HIV-1 CRF01_AE subtype and HIV-1 DNA level among patients with chronic HIV-1 infection: a correlation study

Abstract Background The impact of HIV-1 subtype (CRF01_AE and non-CRF01_AE) on HIV-1 DNA levels in HIV-1 chronically infected patients with suppressive antiretroviral therapy (ART) remains poorly understood. To evaluate the correlation of HIV-1 subtype with DNA level, and identify baseline predictors of HIV-1 DNA decay. Methods ART-naïve HIV-1-infected patients from two large multi-center studies in China were classified into CRF01_AE and non-CRF01_AE subtype groups. Peripheral blood samples were collected at baseline and week 12, 24, 48 and 96 after ART initiation and total HIV-1 DNA levels were quantified by real-time PCR. HIV-1 DNA levels at week 96 were categorized into high, moderate, and low levels, reflecting HIV-1 DNA ≥ 3, 2–3, ≤ 2 log10 copies/106 PBMCs, respectively, and the corresponding proportion of CRF01_AE and non-CRF01_AE subtype were compared. The baseline predictors of low HIV-1 total DNA levels (≤ 2 log10 copies/106 PBMCs) at week 96 were evaluated using a logistic regression model. Results Compared to the non-CRF01_AE subtypes (n=185), patients with CRF01_AE subtype (n=188) harboured a higher level of HIV-1 DNA (median: 3.19 vs. 2.95 log10 copies/106 PBMCs, P < 0.001) prior to treatment. After 96 weeks of ART, HIV-1 DNA levels remained higher in the CRF01_AE subtype group (median: 2.63 vs. 2.39 log10 copies/106 PBMCs, P = 0.002). There was no significant difference in the proportion of patients achieving high (22.3% vs. 14.6%, P = 0.054), moderate (59.6% vs. 60.5%, P = 0.849) and low levels (18.1% vs 24.9%, P = 0.111) between CRF01_AE and non-CRF01_AE groups. In the multivariable analysis, baseline HIV-1 DNA level and CD4+ T cell count but not the subtype were independent risk factors for achieving HIV-1 DNA level ≤ 2 log10 copies/106 PBMCs. Conclusion HIV-1 CRF01_AE subtype is neither correlated with HIV-1 DNA reservoir decline nor a prognostic factor for achieving lower HIV-1 DNA levels (≤ 2 log10 copies/106 PBMCs) after ART. However, higher HIV-1 DNA level in HIV-1 CRF01_AE patients should be aroused much attention and strengthen surveillance during ART.

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HIV-1 CRF01_AE subtype and HIV-1 DNA level among patients with chronic HIV-1 infection: a correlation study

10.21203/rs.2.10946/v3 ◽

2020 ◽

Author(s):

Tingxia Lyu ◽

Yongsong Yue ◽

Hsieh Evelyn ◽

Yang Han ◽

Ting Zhu ◽

...

Keyword(s):

