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We report that people with human immunodeficiency virus (HIV) diagnosed with coronary artery atherosclerotic plaques display higher levels of HIV DNA compared with those without atherosclerotic plaques. In a multivariable prediction model that included 27 traditional and HIV-related risk factors, measures of HIV DNA were among the most important predictors of atherosclerotic plaque formation. [ABSTRACT FROM AUTHOR]

Despite the success of antiretroviral therapy (ART), people living with HIV (PLWH) are still at higher risk for cardiovascular diseases (CVDs) that are mediated by chronic inflammation. Identification of novel inflammatory mediators with the inherent potential to be used as CVD biomarkers and also as therapeutic targets is critically needed for better risk stratification and disease management in PLWH. Here, we investigated the expression and potential role of the multi-isoform proinflammatory cytokine IL-32 in subclinical atherosclerosis in PLWH (n=49 with subclinical atherosclerosis and n=30 without) and HIV- controls (n=25 with subclinical atherosclerosis and n=24 without). While expression of all tested IL-32 isoforms (α, β, γ, D, ϵ, and θ) was significantly higher in peripheral blood from PLWH compared to HIV- controls, IL-32D and IL-32θ isoforms were further upregulated in HIV+ individuals with coronary artery atherosclerosis compared to their counterparts without. Upregulation of these two isoforms was associated with increased plasma levels of IL-18 and IL-1β and downregulation of the atheroprotective protein TRAIL, which together composed a unique atherosclerotic inflammatory signature specific for PLWH compared to HIV- controls. Logistic regression analysis demonstrated that modulation of these inflammatory variables was independent of age, smoking, and statin treatment. Furthermore, our in vitro functional data linked IL-32 to macrophage activation and production of IL-18 and downregulation of TRAIL, a mechanism previously shown to be associated with impaired cholesterol metabolism and atherosclerosis. Finally, increased expression of IL-32 isoforms in PLWH with subclinical atherosclerosis was associated with altered gut microbiome (increased pathogenic bacteria; Rothia and Eggerthella species) and lower abundance of the gut metabolite short-chain fatty acid (SCFA) caproic acid, measured in fecal samples from the study participants. Importantly, caproic acid diminished the production of IL-32, IL-18, and IL-1β in human PBMCs in response to bacterial LPS stimulation. In conclusion, our studies identified an HIV-specific atherosclerotic inflammatory signature including specific IL-32 isoforms, which is regulated by the SCFA caproic acid and that may lead to new potential therapies to prevent CVD in ART-treated PLWH. [ABSTRACT FROM AUTHOR]

The identification of transmission clusters (TCs) of HIV-1 using phylogenetic analyses can provide insights into viral transmission network and help improve prevention strategies. We compared the use of partial HIV-1 envelope fragment of 1,070 bp with its loop 3 (108 bp) to determine its utility in inferring HIV-1 transmission clustering. Serum samples of recently (n = 106) and chronically (n = 156) HIV-1-infected patients with status confirmed were sequenced. HIV-1 envelope nucleotide-based phylogenetic analyses were used to infer HIV-1 TCs. Those were constructed using ClusterPickerGUI_1.2.3 considering a pairwise genetic distance of ≤10% threshold. Logistic regression analyses were used to examine the relationship between the demographic factors that were likely associated with HIV-1 clustering. Ninety-eight distinct consensus envelope sequences were subjected to phylogenetic analyses. Using a partial envelope fragment sequence, 42 sequences were grouped into 15 distinct small TCs while the V3 loop reproduces 10 clusters. The agreement between the partial envelope and the V3 loop fragments was significantly moderate with a Cohen's kappa (κ) coefficient of 0.59, p < .00001. The mean age (<38.8 years) and HIV-1 B subtype are two factors identified that were significantly associated with HIV-1 transmission clustering in the cohort, odds ratio (OR) = 0.25, 95% confidence interval (CI, 0.04–0.66), p = .002 and OR: 0.17, 95% CI (0.10–0.61), p = .011, respectively. The present study confirms that a partial fragment of the HIV-1 envelope sequence is a better predictor of transmission clustering. However, the loop 3 segment may be useful in screening purposes and may be more amenable to integration in surveillance programs. [ABSTRACT FROM AUTHOR]

