Multiomics plasma effects of switching from triple antiretroviral regimens to dolutegravir plus lamivudine.

Introduction: The DOLAM trial revealed that switching from triple antiretroviral therapy (three-drug regimen; 3DR) to dolutegravir plus lamivudine (two-drug regimen; 2DR) was virologically non-inferior to continuing 3DR after 48 weeks of follow-up. Weight increased with 2DR relative to 3DR but it did not impact on metabolic parameters.

Methods: Multiomics plasma profile was performed to gain further insight into whether this therapy switch might affect specific biological pathways.

The HIV-1 reservoir landscape in persistent elite controllers and transient elite controllers.

BACKGROUNDPersistent controllers (PCs) maintain antiretroviral-free HIV-1 control indefinitely over time, while transient controllers (TCs) eventually lose virological control. It is essential to characterize the quality of the HIV reservoir in terms of these phenotypes in order to identify the factors that lead to HIV progression and to open new avenues toward an HIV cure.METHODSThe characterization of HIV-1 reservoir from peripheral blood mononuclear cells was performed using next-generation sequencing techniques, such as full-length individual and matched integration site proviral sequencing (FLIP-Seq; MIP-Seq).

Multi-omics in HIV: searching insights to understand immunological non-response in PLHIV.

Antiretroviral therapy (ART) induces persistent suppression of HIV-1 replication and gradual recovery of T-cell counts, and consequently, morbidity and mortality from HIV-related illnesses have been significantly reduced. However, in approximately 30% of people living with HIV (PLHIV) on ART, CD4 T-cell counts fail to normalize despite ART and complete suppression of HIV viral load, resulting in severe immune dysfunction, which may represent an increased risk of clinical progression to AIDS and non-AIDS events as well as increased mortality. These patients are referred to as "immune inadequate responders", "immunodiscordant responders" or "immune nonresponders (INR)".

Lipoprotein Profile in Immunological Non-Responders PLHIV after Antiretroviral Therapy Initiation.

Nuclear magnetic resonance (NMR)-based advanced lipoprotein tests have demonstrated that LDL and HDL particle numbers (LDL-P and HDL-P) are more powerful cardiovascular (CV) risk biomarkers than conventional cholesterol markers. Of interest, in people living with HIV (PLHIV), predictors of preclinical atherosclerosis and vascular dysfunction may be associated with impaired immune function. We previously stated that immunological non-responders (INR) were at higher CV risk than immunological responders (IR) before starting antiretroviral therapy (ART).

Elevated α-Ketoglutaric Acid Concentrations and a Lipid-Balanced Signature Are the Key Factors in Long-Term HIV Control.

Long-term elite controllers (LTECs) are a fascinating small subset of HIV individuals with viral and immunological HIV control in the long term that have been designated as models of an HIV functional cure. However, data on the LTEC phenotype are still scarce, and hence, the metabolomics and lipidomics signatures in the LTEC-extreme phenotype, LTECs with more than 10 years of viral and immunological HIV control, could be pivotal to finding the keys for functional HIV remission. Metabolomics and lipidomics analyses were performed using high-resolution mass spectrometry (ultra-high-performance liquid chromatography-electrospray ionization-quadrupole time of flight [UHPLC-(ESI) qTOF] in plasma samples of 13 patients defined as LTEC-extreme, a group of 20 LTECs that lost viral and/or immunological control during the follow-up study (LTEC-losing) and 9 EC patients with short-term viral and immunological control (less than 5 years; no-LTEC patients).

Adipokines as New Biomarkers of Immune Recovery: Apelin Receptor, RBP4 and ZAG Are Related to CD4 T-Cell Reconstitution in PLHIV on Suppressive Antiretroviral Therapy.

A significant proportion of people living with HIV (PLHIV) who successfully achieve virological suppression fail to recover CD4 T-cell counts. Since adipose tissue has been discovered as a key immune organ, this study aimed to assess the role of adipokines in the HIV immunodiscordant response. This is a multicenter prospective study including 221 PLHIV starting the first antiretroviral therapy (ART) and classified according to baseline CD4 T-cell counts/µL (controls > 200 cells/µL and cases ≤ 200 cells/µL).

Early antiretroviral therapy initiation effect on metabolic profile in vertically HIV-1-infected children.