Multivariable Analysis ◽

Correlation Study ◽

Art Initiation ◽

Significant Difference ◽

Total Dna ◽

Independent Risk Factors ◽

Low Levels ◽

The Impact ◽

Hiv 1 ◽

Dna Reservoir

Abstract Background: The impact of HIV-1 subtype (CRF01_AE and non-CRF01_AE) on HIV-1 DNA levels in HIV-1 chronically infected patients with suppressive antiretroviral therapy (ART) remains poorly understood. To evaluate the correlation of HIV-1 subtype with DNA level, and identify baseline predictors of HIV-1 DNA decay. Methods : ART-naïve HIV-1-infected patients from two large multi-center studies in China were classified into CRF01_AE and non-CRF01_AE subtype groups. Peripheral blood samples were collected at baseline and week 12, 24, 48 and 96 after ART initiation and total HIV-1 DNA levels were quantified by real-time PCR. HIV-1 DNA levels at week 96 were categorized into high, moderate, and low levels, reflecting HIV-1 DNA ≥ 3, 2–3, ≤ 2 log 10 copies/10 6 PBMCs, respectively , and the corresponding proportion of CRF01_AE and non-CRF01_AE subtype were compared. The baseline predictors of low HIV-1 total DNA levels (≤ 2 log 10 copies/10 6 PBMCs) at week 96 were evaluated using a logistic regression model. Results: Compared to the non-CRF01_AE subtypes (n=185), patients with CRF01_AE subtype (n=188) harboured a higher level of HIV-1 DNA (median: 3.19 vs. 2.95 log 10 copies/10 6 PBMCs, P < 0.001) prior to treatment. After 96 weeks of ART, HIV-1 DNA levels remained higher in the CRF01_AE subtype group (median: 2.63 vs. 2.39 log 10 copies/10 6 PBMCs, P = 0.002). There was no significant difference in the proportion of patients achieving high (22.3% vs. 14.6%, P = 0.054), moderate (59.6% vs. 60.5%, P = 0.849) and low levels (18.1% vs 24.9%, P = 0.111) between CRF01_AE and non-CRF01_AE groups. In the multivariable analysis, baseline HIV-1 DNA level and CD4 + T cell count but not the subtype were independent risk factors for achieving HIV-1 DNA level ≤ 2 log 10 copies/10 6 PBMCs. Conclusion: HIV-1 CRF01_AE subtype is neither correlated with HIV-1 DNA reservoir decline nor a prognostic factor for achieving lower HIV-1 DNA levels (≤ 2 log 10 copies/10 6 PBMCs) after ART. However, higher HIV-1 DNA level in HIV-1 CRF01_AE patients should be aroused much attention and strengthen surveillance during ART.

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HIV-1 CRF01_AE subtype and HIV-1 DNA level among patients with chronic HIV-1 infection: a correlation study

10.21203/rs.2.10946/v2 ◽

2019 ◽

Author(s):

Tingxia Lyu ◽

Yongsong Yue ◽

Hsieh Evelyn ◽

Yang Han ◽

Ting Zhu ◽

...

Keyword(s):

Multivariable Analysis ◽

Correlation Study ◽

Art Initiation ◽

Significant Difference ◽

Total Dna ◽

Independent Risk Factors ◽

Low Levels ◽

The Impact ◽

Hiv 1 ◽

Dna Reservoir

Abstract Background: The impact of HIV-1 subtype (CRF01_AE and non-CRF01_AE) on HIV-1 DNA levels in HIV-1 chronically infected patients with suppressive antiretroviral therapy (ART) remains poorly understood. To evaluate the correlation of HIV-1 subtype with DNA level, and identify baseline predictors of HIV-1 DNA decay. Methods: ART-naïve HIV-1-infected patients from two large multi-center studies in China were classified into CRF01_AE and non-CRF01_AE subtype groups. Peripheral blood samples were collected at baseline and week 12, 24, 48 and 96 after ART initiation and total HIV-1 DNA levels were quantified by real-time PCR. HIV-1 DNA levels at week 96 were categorized into high, moderate, and low levels, reflecting HIV-1 DNA ≥ 3, 2–3, ≤ 2 log10 copies/106 PBMCs, respectively, and the corresponding proportion of CRF01_AE and non-CRF01_AE subtype were compared. The baseline predictors of low HIV-1 total DNA levels (≤ 2 log10 copies/106 PBMCs) at week 96 were evaluated using a logistic regression model. Results: Compared to the non-CRF01_AE subtypes (n=185), patients with CRF01_AE subtype (n=188) harboured a higher level of HIV-1 DNA (median: 3.19 vs. 2.95 log10 copies/106 PBMCs, P < 0.001) prior to treatment. After 96 weeks of ART, HIV-1 DNA levels remained higher in the CRF01_AE subtype group (median: 2.63 vs. 2.39 log10 copies/106 PBMCs, P = 0.002). There was no significant difference in the proportion of patients achieving high (22.3% vs. 14.6%, P = 0.054), moderate (59.6% vs. 60.5%, P = 0.849) and low levels (18.1% vs 24.9%, P = 0.111) between CRF01_AE and non-CRF01_AE groups. In the multivariable analysis, baseline HIV-1 DNA level and CD4+ T cell count but not the subtype were independent risk factors for achieving HIV-1 DNA level ≤ 2 log10 copies/106 PBMCs. Conclusion: HIV-1 CRF01_AE subtype is neither correlated with HIV-1 DNA reservoir decline nor a prognostic factor for achieving lower HIV-1 DNA levels (≤ 2 log10 copies/106 PBMCs) after ART. However, higher HIV-1 DNA level in HIV-1 CRF01_AE patients should be aroused much attention and strengthen surveillance during ART.