Female sex workers (FSWs) continue to carry a heavy burden of sexually transmitted infections (STI). For prevention purposes, there is a need to identify most-at-risk subgroups among them. The objective of this longitudinal cohort study conducted at Dispensaire IST, Cotonou, Benin, was to assess Neisseria gonorrhoeae (NG) / Chlamydia trachomatis (CT) incidence and determinants; and HIV incidence among FSWs in presence of STI/HIV risk reduction activities. Overall, 319 adult FSWs were followed quarterly from September 2008 to March 2012. NG/CT were detected from endocervical swabs by Amplified DNA Assays employing Strand displacement amplification technology. HIV testing was done on capillary blood using two consecutive rapid diagnostic tests. Anderson-Gill proportional hazard models (HR) were used to determine factors independently associated with NG/CT incidence. The majority of FSWs were HIV-negative (188, 58.9%). There were 6 HIV seroconversions among these 188 HIV-negative women. HIV incidence (95% Confidence interval, CI) was 1.41 (0.28–2.54) seroconversions per 100 person-years at risk (PYAR): 6 events / 425.1 PYAR. Sixty-two out of 319 women experienced 83 new episodes of NG/CT for an overall incidence rate (95% CI) of 10.8 (8.17–13.88) events / 100 PYAR. From month-24 onwards, HIV-positive women (treated: HR (95%CI): 4.2 (1.60–10.77); untreated: HR (95%CI): 4.2 (1.59–11.49) were more likely to acquire NG/CT compared to HIV-negative FSWs. Longer duration in sex work (>2 years: HR; 95%CI: 0.4 (0.22–0.72)) was protective against NG/CT. Refusal by clients (55.8%) was the main reason for non-condom use. Enrolling women from one clinic (Dispensaire IST) may have impaired generalizability of the findings. New NG/CT/HIV infections were observed among FSWs notwithstanding ongoing prevention interventions. To eliminate HIV transmission among FSWs, STI/HIV control programs need to promote women’s empowerment and address vulnerability to infection of HIV-positive FSWs. [ABSTRACT FROM AUTHOR]

Identifying recent HIV-1 infections is crucial for monitoring HIV-1 incidence and optimizing public health prevention efforts. To identify recent HIV-1 infections, we evaluated and compared the performance of 4 sequence-based diversity measures including percent diversity, percent complexity, Shannon entropy and number of haplotypes targeting 13 genetic segments within the env gene of HIV-1. A total of 597 diagnostic samples obtained in 2013 and 2015 from recently and chronically HIV-1 infected individuals were selected. From the selected samples, 249 (134 from recent versus 115 from chronic infections) env coding regions, including V1-C5 of gp120 and the gp41 ectodomain of HIV-1, were successfully amplified and sequenced by next generation sequencing (NGS) using the Illumina MiSeq platform. The ability of the four sequence-based diversity measures to correctly identify recent HIV infections was evaluated using the frequency distribution curves, median and interquartile range and area under the curve (AUC) of the receiver operating characteristic (ROC). Comparing the median and interquartile range and evaluating the frequency distribution curves associated with the 4 sequence-based diversity measures, we observed that the percent diversity, number of haplotypes and Shannon entropy demonstrated significant potential to discriminate recent from chronic infections (p<0.0001). Using the AUC of ROC analysis, only the Shannon entropy measure within three HIV-1 env segments could accurately identify recent infections at a satisfactory level. The env segments were gp120 C2_1 (AUC = 0.806), gp120 C2_3 (AUC = 0.805) and gp120 V3 (AUC = 0.812). Our results clearly indicate that the Shannon entropy measure represents a useful tool for predicting HIV-1 infection recency. [ABSTRACT FROM AUTHOR]