Background: Early combined antiretroviral treatment (cART) in perinatally acquired HIV-1 children has been associated with a rapid viral suppression, small HIV-1 reservoir size and reduced mortality and morbidity. Immunometabolism has emerged as an important field in HIV-1 infection offering both relevant knowledge regarding immunopathogenesis and potential targets for therapies against HIV-1.

Objectives: To characterize the proteomic, lipidomic and metabolomic profile of HIV-1-infected children depending on their age at cART initiation.

High circulating SDF-1and MCP-1 levels and genetic variations in CXCL12, CCL2 and CCR5: Prognostic signature of immune recovery status in treated HIV-positive patients.

Background: The underlying mechanisms of incomplete immune reconstitution in treated HIV-positive patients are very complex and may be multifactorial, but perturbation of chemokine secretion could play a key role in CD4T-cell turnover.

Methods: We evaluated the circulating baseline and 48-week follow-up concentrations of SDF-1/CXCL12, fractalkine/CX3CL1, MCP-1/CCL2, MIP-α/CCL3, MIP-β/CCL4 and RANTES/CCL5, and we estimated their association with CXCL12, CX3CR1, CCR2, CCL5 and CCR5 single nucleotide polymorphisms (SNPs) to investigate multiple chemokine-chemokine receptor signatures associated with immune dysregulation preceding poor immune recovery.

Findings: The circulating concentrations and gene expression patterns of SDF-1/CXCL12 (CXCL12 rs1801157) and MCP-1/CCL2 (CCR2 rs1799864_814) were associated with immune recovery status.

IL-7/IL-7R gene variants impact circulating IL-7/IL-7R homeostasis and ART-associated immune recovery status.

A relationship between polymorphisms in genes encoding interleukin 7 (IL-7) and its cellular receptor (IL-7R) and antiretroviral therapy (ART)-associated immune recovery in HIV subjects has been previously reported. However, details of this relationship remain unclear, and the association of these polymorphisms with circulating IL-7/IL-7R levels is scarce. Here, we explored whether IL-7/IL-7R axis was associated with quantitative CD4 T-cell recovery in HIV-infected subjects.

Glutaminolysis and lipoproteins are key factors in late immune recovery in successfully treated HIV-infected patients.

The immunological, biochemical and molecular mechanisms associated with poor immune recovery are far from known, and metabolomic profiling offers additional value to traditional soluble markers. Here, we present novel and relevant data that could contribute to better understanding of the molecular mechanisms preceding a discordant response and HIV progression under suppressive combined antiretroviral therapy (cART). Integrated data from nuclear magnetic resonance (NMR)-based lipoprotein profiles, mass spectrometry (MS)-based metabolomics and soluble plasma biomarkers help to build prognostic and immunological progression tools that enable the differentiation of HIV-infected subjects based on their immune recovery status after 96 weeks of suppressive cART.

Immunometabolism is a key factor for the persistent spontaneous elite control of HIV-1 infection.

Background: Approximately 25% of elite controllers (ECs) lose their virological control by mechanisms that are only partially known. Recently, immunovirological and proteomic factors have been associated to the loss of spontaneous control. Our aim was to perform a metabolomic approach to identify the underlying mechanistic pathways and potential biomarkers associated with this loss of control.

Proteomic Profile Associated With Loss of Spontaneous Human Immunodeficiency Virus Type 1 Elite Control.

Background: Elite controllers (ECs) spontaneously control plasma human immunodeficiency virus type 1 (HIV-1) RNA without antiretroviral therapy. However, 25% lose virological control over time. The aim of this work was to study the proteomic profile that preceded this loss of virological control to identify potential biomarkers.

Circulating metabolomic profile can predict dyslipidemia in HIV patients undergoing antiretroviral therapy.

Background And Aims: Dyslipidemia in HIV-infected patients is unique and pathophysiologically associated with host factors, HIV itself and the use of antiretroviral therapy (ART). The use of nuclear magnetic resonance spectroscopy (NMR) provides additional data to conventional lipid measurements concerning the number of lipoprotein subclasses and particle sizes.

Methods: To investigate the ability of lipoprotein profile, we used a circulating metabolomic approach in a cohort of 103 ART-naive HIV-infected patients, who were initiating non-nucleoside analogue transcriptase inhibitor (NNRTI)-based ART, and we subsequently followed up these patients for 36 months.

A baseline metabolomic signature is associated with immunological CD4+ T-cell recovery after 36 months of antiretroviral therapy in HIV-infected patients.

