Autophagy-enhancing ATG16L1 polymorphism is associated with improved clinical outcome and T-cell immunity in chronic HIV-1 infection.

Chronic HIV-1 infection is characterized by T-cell dysregulation that is partly restored by antiretroviral therapy. Autophagy is a critical regulator of T-cell function. Here, we demonstrate a protective role for autophagy in HIV-1 disease pathogenesis.

CD9 and ITGA3 are regulated during HIV-1 infection in macrophages to support viral replication.

Monocytes/macrophages are important target cells for HIV-1. Here, we investigated whether HIV-1 induces changes in the macrophage gene expression profile to support viral replication. We observed that the macrophage gene expression profiles dramatically changed upon HIV-1 infection.

Nef Obtained from Individuals with HIV-1 Vary in Their Ability to Antagonize SERINC3- and SERINC5-Mediated HIV-1 Restriction.

Nef is a multifunctional viral protein that has the ability to downregulate cell surface molecules, including CD4 and major histocompatibility complex class I (MHC-I) and, as recently shown, also members of the serine incorporator family (SERINC). Here, we analyzed the impact of naturally occurring mutations in HIV-1 Nef on its ability to counteract SERINC restriction and the clinical course of infection. HIV-1 Nef sequences were obtained from 123 participants of the Amsterdam Cohort Studies and showed multiple amino acid variations and mutations.

Human Immunodeficiency Virus-Negative Men Who Have Sex With Men Have an Altered T-Cell Phenotype and Bioenergy Metabolism.

Background: We recently reported that the levels of activation, exhaustion, and terminal differentiation within the peripheral T-cell compartment were increased in men who have sex with men (MSM) compared with blood bank donors. During activation and differentiation, T cells undergo metabolic changes to maintain their energy demand.

Methods: The effect of cytomeglovirus (CMV) infection and risk behavior on the immune phenotype of peripheral T cells and the immune bioenergy metabolism profile in human immunodeficiency virus-negative MSM (with high or low sexual risk behavior) and blood bank donors was evaluated.

Genetic variations in the host dependency factors ALCAM and TPST2 impact HIV-1 disease progression.

Objectives: Recently, the activated leukocyte cell adhesion molecule (ALCAM) and tyrosylprotein sulfotransferase 2 (TPST2) have been identified as important host dependency factors (HDFs) for in-vitro HIV-1 replication. To determine whether these genes play a role in HIV-1 pathogenesis, we analysed whether naturally occurring genetic variations were associated with the clinical course of infection.

Design/methods: Single nucleotide polymorphisms (SNPs) in ALCAM and TPST2 were analysed in a cohort of 304 HIV-1-infected men who have sex with men and survival analysis was used to determine their effect on the outcome of untreated HIV-1 infection.

Systemic DPP4 activity is reduced during primary HIV-1 infection and is associated with intestinal RORC CD4 cell levels: a surrogate marker candidate of HIV-induced intestinal damage.

Introduction: Combined anti-retroviral therapy (cART) transformed HIV-1 from a deadly disease into a chronic infection, but does not cure HIV infection. It also does not fully restore HIV-induced gut damage unless administered extremely early after infection. Additional biomarkers are needed to evaluate the capacity of therapies aimed at HIV remission/cure to restore HIV-induced intestinal immune damage and limit chronic inflammation.

Terminal differentiation of T cells is strongly associated with CMV infection and increased in HIV-positive individuals on ART and lifestyle matched controls.

HIV-1-positive individuals on successful antiretroviral therapy (ART) are reported to have higher rates of age-associated non-communicable comorbidities (AANCCs). HIV-associated immune dysfunction has been suggested to contribute to increased AANCC risk. Here we performed a cross-sectional immune phenotype analysis of T cells in ART-treated HIV-1-positive individuals with undetectable vireamia (HIV-positives) and HIV-1-negative individuals (HIV-negatives) over 45 years of age.

High Cellular Monocyte Activation in People Living With Human Immunodeficiency Virus on Combination Antiretroviral Therapy and Lifestyle-Matched Controls Is Associated With Greater Inflammation in Cerebrospinal Fluid.

