CD46 Genetic Variability and HIV-1 Infection Susceptibility

CD46 is the main receptor for complement protein C3 and plays an important role in adaptive immune responses. CD46 genetic variants are associated with susceptibility to several infectious and autoimmune diseases. Additionally, CD46 function can be subverted by HIV-1 to evade attack by complement, a strategy shared by viruses of other families. We sought to determine the association between CD46 gene variants and HIV-1 acquired through intravenous drug use (IDU) and sexual routes (n = 823). Study subjects were of European ancestry and were HIV-1 infected (n = 438) or exposed but seronegative (n = 387). Genotyping of the rs2796265 SNP located in the CD46 gene region was done by allele-specific real-time PCR. A meta-analysis merging IDU and sexual cohorts indicates that the minor genotype (CC) was associated with increased resistance to HIV-1 infection OR= 0.2, 95% CI (0.07–0.61), p = 0.004. The HIV-1-protective genotype is correlated with reduced CD46 expression and alterations in the ratio of CD46 mRNA splicing isoforms.

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Impact of HMGB1/TLR Ligand Complexes on HIV-1 Replication: Possible Role for Flagellin during HIV-1 Infection

International Journal of Microbiology ◽

10.1155/2012/263836 ◽

2012 ◽

Vol 2012 ◽

pp. 1-10 ◽

Cited By ~ 12

Author(s):

Piotr Nowak ◽

Samir Abdurahman ◽

Annica Lindkvist ◽

Marius Troseid ◽

Anders Sönnerborg

Keyword(s):

Immune Responses ◽

Cpg Odn ◽

Cell Necrosis ◽

Adaptive Immune ◽

Microbial Product ◽

P24 Antigen ◽

Culture Supernatants ◽

Hiv 1

Objective. We hypothesized that HMGB1 in complex with bacterial components, such as flagellin, CpG-ODN, and LPS, promotes HIV-1 replication. Furthermore, we studied the levels of antiflagellin antibodies during HIV-1-infection.Methods. Chronically HIV-1-infected U1 cells were stimulated with necrotic extract/recombinant HMGB1 in complex with TLR ligands or alone. HIV-1 replication was estimated by p24 antigen in culture supernatants 48–72 hours after stimulation. The presence of systemic anti-flagellin IgG was determined in 51 HIV-1-infected patients and 19 controls by immunoblotting or in-house ELISA.Results. Flagellin, LPS, and CpG-ODN induced stronger HIV-1 replication when incubated together with necrotic extract or recombinant HMGB1 than activation by any of the compounds alone. Moreover, the stimulatory effect of necrotic extract was inhibited by depletion of HMGB1. Elevated levels of anti-flagellin antibodies were present in plasma from HIV-1-infected patients and significantly decreased during 2 years of antiretroviral therapy.Conclusions. Our findings implicate a possible role of HGMB1-bacterial complexes, as a consequence of microbial translocation and cell necrosis, for immune activation in HIV-1 pathogenesis. We propose that flagellin is an important microbial product, that modulates viral replication and induces adaptive immune responsesin vivo.

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Lack of endogenous TRIM5α-mediated restriction in rhesus macaque dendritic cells

Blood ◽

10.1182/blood-2008-04-151761 ◽

2008 ◽

Vol 112 (9) ◽

pp. 3772-3776 ◽

Cited By ~ 10

Author(s):

Nathalie J. Arhel ◽

Sébastien Nisole ◽

Laetitia Carthagena ◽

Frédéric Coutant ◽

Philippe Souque ◽

...