From September 2008 to December 2011, we enrolled and followed-up 247 HIV-negative, 88 untreated and 32 treated HIV-positive female sex workers (FSWs), as well as 238 untreated and 115 treated HIV-positive patients from the general population (GP) of Cotonou, Benin. We wanted to assess the effect of antiretroviral therapy (ART) on sexual risk-taking in FSWs and patients from the GP. We used multivariate log binomial regression models for repeated measures to compare risky behaviours reported during pre-ART and post-ART visits and we performed linear time-trend analyses to assess changes in condom use in all five groups. At 58.8% of pre-ART and 45.3% of post-ART visits (adjustedp-value=0.293), treated FSWs have reported ≥16 clients during the last week of work. Inconsistent condom use with clients over the same period decreased by more than 50% (from 20.7 to 10.0%, adjustedp-value=0.082). In treated patients from the GP, inconsistent condom use with regular partners during the last four months was reported at 52.8% of pre-ART and 53.5% of post-ART visits (p=0.778). Reported casual sex was stable (36.8% versus 38.7%, adjustedp-value=0.924). In linear time-trend analyses, there was a significant downward trend in inconsistent condom use at the early stage of the study and stability thereafter in all HIV-negative and HIV-positive FSWs. There was no negative alteration in sexual behaviour following ART initiation either inpatients from the GP or in FSWs. The results underscore the key role of concomitant sexual risk-reduction strategies. [ABSTRACT FROM PUBLISHER]

Background: Resistance to CCR5 inhibitors, such as maraviroc and vicriviroc is characterized by reduction of maximal percent inhibition which indicates the use of an inhibitor-bound conformation of CCR5 for human immunodeficiency virus-1(HIV-1) entry. It is accompanied by substitutions in gp120 and gp41. Variable domain 3 (V3) plays the most important role, but substitutions outside V3 could also be involved in phenotype resistance. In this work, we investigated how mutations in variable regions of the viral envelope protein gp120 can contribute to CCR5 inhibitor resistance. Methods: Resistant isolates were selected by passaging CC1/85 and BaL viruses with sub-inhibitory MVC and VCV concentrations. Mutations in gp160 were identified and mutants containing V2 (V169M), V3 (L317W) and V4 (I408T) were constructed. Results: MVC and VCV susceptibility and viral tropism were assessed by single cycle assay. Mutant I408T showed 4-fold change (FC) increase in the half maximal inhibitory concentration (IC50) to MVC, followed by L317W (1.52-FC), V169M (1.23-FC), V169M/I408T (4-FC) L317W/I408T (3-FC), V169M/L317W (1.30-FC), and V169M/L317W/I408T (3.31-FC). MPI reduction was observed for mutants I408T (85%), L317W (95%), V169M/I408T (84%), L317W/I408T (85%) and V169M/L317W/I408T (83%). For VCV, I408T increased the IC50 by 2-FC and few mutants showed MPI reduction less than 95%: I408T (94%), L317W/I408T (94%) and V169M/L317W/I408T (94%). All mutants remained R5-tropic and presented decreased infectivity. Conclusions: These results suggest that mutations in the V4 loop of HIV-1 may contribute to MVC and VCV resistance alone or combined with mutations in V2 and V3 loops. [ABSTRACT FROM AUTHOR]

Background: Gene expression analyses are used to investigate signaling pathways involved in diseases. In asthma, they have been primarily derived from the analysis of bronchial biopsies harvested from mild to moderate asthmatic subjects and controls. Due to ethical considerations, there is currently limited information on the transcriptome profile of the peripheral lung tissues in asthma. Objective: To identify genes contributing to chronic inflammation and remodeling in the peripheral lung tissue of horses with heaves, a naturally occurring asthma-like condition. Methods: Eleven adult horses (6 heaves-affected and 5 controls) were studied while horses with heaves were in clinical remission (Pasture), and during disease exacerbation induced by a 30-day natural antigen challenge during stabling (Challenge). Large peripheral lung biopsies were obtained by thoracoscopy at both time points. Using suppression subtractive hybridization (SSH), lung cDNAs of controls (Pasture and Challenge) and asymptomatic heaves-affected horses (Pasture) were subtracted from cDNAs of horses with heaves in clinical exacerbation (Challenge). The differential expression of selected genes of interest was confirmed using quantitative PCR assay. Results: Horses with heaves, but not controls, developed airway obstruction when challenged. Nine hundred and fifty cDNA clones isolated from the subtracted library were screened by dot blot array and 224 of those showing the most marked expression differences were sequenced. The gene expression pattern was confirmed by quantitative PCR in 15 of 22 selected genes. Novel genes and genes with an already defined function in asthma were identified in the subtracted cDNA library. Genes of particular interest associated with asthmatic airway inflammation and remodeling included those related to PPP3CB/NFAT, RhoA, and LTB4/GPR44 signaling pathways. Conclusions: Pathways representing new possible targets for anti-inflammatory and anti-remodeling therapies for asthma were identified. The findings of genes previously associated with asthma validate this equine model for gene expression studies. [ABSTRACT FROM AUTHOR]