Objectives: Poor immunological recovery in treated HIV-infected patients is associated with greater morbidity and mortality. To date, predictive biomarkers of this incomplete immune reconstitution have not been established. We aimed to identify a baseline metabolomic signature associated with a poor immunological recovery after antiretroviral therapy (ART) to envisage the underlying mechanistic pathways that influence the treatment response.

Relationship between plasma bilirubin level and oxidative stress markers in HIV-infected patients on atazanavir- vs. efavirenz-based antiretroviral therapy.

Objectives: Chronic oxidative stress (OS) may play a role in cardiovascular disease in HIV-infected patients, and increased bilirubin levels may have a beneficial role in counteracting OS. Atazanavir (ATV) inhibits UDP-glucuronosyl-transferase 1A1 (UGT1A1), thus increasing unconjugated bilirubin levels. We aimed to compare changes in OS markers in patients on ATV/ritonavir (ATV/r)- vs.

HIV-1/HAART-Related Lipodystrophy Syndrome (HALS) Is Associated with Decreased Circulating sTWEAK Levels.

Background And Objectives: Obesity and HIV-1/HAART-associated lipodystrophy syndrome (HALS) share clinical, pathological and mechanistic features. Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a multifunctional cytokine that plays an important role in obesity and related diseases. We sought to explore the relationship between HALS and circulating levels of soluble (s) TWEAK and its scavenger receptor sCD163.

HIV/antiretroviral therapy-related lipodystrophy syndrome (HALS) is associated with higher RBP4 and lower omentin in plasma.

Very little information is available on the involvement of newly characterized adipokines in human immunodeficiency virus (HIV)/antiretroviral therapy (ART)-associated lipodystrophy syndrome (HALS). Our aim was to determine whether apelin, apelin receptor, omentin, RBP4, vaspin and visfatin genetic variants and plasma levels are associated with HALS. We performed a cross-sectional multicentre study that involved 558 HIV type 1-infected patients treated with a stable highly active ART regimen, 240 of which had overt HALS and 318 who did not have HALS.

Involvement of the LPS-LPB-CD14-MD2-TLR4 inflammation pathway in HIV-1/HAART-associated lipodystrophy syndrome (HALS).

Objectives: A relationship between obesity and intestinal bacterial translocation has been reported. Very little information is available with respect to the involvement of the bacterial translocation mechanistic pathway in HIV-1/highly active antiretroviral therapy (HAART)-associated lipodystrophy syndrome (HALS). We determined whether lipopolysaccharide (LPS)-binding protein (LBP), cluster of differentiation 14 (CD14), myeloid differentiation protein 2 (MD2) and toll-like receptor 4 (TLR4) single-nucleotide polymorphisms and LPS, LBP and soluble CD14 (sCD14) plasma levels are involved in HALS.

Evaluation of the pharmacogenetics of immune recovery in treated HIV-infected patients.

Introduction: Combination antiretroviral therapy has markedly improved the survival rate and quality of life in patients infected with HIV due to the powerful suppressor effect that current antiretroviral drugs have on the viral load. Consequently, the immune system undergoes a substantial qualitative and quantitative improvement; and this leads to an increase in the absolute CD4(+) T-lymphocyte count and the restoration of lost T-cell responses against certain opportunistic pathogens. Unfortunately, not all patients who successfully suppress plasma viremia experience sufficient CD4(+) T-cell gain and these patients, in turn, are associated with worse outcomes.

Adipogenic/lipid, inflammatory, and mitochondrial parameters in subcutaneous adipose tissue of untreated HIV-1-infected long-term nonprogressors: significant alterations despite low viral burden.

Background: HIV-1 can induce disturbances in adipose tissue in infected subjects through the effects of some of its proteins or inflammation. It is not known whether this also takes place in HIV-1-infected long-term nonprogressors (LTNPs). Our objectives were to determine whether adipocyte differentiation/lipid, inflammatory, and mitochondrial parameters are perturbed in abdominal wall subcutaneous adipose tissue of untreated HIV-1-infected patients LTNPs.

Leptin and adiponectin, but not IL18, are related with insulin resistance in treated HIV-1-infected patients with lipodystrophy.

Leptin, adiponectin and IL18 are adipokines related with obesity, insulin resistance and dyslipidemia in the general population. Treated HIV-1-infected patients with lipodystrophy may develop insulin resistance and proatherogenic dyslipidemia. We assessed the relationship between plasma adipokine levels, adipokine genetics, lipodystrophy and metabolic disturbances.