIV infection.

scholarly journals MDL 74,968, a new acyclonucleotide analog: activity against human immunodeficiency virus in vitro and in the hu-PBL-SCID.beige mouse model of infection.

1996 ◽  
Vol 40 (5) ◽  
pp. 1072-1077 ◽  
Author(s):  
C G Bridges ◽  
D L Taylor ◽  
P S Ahmed ◽  
T M Brennan ◽  
J M Hornsperger ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Hiv Infection ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Placebo Control ◽  
Intravenous Route ◽  
Peripheral Blood Mononuclear ◽  
Immunodeficiency Virus ◽  
Orally Bioavailable

The novel acyclonucleotide derivative of guanine, 9-[2-methylidene-3-(phosphonomethoxy)propyl] guanine (MDL 74,968), had antiviral activity comparable to those of 9-(2-phosphonomethoxyethyl) adenine (PMEA) and 2',3'-dideoxyinosine against laboratory strains of both human immunodeficiency virus (HIV) types 1 and 2 cultured in MT-4 cells and several clinical HIV isolates cultured in human peripheral blood mononuclear cells (PBMCs). MDL 74,968 was at least fourfold less toxic than PMEA to MT-4 cells or PBMCs, thereby producing a more favorable in vitro selectivity index for the former compound. Studies of acute toxicity in CD-1 mice showed that MDL 74,968 was not toxic at doses of 1,600 mg/kg of body weight via the intraperitoneal route or at doses of 500 mg/kg via the intravenous route. Furthermore, no adverse effects of MDL 74,968 were apparent when mice were treated at doses of 200 mg/kg twice daily for 5 days. Treatment by continuous subcutaneous infusion of MDL 74,968 or PMEA at the daily dose of 20 mg/kg in the hu-PBL-SCID.beige murine model of HIV infection significantly reduced the severity of infection compared with that in placebo-treated controls. Quantitation of virus recovery by endpoint titration of spleen cells in coculture with mitogen-activated PBMCs demonstrated that MDL 74,968 as well as PMEA significantly reduced the amount of virus (P < 0.02). Moreover, by using DNA extracted from spleens, the mean HIV:HLA PCR product ratio, which takes into account individual variation in immune system reconstitution, were 0.50 and 0.40 for MDL 74,968 and PMEA treatments, respectively, whereas animals receiving the placebo control had significantly higher levels of HIV proviral DNA (mean 0.78; P < 0.02). Taken together, these promising findings suggest that an orally bioavailable prodrug of MDL 74,968 should be developed for the treatment of HIV infection.

scholarly journals Establishment of a Novel Humanized Mouse Model To Investigate In Vivo Activation and Depletion of Patient-Derived HIV Latent Reservoirs

2019 ◽  
Vol 93 (6) ◽  
Author(s):  
Nina C. Flerin ◽  
Ariola Bardhi ◽  
Jian Hua Zheng ◽  
Maria Korom ◽  
Joy Folkvord ◽  
...  
Keyword(s):  
Mouse Model ◽  
Hiv Infection ◽  
Mononuclear Cells ◽  
Systemic Infection ◽  
Humanized Mouse Model ◽  
Peripheral Blood Mononuclear ◽  
Immunodeficient Mice ◽  
Latently Infected ◽  
Infected Cells