The inflammatory component in obesity is now well established. The CX3CR1 gene encodes the fractalkine (CX3CL1) receptor and has two coding single-nucleotide polymorphisms, V249I and T280M, linked to a lower risk of other inflammatory diseases such as coronary artery disease (CAD) and asthma. To determine whether CX3CR1 is associated with obesity, we genotyped the V249I and T280M polymorphisms of the CX3CR1 gene in subjects with a BMI ≥30 kg/m2 and nonobese controls with a BMI <30 kg/m2. Binary logistic regression analyses revealed that the 280MM genotype was associated with obesity (P = 0.022). A gender-specific one-way ANOVA was also conducted to investigate mean BMI and waist circumference differences between genotypes of each polymorphism. For both polymorphisms independently, women carrying two copies of the minor allele had significant higher mean waist circumference than those carrying only one copy of the minor allele (MM > TM, P = 0.031; II > VI, P = 0.013) or those who were homozygous for the major allele (MM > TT, P = 0.005; II > VV, P = 0.006). We also observed significant higher mean waist circumference in men carrying one copy of the minor allele when compared to those who were homozygous for the major allele for the T280M polymorphism (TM > TT, P = 0.029). This study suggests that CX3CR1, a biomarker of obesity in this sample, constitutes a potential target for further investigation of the role of inflammation in the expression of obesity-related phenotypes. [ABSTRACT FROM AUTHOR]

Allergic asthma is a complex trait. Several approaches have been used to identify biomarkers involved in this disease. This study aimed at demonstrating the relevance and validity of microarrays in the definition of allergic asthma expression pattern. The authors compared the transcript expressions of bronchial biopsy of 2 different microarray experiments done 2 years apart, both including nonallergic healthy and allergic asthmatic subjects (n = 4 in each experiment). U95Av2 and U133A GeneChips detected respectively 89 and 40 differentially expressed genes. Fifty-five percent of the U133A genes were previously identified with the U95Av2 arrays. The immune signaling molecules and the proteolytic enzymes were the most preserved categories between the 2 experiments, because 3/4 of the genes identified by the U133A were also significant in the U95Av2 study for both categories. These results demonstrate the relevance of microarray experiments using bronchial tissues in allergic asthma. The comparison of these GeneChip studies suggests that earlier microarray results are as relevant as actual ones to target new genes of interest, particularly in function categories linked to the studied disease. Moreover, it demonstrates that microarrays are a valuable technology to target novel allergic asthma pathways as well as biomarkers. [ABSTRACT FROM AUTHOR]