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The Efficacy of Etoposide-Based Therapy in Adult Secondary Hemophagocytic Lymphohistiocytosis

Acta Haematologica ◽

10.1159/000514920 ◽

2021 ◽

pp. 1-9

Author(s):

Leonard Naymagon ◽

Douglas Tremblay ◽

John Mascarenhas

Keyword(s):

Hemophagocytic Lymphohistiocytosis ◽

Proportional Hazards ◽

Multivariable Analysis ◽

Cox Proportional Hazards ◽

Rank Test ◽

Kaplan Meier ◽

Hazard Ratios ◽

Significant Difference ◽

The Impact

Data supporting the use of etoposide-based therapy in hemophagocytic lymphohistiocytosis (HLH) arise largely from pediatric studies. There is a lack of comparable data among adult patients with secondary HLH. We conducted a retrospective study to assess the impact of etoposide-based therapy on outcomes in adult secondary HLH. The primary outcome was overall survival. The log-rank test was used to compare Kaplan-Meier distributions of time-to-event outcomes. Multivariable Cox proportional hazards modeling was used to estimate adjusted hazard ratios (HRs) with 95% confidence intervals (CIs). Ninety adults with secondary HLH seen between January 1, 2009, and January 6, 2020, were included. Forty-two patients (47%) received etoposide-based therapy, while 48 (53%) received treatment only for their inciting proinflammatory condition. Thirty-three patients in the etoposide group (72%) and 32 in the no-etoposide group (67%) died during follow-up. Median survival in the etoposide and no-etoposide groups was 1.04 and 1.39 months, respectively. There was no significant difference in survival between the etoposide and no-etoposide groups (log-rank <i>p</i> = 0.4146). On multivariable analysis, there was no association between treatment with etoposide and survival (HR for death with etoposide = 1.067, 95% CI: 0.633–1.799, <i>p</i> = 0.8084). Use of etoposide-based therapy was not associated with improvement in outcomes in this large cohort of adult secondary HLH patients.

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INSTI-Based Triple Regimens in Treatment-Naïve HIV-Infected Patients Are Associated With HIV-RNA Viral Load Suppression at Ultralow Levels

Open Forum Infectious Diseases ◽

10.1093/ofid/ofz177 ◽

2019 ◽

Vol 6 (5) ◽

Cited By ~ 2

Author(s):

Sidonie Lambert-Niclot ◽

Anders Boyd ◽

Djeneba Fofana ◽

Nadia Valin ◽

Marc Wirden ◽

...

Keyword(s):

Multivariable Analysis ◽

Female Gender ◽

Strand Transfer ◽

University Hospitals ◽

Viral Load Suppression ◽

Hiv Rna ◽

Art Initiation ◽

Treatment Naïve ◽

Hiv 1

Abstract Background During antiretroviral therapy (ART), HIV-1-infected patients may present with ultralow (UL) HIV-RNA viral loads (VLs) below quantification levels of current assays. Reasons for UL-VL detection and its relation to virological rebound (VR) are unclear. Methods HIV-1-infected, ART-naïve patients followed at 2 university hospitals were included. All participants had an HIV-RNA >200 copies/mL at ART initiation and achieved a VL <50 copies/mL during ART. UL-VL was determined by the presence/absence of polymerase chain reaction signal detected using a commercially available assay (COBAS, TaqMan, Roche). Random-effects Poisson regression was used for assessing determinants of UL-VL not detected overtime and conditional risk set analysis for VR (1 VL > 200 copies/mL or 2 VL > 50 copies/mL) while accounting for frequency of VL measurements. Results Between 2009 and 2013, 717 patients initiated ART containing 2 nucleos(-t)ide reverse transcriptase inhibitors (NRTIs) plus a non-NRTI (29.4%), a protease inhibitor (58.4%), or an integrase-strand transfer inhibitor (INSTI; 12.1%). During a median (interquartile range) 3.4 (2.3–4.6) years, 676 (94.3%) patients achieved UL-VL not detected. In multivariable analysis, UL-VL not detected overtime was associated with younger age (P < .001), female gender (P = .04), lower baseline VL (P < .001), baseline CD4+ >500 vs <350/mm3 (P < .001), and INSTI-containing ART (P = .009). One hundred thirty-one (18.3%) patients had VR during follow-up, which was independently associated with a CD4/CD8 ratio <0.8 during follow-up (P = .01) and time spent with UL-VL not detected (P < .001). When UL-VL not detected occurred for ≥50% of the follow-up duration (n = 290), faster time to reach UL-VL not detected (P < .001), faster CD4+ T-cell count increase (P = .03), and faster CD4/CD8 ratio increase (P = .001) were observed. Conclusions VL suppression at an ultralow level is associated with INSTI-class ART initiation. Extensive VL suppression below ultralow detection could improve immune reconstitution.

