In this review we discuss the structure and functions of the aspartate/glutamate carriers (AGC1-aralar and AGC2-citrin). Those proteins supply the aspartate synthesized within mitochondrial matrix to ...the cytosol in exchange for glutamate and a proton. A structure of an AGC carrier is not available yet but comparative 3D models were proposed. Moreover, transport assays performed by using the recombinant AGC1 and AGC2, reconstituted into liposome vesicles, allowed to explore the kinetics of those carriers and to reveal their specific transport properties. AGCs participate to a wide range of cellular functions, as the control of mitochondrial respiration, calcium signaling and antioxydant defenses. AGC1 might also play peculiar tissue-specific functions, as it was found to participate to cell-to-cell metabolic symbiosis in the retina. On the other hand, AGC1 is involved in the glutamate-mediated excitotoxicity in neurons and AGC gene or protein alterations were discovered in rare human diseases. Accordingly, a mice model of AGC1 gene knock-out presented with growth delay and generalized tremor, with myelinisation defects. More recently, AGC was proposed to play a crucial role in tumor metabolism as observed from metabolomic studies showing that the asparate exported from the mitochondrion by AGC1 is employed in the regeneration of cytosolic glutathione. Therefore, given the central role of AGCs in cell metabolism and human pathology, drug screening are now being developed to identify pharmacological modulators of those carriers. This article is part of a Special Issue entitled: Mitochondrial Channels edited by Pierre Sonveaux, Pierre Maechler and Jean-Claude Martinou.
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•AGC1 and AGC2 export aspartate from mitochondria in exchange for cytosolic glutamate and a proton.•The kinetic properties of AGCs were extensively studied in proteoliposomes.•AGCs participate to cellular REDOX homeostasis and the calcium-mediated control of mitochondrial respiration via the malate-aspartate shuttle.•AGCs gene deficiencies are responsible for rare diseases.•AGC1 is central to neuronal physiology and also plays a role in glutamate-induced excitotoxicity.•AGCs are overexpressed in several types of human tumors.•In silico and in vitro screenings of chemical libraries for identifying new AGC pharmacological modulators are in progress
To examine the impact of transmitted drug resistance (TDR) on response to first-line regimens with integrase strand transfer inhibitors (INSTIs) or boosted protease inhibitors (bPIs).
From an Italian ...observational database (ARCA) we selected HIV-1-infected drug-naive patients starting two NRTIs and either an INSTI or a bPI, with an available pre-ART resistance genotype. The endpoint was virological failure (VF; plasma HIV-1 RNA >200 copies/mL after week 24). WHO surveillance drug resistance mutations and the Stanford algorithm were used to classify patients into three resistance categories: no TDR (A), TDR but fully-active ART prescribed (B), TDR and at least low-level resistance to one or more prescribed drug (C).
We included 1365 patients with a median follow-up of 96 weeks (IQR 54-110): 1205 (88.3%) starting bPI and 160 (11.7%) INSTI. Prevalence of TDR was 6.1%, 12.5%, 2.6% and 0% for NRTI, NNRTI, bPI and INSTI, respectively. Cumulative Kaplan-Meier estimates for VF at 48 weeks were 11% (95% CI 10.1%-11.9%) for the bPI group and 7.7% (95% CI 5.4%-10%) for the INSTI group. In the INSTI group, cumulative estimates for VF at 48 weeks were 6% (95% CI 4%-8%) in resistance category A, 5% (95% CI 1%-10%) in B and 50% (95% CI 30%-70%) in C (P < 0.001). Resistance category C versus A, adjusted hazard ratio (aHR) 12.6, 95% CI 3.2-49.8, P < 0.001 and nadir CD4 (+100 cells/mm3, aHR 0.6, 95% CI 0.4-0.9, P = 0.03) predicted VF. In the bPI group, VF rates were not influenced by baseline resistance.
Our data support the need for NRTI resistance genotyping in patients starting an INSTI-based first-line ART.