Background: HIV-1 transmitted/founder viruses (TF) are selected during the acute phase of infection from a multitude of virions present during transmission. They possess the capacity to establish infection and viral dissemination in a new host. Deciphering the discrete genetic determinant of infectivity in their envelope may provide clues for vaccine design. Methods: One hundred twenty-six clade B HIV-1 consensus envelope sequences from untreated acute and early infected individuals were compared to 105 sequences obtained from chronically infected individuals using next generation sequencing and molecular analyses. Results: We identified an envelope amino acid signature associated with TF viruses. They are more likely to have an isoleucine (I) in position 841 instead of an arginine (R). This mutation of R to I (R841I) in the gp41 cytoplasmic tail (gp41CT), specifically in lentivirus lytic peptides segment 1 (LLP-1), is significantly enriched compared to chronic viruses (OR = 0.2, 95% CI (0.09, 0.44), p = 0.00001). Conversely, a mutation of lysine (K) to isoleucine (I) located in position six (K6I) of the envelope signal peptide was selected by chronic viruses and compared to TF (OR = 3.26, 95% CI (1.76–6.02), p = 0.0001). Conclusions: The highly conserved gp41 CT_ LLP-1 domain plays a major role in virus replication in mediating intracellular traffic and Env incorporation into virions in interacting with encoded matrix protein. The presence of an isoleucine in gp41 in the TF viruses' envelope may sustain its role in the successful establishment of infection during the acute stage. [ABSTRACT FROM AUTHOR]

An abstract of the article "Loss of Viral Control in a Subset of HIV-Infected Long-term Non-progressors Is Associated with a Decline of an Array of Antiviral Responses" by Mohamed El-Far, Pascale Kouassi, Odalis Asin-Milan, and colleagues is presented.

Recent studies indicate that sexual transmission of human immunodeficiency virus type 1 (HIV-1) generally results from productive infection by only one virus, a finding attributable to the mucosal barrier. Surprisingly, a recent study of injection drug users (IDUs) from St. Petersburg, Russia, also found most subjects to be acutely infected by a single virus. Here, we show by single-genome amplification and sequencing in a different IDU cohort that 60% of IDU subjects were infected by more than one virus, including one subject who was acutely infected by at least 16 viruses. Multivariant transmission was more common in IDUs than in heterosexuals (60% versus 19%; odds ratio, 6.14; 95% confidence interval [CI], 1.37 to 31.27; P = 0.008). These findings highlight the diversity in HIV-1 infection risks among different IDU cohorts and the challenges faced by vaccines in protecting against this mode of infection. [ABSTRACT FROM AUTHOR]

Background: Human IL-32 is a polyfunctional cytokine that was initially reported to inhibit HIV-1 infection. However, recent data suggest that IL-32 may enhance HIV-1 replication by activating the HIV-1 primary targets, CD4 T-cells. Indeed, IL-32 is expressed in multiple isoforms, some of which are proinflammatory, whereas others are anti-inflammatory., Setting and Methods: Here, we aimed to determine the relative expression of IL-32 isoforms and to test their inflammatory nature and potential to induce HIV-1 production in latently infected cells from virologically suppressed HIV-infected individuals. IL-32 and other cytokines were quantified from plasma and supernatant of CD4 T-cells by ELISA. Transcripts of IL-32 isoforms were quantified by qRT-PCR in peripheral blood mononuclear cells. The impact of recombinant human IL-32 isoforms on HIV-1 transcription was assessed in CD4 T-cells from HIV-1cART individuals by qRT-PCR., Results: All IL-32 isoforms were significantly upregulated in HIV-1cART compared to HIV individuals with IL-32β representing the dominantly expressed isoform, mainly in T-cells and NK-cells. At the functional level, although IL-32γ induced typical proinflammatory cytokines (IL-6 and IFN-γ) in TCR-activated CD4 T-cells, IL-32α showed an anti-inflammatory profile by inducing IL-10 but not IL-6 or IFN-γ. However, IL-32β showed a dual phenotype by inducing both pro- and anti-inflammatory cytokines. Interestingly, consistent with its highly pro-inflammatory nature, IL-32γ, but not IL-32α or IL-32β, induced HIV-1 production in latently infected CD4 T-cells isolated from combined antiretroviral therapy-treated individuals., Conclusions: Our data report on the differential expression of IL-32 isoforms and highlight the potential role of IL-32, particularly the γ isoform, in fueling persistent inflammation and transcription of viral reservoir in HIV-1 infection.