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The Effects of Anti-retroviral Therapy on Epigenetic Age Acceleration Observed in HIV-1-infected Adults

Pathogens and Immunity ◽

10.20411/pai.v5i1.376 ◽

2020 ◽

Vol 5 (1) ◽

pp. 291-311

Author(s):

Mary E. Sehl ◽

Tammy M. Rickabaugh ◽

Roger Shih ◽

Otoniel Martinez-Maza ◽

Steve Horvath ◽

...

Keyword(s):

Peripheral Blood ◽

Epigenetic Clock ◽

Time Points ◽

Art Initiation ◽

Age Related ◽

Epigenetic Age ◽

Significant Difference ◽

Epigenetic Age Acceleration ◽

Hiv 1 ◽

Time Point

Background: HIV-1 infection is associated with acceleration of age-related methylation patterns in peripheral blood and brain of infected individuals although the relative contributions of HIV-1 infection versus its treatment to the observed accelerations in biological aging have not yet been investigated.Methods: In this longitudinal study of the effects of antiretroviral therapy (ART) on epigenetic aging patterns, we extracted DNA from peripheral blood mononuclear cells from 15 HIV-1-infected individuals infected at three time points: 6 months-1year pre-ART, 6-12 months post-initiation of ART, and 18-24 months after initiating ART. We compared these trajectories with those of 15 age-matched uninfected control participants at three time points with similar intervals. Methylation studies were performed using the Infinium methylation 450 arrays. We examined four epigenetic clock measurements: Age acceleration residual (AAR), Extrinsic (EEAA), Phenotypic (PEAA), and Grim (GEAA) epigenetic age acceleration. Weighted correlation network (WGCNA) analysis was used to identify clusters of highly co-methylated CpGs.Results: We found that prior to the initiation of ART all four epigenetic measures were significantly higher in HIV-1-infected individuals compared with uninfected individuals (P<0.001 for AAR, P=0.008 for EEAA, P=0.012 for GEAA, P<0.001 for PEAA using Wilcoxon rank sum tests between serostatus groups). These effects persisted after the initiation of ART, although the magnitude of these differences diminished. At 18-24 months post-ART initiation (time point 3), PEAA and GEAA were no longer significantly different between HIV-1-infected and uninfected individuals (P=0.059 for PEAA, P=0.11 for GEAA), while AAR and EEAA remained significantly higher in HIV-1-infected individuals compared with uninfected individuals. We further examined for global patterns of methylation differences between HIV-1-infected and uninfected at each time point, and found 14 groups of co-methylated CpGs that were significantly different between groups at baseline, and remained different after the initiation of ART.Conclusion: We confirm that epigenetic age acceleration associated with HIV-1 infection is most dramatic before ART initiation, and this observation is consistent across four epigenetic clock measurements, as well as in additional groups of co-methylated CpGs identified using WGCNA. Following initiation of ART, there is a partial reduction in age acceleration in all measures, with loss of any significant difference in PEAA and GEAA between serostatus groups. Our findings support the need for future studies examining for a link between epigenetic age acceleration and clinical outcomes in HIV-1-infected individuals.