Keyword(s):

Dendritic Cells ◽

Immune Responses ◽

Rhesus Macaque ◽

Rhesus Macaques ◽

Cell Types ◽

Primary Cells ◽

Adaptive Immune ◽

Trim Protein ◽

Tripartite Motif ◽

Hiv 1

Rhesus macaques are resistant to infection by HIV-1 as a result of an innate cellular restriction mechanism attributable to the expression of rhTRIM5α, a member of the large tripartite motif (TRIM) protein family. TRIM5α-mediated restriction, which occurs before reverse transcription through targeting of the HIV-1 capsid, has been identified in a number of macaque primary cells and cell lines and is thought to occur in all macaque cell types. We report, however, that rhesus macaque dendritic cells (DCs) lack TRIM5α-mediated restriction and are equally permissive to HIV-1 infection as human DCs. Evidence suggests that, although TRIM5α RNA levels are normal in these cells, the protein may be dysfunctional. We propose that abrogation of TRIM5α-mediated restriction in DCs, although still operative in cells that replicate HIV-1 (macrophages, T lymphocytes), illustrates the need for innate mechanisms to not inhibit adaptive immune responses to ensure an optimal fight against pathogens.

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Endotoxemia Is Associated with Altered Innate and Adaptive Immune Responses in Untreated HIV-1 Infected Individuals

PLoS ONE ◽

10.1371/journal.pone.0021275 ◽

2011 ◽

Vol 6 (6) ◽

pp. e21275 ◽

Cited By ~ 25

Author(s):

Anne Roslev Bukh ◽

Jesper Melchjorsen ◽

Rasmus Offersen ◽

Jens Magnus Bernth Jensen ◽

Lars Toft ◽

...

Keyword(s):

Immune Responses ◽

Adaptive Immune Responses ◽

Adaptive Immune ◽

Hiv 1

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Host Genetic and Viral Determinants of HIV-1 RNA Set Point among HIV-1 Seroconverters from Sub-Saharan Africa

Journal of Virology ◽

10.1128/jvi.01573-14 ◽

2014 ◽

Vol 89 (4) ◽

pp. 2104-2111 ◽

Cited By ~ 17

Author(s):

Romel D. Mackelprang ◽

Mary Carrington ◽

Katherine K. Thomas ◽

James P. Hughes ◽

Jared M. Baeten ◽

...

Keyword(s):

Immune Responses ◽

Human Leukocyte ◽

Sub Saharan Africa ◽

Host Responses ◽

Adaptive Immune Responses ◽

Hla Alleles ◽

Set Point ◽

Transmission Potential ◽

Adaptive Immune ◽

Hiv 1

ABSTRACTWe quantified the collective impact of source partner HIV-1 RNA levels, human leukocyte antigen (HLA) alleles, and innate responses through Toll-like receptor (TLR) alleles on the HIV-1 set point. Data came from HIV-1 seroconverters in African HIV-1 serodiscordant couple cohorts. Linear regression was used to determine associations with set point andR2to estimate variation explained by covariates. The strongest predictors of set point were HLA alleles (B*53:01, B*14:01, and B*27:03) and plasma HIV-1 levels of the transmitting partner, which explained 13% and 10% of variation in set point, respectively. HLA-A concordance between partners and TLR polymorphisms (TLR2rs3804100 andTLR7rs179012) also were associated with set point, explaining 6% and 5% of the variation, respectively. Overall, these factors and genital factors of the transmitter (i.e., male circumcision, bacterial vaginosis, and use of acyclovir) explained 46% of variation in set point. We found that both innate and adaptive immune responses, together with plasma HIV-1 levels of the transmitting partner, explain almost half of the variation in viral load set point.IMPORTANCEAfter HIV-1 infection, uncontrolled virus replication leads to a rapid increase in HIV-1 concentrations. Once host immune responses develop, however, HIV-1 levels reach a peak and subsequently decline until they reach a stable level that may persist for years. This stable HIV-1 set point represents an equilibrium between the virus and host responses and is predictive of later disease progression and transmission potential. Understanding how host and virus factors interact to determine HIV-1 set point may elucidate novel mechanisms or biological pathways for treating HIV-1 infection. We identified host and virus factors that predict HIV-1 set point in people who recently acquired HIV-1, finding that both innate and adaptive immune responses, along with factors that likely influence HIV-1 virulence and inoculum, explain ∼46% of the variation in HIV-1 set point.