ABSTRACT Curing HIV infection has been thwarted by the persistent reservoir of latently infected CD4+ T cells, which reinitiate systemic infection after antiretroviral therapy (ART) interruption. To evaluate reservoir depletion strategies, we developed a novel preclinical in vivo model consisting of immunodeficient mice intrasplenically injected with peripheral blood mononuclear cells (PBMC) from long-term ART-suppressed HIV-infected donors. In the absence of ART, these mice developed rebound viremia which, 2 weeks after PBMC injection, was 1,000-fold higher (mean = 9,229,281 HIV copies/ml) in mice injected intrasplenically than in mice injected intraperitoneally (mean = 6,838 HIV copies/ml) or intravenously (mean = 591 HIV copies/ml). One week after intrasplenic PBMC injection, in situ hybridization of the spleen demonstrated extensive disseminated HIV infection, likely initiated from in vivo-reactivated primary latently infected cells. The time to viremia was delayed significantly by treatment with a broadly neutralizing antibody, 10-1074, compared to treatment with 10-1074-FcRnull, suggesting that 10-1074 mobilized Fc-mediated effector mechanisms to deplete the replication-competent reservoir. This was supported by phylogenetic analysis of Env sequences from viral-outgrowth cultures and untreated, 10-1074-treated, or 10-1074-FcRnull-treated mice. The predominant sequence cluster detected in viral-outgrowth cultures and untreated mouse plasma was significantly reduced in the plasma of 10-1074-treated mice, whereas two new clusters emerged that were not detected in viral-outgrowth cultures or plasma from untreated mice. These new clusters lacked mutations associated with 10-1074 resistance. Taken together, these data indicated that 10-1074 treatment depletes the reservoir of latently infected cells harboring replication competent HIV. Furthermore, this mouse model represents a new in vivo approach for the preclinical evaluation of new HIV cure strategies. IMPORTANCE Sustained remission of HIV infection is prevented by a persistent reservoir of latently infected cells capable of reinitiating systemic infection and viremia. To evaluate strategies to reactivate and deplete this reservoir, we developed and characterized a new humanized mouse model consisting of highly immunodeficient mice intrasplenically injected with peripheral blood mononuclear cells from long-term ART-suppressed HIV-infected donors. Reactivation and dissemination of HIV infection was visualized in the mouse spleens in parallel with the onset of viremia. The applicability of this model for evaluating reservoir depletion treatments was demonstrated by establishing, through delayed time to viremia and phylogenetic analysis of plasma virus, that treatment of these humanized mice with a broadly neutralizing antibody, 10-1074, depleted the patient-derived population of latently infected cells. This mouse model represents a new in vivo approach for the preclinical evaluation of new HIV cure strategies.

scholarly journals Telomere Shortening in Formerly Abused and Never Abused Women

2011 ◽  
Vol 14 (2) ◽  
pp. 115-123 ◽  
Author(s):  
Janice Humphreys ◽  
Elissa S. Epel ◽  
Bruce A. Cooper ◽  
Jue Lin ◽  
Elizabeth H. Blackburn ◽  
...  
Keyword(s):  
Telomere Length ◽  
Chronic Stress ◽  
Partner Violence ◽  
Molecular Mechanisms ◽  
Mononuclear Cells ◽  
Quantitative Polymerase Chain Reaction ◽  
Cellular Aging ◽  
Abused Women ◽  
Peripheral Blood Mononuclear ◽  
Convenience Sample

Recent studies suggest that chronic psychological stress may accelerate aging at the cellular level. Telomeres are protective components that stabilize the ends of chromosomes and modulate cellular aging. Women exposed to intimate partner violence (IPV) experience chronic stress and report worse health. The purpose of this exploratory study was to examine telomeric DNA length in women who have experienced chronic stress related to IPV. We hypothesized that IPV exposure would be associated with shorter telomere length. The investigation used a cross-sectional design to study telomere length in women with a history of IPV exposure and control women who reported no prior exposure to IPV. Advertisements and public notices were used to recruit a convenience sample of healthy women. Mean leukocyte telomere length was measured in DNA samples from peripheral blood mononuclear cells (PBMCs) by a quantitative polymerase chain reaction assay (qPCR). Telomere length was significantly shorter in the 61 formerly abused women compared to the 41 controls ( t = 2.4, p = .02). Length of time in the abusive relationship and having children were associated with telomere length after controlling for age and body mass index (BMI) ( F(2, 99) = 10.23, p < .001). Numerous studies suggest that women who experience IPV have poorer overall health. It is often presumed that the stress of IPV may be causing greater morbidity. Findings from this descriptive study suggest a link between IPV exposure, duration of IPV-related stress, and telomere length molecular mechanisms that regulate cellular aging.

Telomere Length in Peripheral Blood Mononuclear Cells of Patients on Chronic Hemodialysis Is Related With Telomerase Activity and Treatment Duration

2015 ◽  
Vol 39 (9) ◽  
pp. 756-764 ◽  
Author(s):  
Ioannis Stefanidis ◽  
Georgios Voliotis ◽  
Vassilios Papanikolaou ◽  
Ioanna Chronopoulou ◽  
Theodoros Eleftheriadis ◽  
...  
Keyword(s):  
Telomere Length ◽  
Peripheral Blood Mononuclear Cells ◽  
Peripheral Blood ◽  
Treatment Duration ◽  
Mononuclear Cells ◽  
Telomerase Activity ◽  
Chronic Hemodialysis ◽  
Peripheral Blood Mononuclear ◽  
Blood Mononuclear Cells
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