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Body mass index and severity/fatality from coronavirus disease 2019: A nationwide epidemiological study in Korea

PLoS ONE ◽

10.1371/journal.pone.0253640 ◽

2021 ◽

Vol 16 (6) ◽

pp. e0253640

Author(s):

In Sook Kang ◽

Kyoung Ae Kong

Keyword(s):

Body Mass Index ◽

Body Mass ◽

Multivariable Analysis ◽

Healthy Weight ◽

Significant Difference ◽

Control And Prevention ◽

Independent Risk Factors ◽

Fatal Illness ◽

Design And Methods ◽

The Relationship

Objective Obesity has been reported as a risk factor for severe coronavirus disease 2019 (COVID-19) in recent studies. However, the relationship between body mass index (BMI) and COVID-19 severity and fatality are unclear. Research design and methods This study included 4,141 COVID-19 patients who were released from isolation or had died as of April 30, 2020. This nationwide data was provided by the Korean Centers for Disease Control and Prevention Agency. BMI was categorized as follows; < 18.5 kg/m2, 18.5–22.9 kg/m2, 23.0–24.9 kg/m2, 25.0–29.9 kg/m2, and ≥ 30 kg/m2. We defined a fatal illness if the patient had died. Results Among participants, those with a BMI of 18.5–22.9 kg/m2 were the most common (42.0%), followed by 25.0–29.9 kg/m2 (24.4%), 23.0–24.9 kg/m2 (24.3%), ≥ 30 kg/m2 (4.7%), and < 18.5 kg/m2 (4.6%). In addition, 1,654 (41.2%) were men and 3.04% were fatalities. Multivariable analysis showed that age, male sex, BMI < 18.5 kg/m2, BMI ≥ 25 kg/m2, diabetes mellitus, chronic kidney disease, cancer, and dementia were independent risk factors for fatal illness. In particular, BMI < 18.5 kg/m2 (odds ratio [OR] 3.97, 95% CI 1.77–8.92), 25.0–29.9 kg/m2 (2.43, 1.32–4.47), and ≥ 30 kg/m2 (4.32, 1.37–13.61) were found to have higher ORs than the BMI of 23.0–24.9 kg/m2 (reference). There was no significant difference between those with a BMI of 18.5–22.9 kg/m2 (1.59, 0.88–2.89) and 23.0–24.9 kg/m2. Conclusions This study demonstrated a non-linear (U-shaped) relationship between BMI and fatal illness. Subjects with a BMI of < 18.5 kg/m2 and those with a BMI ≥ 25 kg/m2 had a high risk of fatal illness. Maintaining a healthy weight is important not only to prevent chronic cardiometabolic diseases, but also to improve the outcome of COVID-19.

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Pharmacodynamics of Abacavir in an In Vitro Hollow-Fiber Model System

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.46.2.464-470.2002 ◽

2002 ◽

Vol 46 (2) ◽

pp. 464-470 ◽

Cited By ~ 19

Author(s):

G. L. Drusano ◽

P. A. Bilello ◽

W. T. Symonds ◽

D. S. Stein ◽

J. McDowell ◽

...

Keyword(s):