Background: Increased monocyte activation and intestinal damage have been shown to be predictive for the increased morbidity and mortality observed in treated people living with human immunodeficiency virus (PLHIV).

Methods: A cross-sectional analysis of cellular and soluble markers of monocyte activation, coagulation, intestinal damage, and inflammation in plasma and cerebrospinal fluid (CSF) of PLHIV with suppressed plasma viremia on combination antiretroviral therapy and age and demographically comparable HIV-negative individuals participating in the Comorbidity in Relation to AIDS (COBRA) cohort and, where appropriate, age-matched blood bank donors (BBD).

Results: People living with HIV, HIV-negative individuals, and BBD had comparable percentages of classical, intermediate, and nonclassical monocytes.

HIV-1 blocks the signaling adaptor MAVS to evade antiviral host defense after sensing of abortive HIV-1 RNA by the host helicase DDX3.

The mechanisms by which human immunodeficiency virus 1 (HIV-1) avoids immune surveillance by dendritic cells (DCs), and thereby prevents protective adaptive immune responses, remain poorly understood. Here we showed that HIV-1 actively arrested antiviral immune responses by DCs, which contributed to efficient HIV-1 replication in infected individuals. We identified the RNA helicase DDX3 as an HIV-1 sensor that bound abortive HIV-1 RNA after HIV-1 infection and induced DC maturation and type I interferon responses via the signaling adaptor MAVS.

Cigarette Smoking and Inflammation, Monocyte Activation, and Coagulation in HIV-Infected Individuals Receiving Antiretroviral Therapy, Compared With Uninfected Individuals.

Smoking may affect cardiovascular disease risk more strongly in human immunodeficiency virus (HIV)-infected individuals than HIV-uninfected individuals. We hypothesized that an interaction at the level of the immune system may contribute to this increased risk. We assessed soluble markers of inflammation (high-sensitivity C-reactive protein [hsCRP]), immune activation (soluble [s]CD14 and sCD163), and coagulation (D-dimer) in HIV-infected and uninfected never, former, and current smokers.

Elevated Basal Pre-infection CXCL10 in Plasma and in the Small Intestine after Infection Are Associated with More Rapid HIV/SIV Disease Onset.

Elevated blood CXCL10/IP-10 levels during primary HIV-1 infection (PHI) were described as an independent marker of rapid disease onset, more robust than peak viremia or CD4 cell nadir. IP-10 enhances the recruitment of CXCR3+ cells, which include major HIV-target cells, raising the question if it promotes the establishment of viral reservoirs. We analyzed data from four cohorts of HIV+ patients, allowing us to study IP-10 levels before infection (Amsterdam cohort), as well as during controlled and uncontrolled viremia (ANRS cohorts).

T-Cell Activation Independently Associates With Immune Senescence in HIV-Infected Recipients of Long-term Antiretroviral Treatment.

Background: Aging-associated noncommunicable comorbidities are more prevalent among human immunodeficiency virus type 1 (HIV)-infected individuals than among HIV-uninfected individuals. Residual HIV-related chronic immune activation and senescence may increase the risk of developing comorbidities.

Methods: Immune phenotyping, thymic output, and telomere length were assessed in 94 HIV-infected individuals who were aged >45 years and receiving antiretroviral therapy (ART; cases) and 95 age-matched uninfected controls.

DYRK1A Controls HIV-1 Replication at a Transcriptional Level in an NFAT Dependent Manner.

Background: Transcription of the HIV-1 provirus is regulated by both viral and host proteins and is very important in the context of viral latency. In latently infected cells, viral gene expression is inhibited as a result of the sequestration of host transcription factors and epigenetic modifications.

Results: In our present study we analyzed the effect of host factor dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) on HIV-1 replication.

Identification of the HIV-1 Vif and Human APOBEC3G Protein Interface.

Human cells express natural antiviral proteins, such as APOBEC3G (A3G), that potently restrict HIV replication. As a counter-defense, HIV encodes the accessory protein Vif, which binds A3G and mediates its proteasomal degradation. Our structural knowledge on how Vif and A3G interact is limited, because a co-structure is not available.