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The CCR5-Delta32 genetic polymorphism and HIV-1 infection susceptibility: a meta-analysis

Open Medicine ◽

10.1515/med-2018-0062 ◽

2018 ◽

Vol 13 (1) ◽

pp. 467-474 ◽

Cited By ~ 1

Author(s):

Jun Ni ◽

Dan Wang ◽

Sheng Wang

Keyword(s):

Chemokine Receptor ◽

Inflammatory Responses ◽

Meta Analysis ◽

Cochrane Library ◽

Allele Carrier ◽

Case Control Studies ◽

Ccr5 Gene ◽

Infection Susceptibility ◽

Exposed Uninfected ◽

Hiv 1

AbstractThe CC chemokine receptor 5 (CCR5) is a chemokine receptor which is widely expressed in several immune cells involved in the inflammatory responses. Previous published studies revealed the relation of the CCR5 gene (CCR5-delta32) with the risk of HIV-1 infection, but the results are debatable and inconclusive. Here by meta-analysis, we have systematically evaluated the relation between the CCR5-delta32 polymorphism and the risk of HIV-1 infection. A comprehensive search in PubMed, EMBASE, CNKI, Cochrane Library, and WanFang database was performed up to April 15, 2018. The pooled odds ratio (ORs) along with its 95% credible interval (95%CI) was used to evaluate the relation between the CCR5-delta32 polymorphism and HIV-1 infection risk. The study included 24 case-control studies involving 4,786 HIV-1 infection patients and 6,283 controls. Compared with the wild-type homozygous genotypes, the results showed that the CCR5-delta32 heterozygotes (OR=1.16, 95%CI=1.02-1.32) had an increased susceptibility to HIV-1 and the delta32 homozygous (OR=0.25, 95%CI=0.09-0.68) had significantly reduced the susceptibility to HIV-1 for healthy controls. Moreover, we have found the delta32 allele carriers (OR=0.71, 95%CI=0.54-0.94) had significantly cut down the HIV-1 infection susceptibility when using exposed uninfected (EU) as controls. We also conducted the stratified analysis by ethnicity, and there significant association was detected in Caucasian in delta32 allele carrier genotype. To summarize, our meta-analysis suggests that the CCR5-delta32 homozygous genotype (delta32/delta32) confer possible protection against HIV-1, especially the exposed uninfected groups.

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Early Innate and Adaptive Immune Responses to Investigational Human Immunodeficiency Virus (HIV)-1 Vaccines (VRC 016 Study)

Open Forum Infectious Diseases ◽

10.1093/ofid/ofv133.621 ◽

2015 ◽

Vol 2 (suppl_1) ◽

Author(s):

Uzma Sarwar ◽

Laura Novik ◽

Mary Enama ◽

Douglas Herrin ◽

Sandeep Narpala ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Immune Responses ◽

Adaptive Immune Responses ◽

Adaptive Immune ◽

Immunodeficiency Virus ◽

Hiv 1

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Vitamin D3 as Potential Treatment Adjuncts for COVID-19

Nutrients ◽

10.3390/nu12113512 ◽

2020 ◽

Vol 12 (11) ◽

pp. 3512 ◽

Cited By ~ 4

Author(s):

Lucia Malaguarnera

Keyword(s):

Vitamin D ◽

Clinical Trials ◽

Immune Responses ◽

Observational Studies ◽

Distress Syndrome ◽

Meta Analysis ◽

Critical Role ◽

Vitamin D Supplementation ◽

Protective Properties ◽

Adaptive Immune

Severe acute respiratory syndrome coronavirus type (SARS-CoV2, also known as COVID-19), which is the latest pandemic infectious disease, constitutes a serious risk to human health. SARS-CoV2 infection causes immune activation and systemic hyperinflammation which can lead to respiratory distress syndrome (ARDS). ARDS victims are characterized by a significant increase in IL-6 and IL-1. Macrophage activation, associated with the “cytokine storm”, promotes the dysregulation of the innate immunity. So far, without vaccines or specific therapy, all efforts to design drugs or clinical trials are worthwhile. Vitamin D and its receptor vitamin D receptor (VDR) exert a critical role in infections due to their remarkable impact on both innate and adaptive immune responses and on the suppression of the inflammatory process. The protective properties of vitamin D supplementation have been supported by numerous observational studies and by meta-analysis of clinical trials for prevention of viral acute respiratory infection. In this review, we compare the mechanisms of the host immune response to SARS-CoV2 infection and the immunomodulatory actions that vitamin D exerts in order to consider the preventive effect of vitamin D supplementation on SARS-CoV2 viral infection.