Continuous Infusion ◽

Hollow Fiber ◽

Drug Binding ◽

Pharmacodynamic Modeling ◽

Genotypic Differences ◽

Once Daily ◽

Significant Difference ◽

The Impact ◽

Hiv 1

ABSTRACT Abacavir is a potent new carbocyclic nucleoside analogue. We employed our hollow-fiber pharmacodynamic modeling system to examine the antiretroviral effects of different abacavir exposures, as well as the impact of the schedule of drug administration on efficacy. Dose ranging of abacavir revealed that a concentration of four times the 50% effective concentration (EC50) (approximately the EC95) was required to inhibit the replication of human immunodeficiency virus type 1 (HIV-1) (strain MN) either in a continuous-infusion hollow-fiber experiment or in a classical tissue culture flask experiment. In contrast to earlier work with another drug class (HIV-1 protease inhibitors), addition of physiological amounts of the human drug binding proteins albumin and α1 acid glycoprotein revealed that there was little impact on the antiviral effect of the drug. Comparison of equivalent exposures (an area under the concentration-time curve [AUC] developed by approximately 500 mg per day of orally administered abacavir), either in a continuous-infusion mode or as a single oral dose of abacavir, demonstrated no difference in the ability to suppress either strain IIIB or strain MN. Comparison of administration of 250 mg every 12 h (q12h) versus once-daily administration of 500 mg for strain MN again showed no significant difference in suppressive effect. These experiments were carried out over 8 to 15 days. Because of these promising initial results, we extended the experiment to 30 days and examined three different schedules of administration that generated the same AUC at 24 h (AUC24): 300 mg q12h, 600 mg q24h, and 1,200 mg q48h. The aim of the last of these regimens was to definitively demonstrate schedule failure. There was little difference between the 1,200-mg q48h treatment group and the untreated control at 30 days. Likewise, there was little difference between the 600-mg q24h and 300-mg q12h treatment groups. However, at circa day 18 of the experiment, there was a small increase in viral output of p24 in the once-daily dosing unit. Examination of virus from all groups demonstrated no phenotypic or genotypic differences. The small difference in hollow-fiber unit p24 in the once-daily dosing group was not due to emergence of resistance over the 30-day single-drug exposure. We conclude that the dose of abacavir currently being studied in clinical trials (300 mg orally q12h) will be efficacious for the majority of sensitive clinical isolates of HIV-1. These in vitro data also suggest that this drug may be able to be administered to patients on a once-daily basis at a dose of 600 mg.

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Fate of contralateral asymptomatic bullae in patients with primary spontaneous pneumothorax

European Journal of Cardio-Thoracic Surgery ◽

10.1093/ejcts/ezaa054 ◽

2020 ◽

Vol 58 (2) ◽

pp. 365-370

Author(s):

Hyo Jun Jang ◽

Jun Ho Lee ◽

Seung Hyuk Nam ◽

Sun Kyun Ro

Keyword(s):

Spontaneous Pneumothorax ◽

Multivariable Analysis ◽

Primary Spontaneous Pneumothorax ◽

First Episode ◽

High Resolution Computed Tomography ◽

Contralateral Lung ◽

Younger Age ◽

Independent Risk Factors ◽

The Impact

Abstract OBJECTIVES This retrospective cohort study aimed to analyse the impact of asymptomatic blebs/bullae on the occurrence of primary spontaneous pneumothorax (PSP) by monitoring the natural course of contralateral blebs/bullae in patients with ipsilateral pneumothorax. METHODS From January 2003 to December 2017, 1055 patients [age 19.6 ± 3.98 years (mean ± standard deviation), 953 men] experiencing the first episode of unilateral PSP were enrolled in this study, excluding patients aged 30 years or more. The presence, number and maximal size of the blebs/bullae were investigated in contralateral asymptomatic lungs based on high-resolution computed tomography. RESULTS Multiple and single blebs/bullae were noted in contralateral lungs in 425 (40.3%) and 88 (8.3%) patients, respectively. The median follow-up period was 44.0 (interquartile range 71.5) months. The 1-, 3- and 5-year cumulative occurrence rates of PSP in contralateral lungs were 7.9%, 13.7% and 16.7%, respectively. On multivariable analysis, younger age [hazard ratio (HR) 1.19, 95% confidence interval (CI) 1.12–1.27; P < 0.001) and multiple bullae (HR 4.42, 95% CI 3.06–6.38; P < 0.001) were independent risk factors for spontaneous pneumothorax in the contralateral lung. The 5-year cumulative occurrence rates of PSP were significantly higher in patients with multiple blebs/bullae than in those with no or a single bleb/bulla (28.2% vs 8.5%, respectively; P < 0.001). CONCLUSIONS Asymptomatic blebs/bullae often lead to PSP. If the patient is eligible for surgery for pneumothorax, preemptive surgery for contralateral bullae could be considered, especially in patients with multiple blebs/bullae.

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Shift in Monocyte Apoptosis with Increasing Viral Load and Change in Apoptosis-Related ISG/Bcl2 Family Gene Expression in Chronically HIV-1-Infected Subjects

Journal of Virology ◽

10.1128/jvi.02382-14 ◽

2014 ◽

Vol 89 (1) ◽

pp. 799-810 ◽

Cited By ~ 11

Author(s):

Sean C. Patro ◽

Sharmistha Pal ◽

Yingtao Bi ◽

Kenneth Lynn ◽

Karam C. Mounzer ◽

...