Here, we evaluated the in vitro anti-HIV-1 activity of the experimental CCR5 inhibitor VCH-286 as a single agent or in combination with various classes of HIV-1 inhibitors. Although VCH-286 used alone had highly inhibitory activity, paired combinations with different drug classes led to synergistic or additive interactions. However, combinations with other CCR5 inhibitors led to effects ranging from synergy to antagonism. We suggest that caution should be exercised when combining CCR5 inhibitors in vivo., (Copyright © 2014, American Society for Microbiology. All Rights Reserved.)

Background: Sub-Saharan Africa has seen dramatic increases in the numbers of people treated with antiretroviral therapy (ART). Although standard ART regimens are now universally applied, viral load measurement is not currently part of standard monitoring protocols in sub-Saharan Africa., Methods: We describe the prevalence of inadequate virological response (IVR) to ART (viral load >or= 500 copies/mL) and identify factors associated with this outcome in 606 HIV-positive patients treated for at least 6 months. Recruitment took place in 7 hospitals and community-based sites in Bamako and Ouagadougou, and information was collected using medical charts and interviews., Results: The overall prevalence of IVR in treatment-naive patients was 12.3% and 24.4% for pretreated patients. There were no differences in rates of IVR according to ART delivery sites and time on treatment. Patients living farther away [odds ratio (OR) = 2.48; 95% confidence interval (CI) 1.40 to 4.39], those on protease inhibitor or nucleoside reverse transcriptase inhibitor regimens (OR = 3.23; 95% CI 1.79 to 5.82) and those reporting treatment interruptions (OR = 2.36; 95% CI 1.35 to 4.15), had increased odds of IVR. Immune suppression (OR = 3.32, 95% CI 1.94 to 5.70) and poor self-rated health (OR = 2.00; 95% CI 1.17 to 3.41) were also associated with IVR., Conclusions: Sufficient expertise and dedication exist in public hospital and community-based programs to achieve rates of treatment success comparable to better-resourced settings.

Background: In a multicentred cohort of patients on antiretroviral therapy (ART) in Burkina Faso and Mali, we analysed the prevalence of HIV drug resistance mutations in patients failing a modified directly observed therapy (mDOT) protocol., Methods: Patients on ART >6 months and with viral load (VL) >500 copies/ml were enrolled in a mDOT protocol. Genotypic resistance testing was performed on pre- and post-mDOT plasma samples of patients who still had VL >500 copies/ml after mDOT., Results: Eight hundred and one patients from seven sites participated in the study. One hundred and thirteen patients (14.1%) had VL >500 copies/ml. Most patients were treated with lamivudine along with zidovudine or stavudine and efavirenz or nevirapine. Genotypes were available for 46 patients. The predominant HIV-1 subtypes were CRFO2&#95;AG in 26 (56.5%) and AGK/K/AK in 12 (26.1%) patients. The prevalence of drug resistance mutations by class were as follows for nucleoside reverse transcriptase inhibitors: 1841/V (82.6%), 215Y/F (32.6%), 219E/Q (19.6%), 70R (19.6%), 67N (21.7%), 41L (15.2%) and 151M(2.2%). For non-nucleoside reverse transcriptase inhibitors the prevalence was: 103N (50%) and 181C/I (19.6%). Phylogenetic analysis showed that, although the genetic distances were small among isolates, there was no clustering of a particular subtype in a specific region and that the high prevalence of AGK subtype in our drug-resistant population was not due to a circulating resistant strain., Conclusion: Although CRFO2&#95;AG is the dominant clade in the Burkina Faso/Mali region, isolates with subtype K reverse transcriptase were frequent in our cohort. Drug resistance mutation pathways in subtype K reverse transcriptase need to be further evaluated in a larger cohort of non-B HIV-infected individuals.

We evaluated the in vitro anti-human immunodeficiency virus type 1 (HIV-1) interactions between 1-beta-D-2,6-diaminopurine dioxolane (DAPD) and enfuvirtide (T-20) against clinical isolates sensitive and resistant to reverse transcriptase and protease inhibitors. Interactions between T-20 and DAPD were synergistic to nearly additive, with combination index values ranging from 0.53 to 1.06 at 95% inhibitory concentrations. These studies suggest that a combination of T-20 and DAPD might be useful in the treatment of antiretroviral drug-experienced patients.