G3BP1 restricts HIV-1 replication in macrophages and T-cells by sequestering viral RNA.

HIV-1 exploits the cellular machinery for replication and therefore several interactions with cellular factors take place, some of which are yet unknown. We identified GTPase-activating protein-(SH3 domain)-binding protein 1 (G3BP1) as a cellular factor that restricts HIV-1, by analyzing transcriptome profiles of in vitro-cytokine-activated macrophages that are non-permissive to HIV-1 replication. Silencing of G3BP1 by RNA interference resulted in increased HIV-1 replication in primary T-cells and macrophages, but did not affect replication of other retroviruses.

Phosphodiesterase 8a supports HIV-1 replication in macrophages at the level of reverse transcription.

Background: HIV-1 infected macrophages play a key role in HIV-1 infection. Even during anti-retroviral treatment, macrophages keep producing virus due to suboptimal tissue penetration and reduced efficacy of antiretrovirals. It is therefore of major importance to understand which host factors are involved in HIV-1 replication in macrophages.

Genetic variation in Trex1 affects HIV-1 disease progression.

Objective: Three prime repair exonuclease 1 (TREX1) plays a pivotal role in HIV-1 infection. In-vitro studies have shown that TREX1 degrades excess HIV-1 DNA, thereby shielding HIV-1 from recognition by innate immune receptors and preventing a type 1 interferon response. To determine whether TREX1 plays a role in HIV-1 pathogenesis, we analyzed whether genetic variation in Trex1 is associated with the clinical course of HIV-1 infection.

Differential expression of HIV-1 interfering factors in monocyte-derived macrophages stimulated with polarizing cytokines or interferons.

HIV-1 replication in macrophages can be regulated by cytokines and infection is restricted in macrophages activated by type I interferons and polarizing cytokines. Here, we observed that the expression levels of the cellular factors Trim5α, CypA, APOBEC3G, SAMHD-1, Trim22, tetherin and TREX-1, and the anti-HIV miRNAs miR-28, miR-150, miR-223 and miR-382 was upregulated by IFN-α and IFN-β in macrophages, which may account for the inhibiting effect on viral replication and the antiviral state of these cells. Expression of these factors was also increased by IFN-γ +/- TNF-α, albeit to a lesser extent; yet, HIV-1 replication in these cells was not restricted at the level of proviral synthesis, indicating that these cellular factors only partially contribute to the observed restriction.

Single nucleotide polymorphism in gene encoding transcription factor Prep1 is associated with HIV-1-associated dementia.

Background: Infection with HIV-1 may result in severe cognitive and motor impairment, referred to as HIV-1-associated dementia (HAD). While its prevalence has dropped significantly in the era of combination antiretroviral therapy, milder neurocognitive disorders persist with a high prevalence. To identify additional therapeutic targets for treating HIV-associated neurocognitive disorders, several candidate gene polymorphisms have been evaluated, but few have been replicated across multiple studies.

Polymorphism in HIV-1 dependency factor PDE8A affects mRNA level and HIV-1 replication in primary macrophages.

Four genome-wide RNAi screens have recently identified hundreds of HIV-1 dependency factors (HDFs). Previously, we reported a large variation in the ability of HIV-1 to replicate in monocyte-derived macrophages (MDM) derived from >400 healthy seronegative blood donors. Here we determined whether SNPs in genes encoding newly identified HDFs were associated with this variation in HIV-1 replication.

Macrophages and HIV-1.

Purpose Of Review: Macrophages play an important role in HIV-1 pathogenesis and contribute to the establishment of the viral reservoir responsible for continuous virus production. This review will discuss new insights into HIV-1 infection in macrophages and the effect of infection on immune function and pathology.

Recent Findings: New cellular factors interacting with various steps of the HIV-1 replication cycle, such as entry, integration, transcription, and assembly of new viral progeny, have been identified.

Thermus thermophilus glycoside hydrolase family 57 branching enzyme: crystal structure, mechanism of action, and products formed.

Branching enzyme (EC 2.4.1.