Keyword(s):

Oxidative Stress ◽

Gene Expression ◽

Viral Load ◽

Multivariable Analysis ◽

Monocyte Activation ◽

Monocyte Apoptosis ◽

Induced Apoptosis ◽

The Impact ◽

And Oxidative Stress ◽

Hiv 1

ABSTRACTAlthough monocytes and macrophages are targets of HIV-1-mediated immunopathology, the impact of high viremia on activation-induced monocyte apoptosis relative to monocyte and macrophage activation changes remains undetermined. In this study, we determined constitutive and oxidative stress-induced monocyte apoptosis in uninfected and HIV+individuals across a spectrum of viral loads (n =35; range, 2,243 to 1,355,998 HIV-1 RNA copies/ml) and CD4 counts (range, 26 to 801 cells/mm3). Both constitutive apoptosis and oxidative stress-induced apoptosis were positively associated with viral load and negatively associated with CD4, with an elevation in apoptosis occurring in patients with more than 40,000 (4.6 log) copies/ml. As expected, expression of Rb1 and interferon-stimulated genes (ISGs), plasma soluble CD163 (sCD163) concentration, and the proportion of CD14++CD16+intermediate monocytes were elevated in viremic patients compared to those in uninfected controls. Although CD14++CD16+frequencies, sCD14, sCD163, and most ISG expression were not directly associated with a change in apoptosis, sCD14 and ISG expression showed an association with increasing viral load. Multivariable analysis of clinical values and monocyte gene expression identified changes in IFI27, IFITM2, Rb1, and Bcl2 expression as determinants of constitutive apoptosis (P= 3.77 × 10−5; adjustedR2= 0.5983), while changes in viral load, IFITM2, Rb1, and Bax expression were determinants of oxidative stress-induced apoptosis (P= 5.59 × 10−5; adjustedR2= 0.5996). Our data demonstrate differential activation states in monocytes between levels of viremia in association with differences in apoptosis that may contribute to greater monocyte turnover with high viremia.IMPORTANCEThis study characterized differential monocyte activation, apoptosis, and apoptosis-related gene expression in low- versus high-level viremic HIV-1 patients, suggesting a shift in apoptosis regulation that may be associated with disease state. Using single and multivariable analysis of monocyte activation parameters and gene expression, we supported the hypothesis that monocyte apoptosis in HIV disease is a reflection of viremia and activation state with contributions from gene expression changes within the ISG and Bcl2 gene families. Understanding monocyte apoptosis response may inform HIV immunopathogenesis, retention of infected macrophages, and monocyte turnover in low- or high-viral-load states.

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Donor and Recipient Envs from Heterosexual Human Immunodeficiency Virus Subtype C Transmission Pairs Require High Receptor Levels for Entry

Journal of Virology ◽

10.1128/jvi.02068-09 ◽

2010 ◽

Vol 84 (8) ◽

pp. 4100-4104 ◽

Cited By ~ 43

Author(s):

Melissa Alexander ◽

Rebecca Lynch ◽

Joseph Mulenga ◽

Susan Allen ◽

Cynthia A. Derdeyn ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Hela Cells ◽

Heterosexual Transmission ◽

Subtype C ◽

Significant Difference ◽

Immunodeficiency Virus ◽

Low Levels ◽

Different Levels ◽

Hiv 1 ◽

Virus Subtype

ABSTRACT Compact, glycan-restricted envelope (Env) glycoproteins are selected during heterosexual transmission of subtype C HIV-1. Donor and recipient glycoproteins (Envs) from six transmission pairs were evaluated for entry into HeLa cells expressing different levels of CD4 and CCR5. Donor and recipient Envs demonstrated efficient entry into cells expressing high levels of CD4 and CCR5, and entry declined as CCR5 levels decreased. Infectivity for all Envs was severely impaired in cells expressing low levels of CD4, even at the highest CCR5 levels. In 5/6 pairs, there was no significant difference in efficiency of receptor utilization between the donor and recipient Envs in these HeLa-derived cell lines. Thus, HIV-1 transmission does not appear to select for viruses that can preferentially utilize low levels of entry receptors.

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