Objectives
The aim was to evaluate the evolution of transmitted HIV‐1 drug resistance (TDR) prevalence in antiretroviral therapy (ART)‐naïve patients from 2006 to 2016.
Methods
HIV‐1 sequences were ...retrieved from the Antiviral Response Cohort Analysis (ARCA) database and TDR was defined as detection of at least one mutation from the World Health Organization (WHO) surveillance list.
Results
We included protease/reverse transcriptase sequences from 3573 patients; 455 had also integrase sequences. Overall, 68.1% of the patients were Italian, the median CD4 count was 348 cells/μL interquartile range (IQR) 169–521 cells/μL, and the median viral load was 4.7 log10 HIV‐1 RNA copies/mL (IQR 4.1–5.3 log10 copies/mL). TDR was detected in 10.3% of patients: 6% carried mutations to nucleos(t)ide reverse transcriptase inhibitors (NRTIs), 4.4% to nonnucleos(t)ide reverse transcriptase inhibitors (NNRTIs), 2.3% to protease inhibitors (PIs), 0.2% to integrase strand transfer inhibitors (INSTIs) and 2.1% to at least two drug classes. TDR declined from 14.5% in 2006 to 7.3% in 2016 (P = 0.003): TDR to NRTIs from 9.9 to 2.9% (P = 0.003) and TDR to NNRTIs from 5.1 to 3.7% (P = 0.028); PI TDR remained stable. The proportion carrying subtype B virus declined from 76.5 to 50% (P < 0.001). The prevalence of TDR was higher in subtype B vs. non‐B (12.6 vs. 4.9%, respectively; P < 0.001) and declined significantly in subtype B (from 17.1 to 8.8%; P = 0.04) but not in non‐B subtypes (from 6.1 to 5.8%; P = 0.44). Adjusting for country of origin, predictors of TDR were subtype B adjusted odds ratio (AOR) for subtype B vs. non‐B 2.91; 95% confidence interval (CI) 1.93–4.39; P < 0.001, lower viral load (per log10 higher: AOR 0.86; 95% CI 0.75–0.99; P = 0.03), site in northern Italy (AOR for southern Italy/island vs. northern Italy, 0.61; 95% CI 0.40–0.91; P = 0.01), and earlier calendar year (per 1 year more recent: AOR 0.95; 95% CI 0.91–0.99; P = 0.02).
Conclusions
The prevalence of HIV‐1 TDR has declined during the last 10 years in Italy.
•We analyzed durability and virological response to DTG-containing regimens.•After exposure to first-generation INIs, treatment with DTG showed long durability.•DTG-containing regimens did not show ...any virological rebound after suppression.•DTG discontinuation was less frequent in patients who had experienced ≥10 regimens.•Non-B HIV-1 subtype represented a greater risk for detectable HIV-RNA at the last F–U.
Dolutegravir (DTG) is a next-generation HIV integrase inhibitor (INI) with an increased genetic barrier to resistance with respect to raltegravir (RAL) or elvitegravir (EVG). Few data are available on the durability of DTG-containing regimens.
We aimed at investigating the duration of the DTG-containing regimen, the occurrence of an HIV-1 RNA blip, and factors associated with DTG virological response.
From the Antiviral Response Cohort Analysis database, we selected 89 HIV-1-positive four-class-experienced subjects who started DTG after receiving RAL or EVG. Factors associated with durability and virological response were analysed by logistic regression.
After a median duration of 18.8 0.4–76.2 months, 79/89 (88.8%) subjects were still on DTG. All subjects remaining on DTG at the end of follow-up had undetectable HIV-1 RNA, compared to 5/10 subjects who discontinued DTG. DTG discontinuation was less frequent in patients who had experienced ≥10 regimens (HR 0.11, p = 0.040). The probability of having an HIV-1 RNA positive value at the last follow-up significantly increased in patients with non-B HIV-1 subtype (HR 5.77, p < .001) and significantly decreased in patients with CD4 nadir >200/μL (HR 0.29, p = 0.038), with more than 10 previous regimens (HR 0.27, p = 0.040), and who harbored virus with IN mutations (HR 0.12, p = 0.023) at DTG start.