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SAMHD1 Limits HIV-1 Antigen Presentation by Monocyte-Derived Dendritic Cells

Journal of Virology ◽

10.1128/jvi.00069-15 ◽

2015 ◽

Vol 89 (14) ◽

pp. 6994-7006 ◽

Cited By ~ 15

Author(s):

Diana Ayinde ◽

Timothée Bruel ◽

Sylvain Cardinaud ◽

Françoise Porrot ◽

Julia G. Prado ◽

...

Keyword(s):

Immune Responses ◽

Antigen Presentation ◽

Cytotoxic T Lymphocytes ◽

Viral Proteins ◽

Productive Infection ◽

Restriction Factors ◽

Adaptive Immune Responses ◽

Mhc I ◽

Adaptive Immune ◽

Hiv 1

ABSTRACTMonocyte-derived dendritic cells (MDDC) stimulate CD8+cytotoxic T lymphocytes (CTL) by presenting endogenous and exogenous viral peptides via major histocompatibility complex class I (MHC-I) molecules. MDDC are poorly susceptible to HIV-1, in part due to the presence of SAMHD1, a cellular enzyme that depletes intracellular deoxynucleoside triphosphates (dNTPs) and degrades viral RNA. Vpx, an HIV-2/SIVsm protein absent from HIV-1, antagonizes SAMHD1 by inducing its degradation. The impact of SAMHD1 on the adaptive cellular immune response remains poorly characterized. Here, we asked whether SAMHD1 modulates MHC-I-restricted HIV-1 antigen presentation. Untreated MDDC or MDDC pretreated with Vpx were exposed to HIV-1, and antigen presentation was examined by monitoring the activation of an HIV-1 Gag-specific CTL clone. SAMHD1 depletion strongly enhanced productive infection of MDDC as well as endogenous HIV-1 antigen presentation. Time-lapse microscopy analysis demonstrated that in the absence of SAMHD1, the CTL rapidly killed infected MDDC. We also report that various transmitted/founder (T/F) HIV-1 strains poorly infected MDDC and, as a consequence, did not stimulate CTL. Vesicular stomatitis virus glycoprotein (VSV-G) pseudotyping of T/F alleviated a block in viral entry and induced antigen presentation only in the absence of SAMHD1. Furthermore, by using another CTL clone that mostly recognizes incoming HIV-1 antigens, we demonstrate that SAMHD1 does not influence exogenous viral antigen presentation. Altogether, our results demonstrate that the antiviral activity of SAMHD1 impacts antigen presentation by DC, highlighting the link that exists between restriction factors and adaptive immune responses.IMPORTANCEUpon viral infection, DC may present antigens derived from incoming viral material in the absence of productive infection of DC or from newly synthesized viral proteins. In the case of HIV, productive infection of DC is blocked at an early postentry step. This is due to the presence of SAMHD1, a cellular enzyme that depletes intracellular levels of dNTPs and inhibits viral reverse transcription. We show that the depletion of SAMHD1 in DCs strongly stimulates the presentation of viral antigens derived from newly produced viral proteins, leading to the activation of HIV-1-specific cytotoxic T lymphocytes (CTL). We further show in real time that the enhanced activation of CTL leads to killing of infected DCs. Our results indicate that the antiviral activity of SAMHD1 not only impacts HIV replication but also impacts antigen presentation by DC. They highlight the link that exists between restriction factors and adaptive immune responses.

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