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

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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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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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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Innate and Adaptive Immune Responses Both Contribute to Pathological CD4 T Cell Activation in HIV-1 Infected Ugandans

PLoS ONE ◽

10.1371/journal.pone.0018779 ◽

2011 ◽

Vol 6 (4) ◽

pp. e18779 ◽

Cited By ~ 31

Author(s):

Michael A. Eller ◽

Kim G. Blom ◽

Veronica D. Gonzalez ◽

Leigh Anne Eller ◽

Prossy Naluyima ◽

...

Keyword(s):

T Cell ◽

Immune Responses ◽

T Cell Activation ◽

Cell Activation ◽

Cd4 T Cell ◽

Adaptive Immune Responses ◽

Adaptive Immune ◽

Hiv 1

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Restriction by SAMHD1 Limits cGAS/STING-Dependent Innate and Adaptive Immune Responses to HIV-1

Cell Reports ◽

10.1016/j.celrep.2016.07.002 ◽

2016 ◽

Vol 16 (6) ◽

pp. 1492-1501 ◽

Cited By ~ 56

Author(s):

Jonathan Maelfait ◽

Anne Bridgeman ◽

Adel Benlahrech ◽

Chiara Cursi ◽

Jan Rehwinkel

Keyword(s):

Immune Responses ◽

Adaptive Immune Responses ◽

Adaptive Immune ◽

Hiv 1

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HIV and SIV in Body Fluids: From Breast Milk to the Genitourinary Tract

Current Immunology Reviews ◽

10.2174/1573395514666180605085313 ◽

2019 ◽

Vol 15 (1) ◽

pp. 139-152

Author(s):

Kattayoun Kordy ◽

Nicole H. Tobin ◽

Grace M. Aldrovandi

Keyword(s):

Antiretroviral Therapy ◽

Breast Milk ◽

Immune Responses ◽

Adaptive Immune Responses ◽

Hiv Rna ◽

Adaptive Immune ◽

Hiv Dna ◽

Current State ◽

Repetitive Exposure ◽

Hiv 1

HIV-1 is present in many secretions including oral, intestinal, genital, and breast milk. However, most people exposed to HIV-1 within these mucosal compartments do not become infected despite often frequent and repetitive exposure over prolonged periods of time. In this review, we discuss what is known about the levels of cell-free HIV RNA, cell-associated HIV DNA and cellassociated HIV RNA in external secretions. Levels of virus are usually lower than contemporaneously obtained blood, increased in settings of inflammation and infection, and decreased in response to antiretroviral therapy. Additionally, each mucosal compartment has unique innate and adaptive immune responses that affect the composition and presence of HIV-1 within each external secretion. We discuss the current state of knowledge about the types and amounts of virus present in the various excretions, touch on innate and adaptive immune responses as they affect viral levels, and highlight important areas for further study.

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Potent adaptive immune responses induced against HIV-1 gp140 and influenza virus HA by a polyanionic carbomer

Vaccine ◽

10.1016/j.vaccine.2010.01.046 ◽

2010 ◽

Vol 28 (13) ◽

pp. 2482-2489 ◽

Cited By ~ 23

Author(s):

George Krashias ◽

Anna-Katharina Simon ◽

Frank Wegmann ◽

Wai-Ling Kok ◽

Ling-Pei Ho ◽

...

Keyword(s):

Influenza Virus ◽

Immune Responses ◽

Adaptive Immune Responses ◽

Adaptive Immune ◽

Hiv 1

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Chemokine Receptor 5 Is Dispensable for Innate and Adaptive Immune Responses to Listeria monocytogenes Infection

Infection and Immunity ◽

10.1128/iai.72.2.1057-1064.2004 ◽

2004 ◽

Vol 72 (2) ◽

pp. 1057-1064 ◽

Cited By ~ 17

Author(s):

Maggie X. Zhong ◽

William A. Kuziel ◽

Eric G. Pamer ◽

Natalya V. Serbina

Keyword(s):

T Cells ◽

Listeria Monocytogenes ◽

Immune Responses ◽

Chemokine Receptor ◽

Cd8 T Cells ◽

Interleukin 12 ◽

Adaptive Immune Responses ◽

Adaptive Immune ◽

Hiv 1 ◽

Chemokine Receptor 5

ABSTRACT Chemokine receptor 5 (CCR5) binds macrophage inflammatory protein 1α (MIP-1α), MIP-1β, RANTES, and members of the monocyte chemotactic protein family and is also a receptor for human immunodeficiency virus (HIV). CCR5 ligands can suppress HIV-1 entry into cells. In humans, homozygous mutations of the ccr5 gene confer resistance to HIV-1 infection. The role of CCR5 in defense against microbial infection is unclear. In this study we examined the innate and adaptive immune responses of CCR5-deficient mice to the intracellular bacterial pathogen Listeria monocytogenes. We found that migration of monocytic cells, formation of L. monocytogenes-containing lesions, and bacterial clearance occurred normally in the spleens and livers of CCR5-deficient animals. Activation of macrophages and dendritic cells during the first 3 days postinfection was normal in the absence of CCR5, as demonstrated by intact expression of inducible nitric oxide synthase (iNOS) and production of the cytokines tumor necrosis factor alpha, gamma interferon, and interleukin-12. Priming of L. monocytogenes-specific CD8 T cells also occured independently of CCR5 expression. Previously immunized, CCR5-deficient animals mounted normal secondary CD8 T-cell responses and cleared bacteria from infected organs similarly to wild-type controls, suggesting that CCR5 is dispensable for migration and activation of memory CD8 T cells. Our data indicate that CCR5-mediated chemotaxis is not required for defense against infection with L. monocytogenes.

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