After previous exposure to first-generation INIs, treatment with DTG showed long durability and did not show virological rebound after virological suppression. Subjects infected with a non-B HIV-1 subtype had a greater risk of having detectable HIV-1 RNA at the last observation.
In this paper we present a rigorous derivation of the luminosity function (LF) in the presence of a background. Our approach is free from the logical contradictions of assigning negative values to ...positively defined quantities and avoids the use of incorrect estimates for the 68 per cent confidence interval (error bar). It accounts for Poisson fluctuations ignored in previous approaches and does not require binning of the data. The method is extensible to more complex situations, does not require the existence of an environment-independent LF, and clarifies issues common to field LF derivations. We apply the method to two clusters of galaxies at intermediate redshift (z∼ 0.3) with among the deepest and widest Ks observations ever taken. Finally, we point out the shortcomings of flip-flopping magnitudes.
Objectives
We assessed whether changes in community viral load (CVL) over time were associated with the rate of new HIV diagnoses (NDs).
Methods
HIV‐1‐positive individuals referred to our institute ...and permanently residing in our province were considered for inclusion in the study. A total of 861 HIV‐infected adults with at least one HIV RNA measurement (12 530 measurements in total) between 2008 and 2014 were included. Viraemia copy‐years were calculated from all HIV RNA values for each patient using the trapezoidal rule; multiple CVL indicators were considered. Total NDs and recent infections (< 1 year) were analysed separately. The association between NDs and CVL was tested by means of mixed Poisson models, with CVL as a fixed effect and year as a random effect.
Results
The incidence of NDs was 2.28 per 100 000 residents in 2008 and 2.52 per 100 000 residents in 2014. Total numbers of NDs and recent infections did not vary significantly over time (P for trend 0.879 and 0.39, respectively). Mean HIV RNA decreased from 31 095.8 HIV‐1 RNA copies/mL in 2008 to 21 231.5 copies/mL in 2014 (P < 0.001); a downward trend was always observed regardless of the CVL indicator considered. Depending on the indicator, there were some differences in CVL by patient characteristics. The most substantial contributors to CVL appeared to be male individuals, men who have sex with men (MSM), non‐Italians, and untreated subjects (all P < 0.05). The relative risk of ND increased among Italians and MSM with an increasing proportion of subjects having an undetectable HIV RNA, and decreased in the same population with increasing levels of CVL.
Conclusions
In our setting, CVL represented a good marker of access to care and treatment; however, reduced CVL did not coincide with a reduction in the rate of NDs.
Prevalence and predictors of transmitted drug resistance (TDR), defined as the presence of at least one WHO surveillance drug resistance mutation (SDRM), were investigated in antiretroviralnaїve ...HIV-1-infected patients, with a genotypic resistance test (GRT) performed ≤6 months before starting cART between 2000 and 2010. 3163 HIV-1 sequences were selected (69% subtype B). Overall, the prevalence of TDR was 12% (13.2% subtype B, 9% non-B). TDR significantly declined overall and for the single drug classes. Older age independently predicted increased odds of TDR, whereas a more recent GRT, a higher HIV-RNA and C vs. B subtype predicted lower odds of TDR.
The prevalence of HIV-1 integrase mutations related to resistance to the next-generation integrase inhibitor (INI), dolutegravir (DTG), was assessed in 440 INI-naïve subjects and in 120 patients ...failing a raltegravir (RTG)-containing regimen. Of the mutations selected by DTG in vitro, S153FY was not detected in any isolate while L101I and T124A were highly prevalent in both groups and significantly associated with non-B subtype. RTG-selected double and triple mutants, mostly the G140S/Q148H variant, were detected in only 32 (26.7%) RTG-treated patients. As L101I and T124A do not appear to exert any major effect in vivo and double and triple mutants resistant to DTG are infrequently selected by RTG, DTG can be effectively used in INI-naïve patients and may retain activity in many patients failing RTG.
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