Early Plasmacytoid Dendritic Cell Changes Predict Plasma HIV Load Rebound during Primary Infection

Pacanowski, Jérôme; Develioglu, Leyla; Kamga, Isabelle; Sinet, Martine; Desvarieux, Moïse; Girard, Pierre‐Marie; Hosmalin, Anne

doi:10.1086/425020

Cited by 42 publications

(33 citation statements)

References 13 publications

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“…With regards to HIV-1 replication, a relationship between viral replication and PDC levels after long-term ART-mediated suppression has also been described in ART-interruption studies, where preinterruption PDC frequency was inversely correlated with viral rebound (42). Our data are consistent with an adverse effect of commonly interrelated factors of chronic HIV-1 infection (immune activation and viral replication) on PDC function, as also reflected by the restored PDC function observed in suppressed subjects after enrichment.…”

Section: Discussionmentioning

confidence: 82%

Baseline Viral Load and Immune Activation Determine the Extent of Reconstitution of Innate Immune Effectors in HIV-1-Infected Subjects Undergoing Antiretroviral Treatment

Chehimi

Azzoni

Farabaugh

et al. 2007

The Journal of Immunology

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We analyzed dendritic cell (DC) and NK cell compartments in relation to CD4 recovery in 21 HIV-infected subjects followed to <50 copies/ml once starting antiretroviral therapy (ART) and observed for 52 wk of sustained suppression. Although CD4 counts increased in all subjects in response to ART, we observed a restoration of functional plasmacytoid DC (PDC) after 52 wk of sustained suppression under ART (from 1850 cells/ml to 4550 cells/ml) to levels comparable to controls (5120 cells/ml) only in subjects with a low baseline viral load, which also rapidly suppressed to <50 copies/ml upon ≤60 days from ART initiation. Recovery of PDC at week 52 correlates with level of CD95 expression on CD8 T cells and PDC frequency following first ART suppression. NK cytotoxic activity increased rapidly upon viral suppression (VS) and correlated with PDC function at week 52. However, restoration of total NK cells was incomplete even after 52 wk on ART (73 cells/μl vs 122 cells/μl in controls). Direct reconstitution experiments indicate that NK cytotoxic activity against virally infected target cells requires DC/NK cooperation, and can be recovered upon sustained VS and recovery of functional PDC (but not myeloid DC) from ART-suppressed subjects. Our data indicate that viremic HIV-infected subjects may have different levels of reconstitution of DC and NK-mediated function following ART, with subjects with lower initial viremia and the greatest reduction of baseline immune activation at VS achieving the greatest level of innate effector cell reconstitution.

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Section: Discussionmentioning

confidence: 82%

Baseline Viral Load and Immune Activation Determine the Extent of Reconstitution of Innate Immune Effectors in HIV-1-Infected Subjects Undergoing Antiretroviral Treatment

Chehimi

Azzoni

Farabaugh

et al. 2007

The Journal of Immunology

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“…Generally, PDCs decrease in their numbers following HIV-1 infection; however, they gradually recover following HAART in ϳ8 -12 mo, though taking longer time in restoration than the MDC-1 counts (10,31,32). It is also known that PDC numbers and function are inversely related to plasma viral load and directly related to CD4 T cell counts with PDCs responding more readily to variations in viral load (26,31,38). In contrast, we observed that PDCs, like CD4 T cells, do not show restoration to normal levels in the discordant patients even after 2 years, despite prolonged viral suppression, indicating that plasma viremia does not entirely influence PDC numbers or functions in some HIV-1-infected patients.…”

Section: Discussionmentioning

confidence: 99%

“…IFN-␣ together with NK cells comprise of major components of innate immune system, in conferring protection from viral infections. Decreases in either PDC count or their ability to produce IFN-␣ has been linked to increase in plasma HIV-1 RNA levels and has been associated with increased opportunistic infections and AIDS-associated malignancies, such as Kaposi's sarcoma during HIV-1 infection (6,26,27). Another type of DCs, the myeloid DCs (MDC) mainly comprise of MDC-1 population that express CD11c and BDCA-1 and a broad range of TLRs, except TLR-7 and TLR-9 (12,13).…”

mentioning

confidence: 99%

Impaired Restoration of Plasmacytoid Dendritic Cells in HIV-1-Infected Patients with Poor CD4 T Cell Reconstitution Is Associated with Decrease in Capacity to Produce IFN-α but Not Proinflammatory Cytokines

Sachdeva

Asthana

Brewer

et al. 2008

The Journal of Immunology

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We analyzed reconstitution characteristics of plasmacytoid dendritic cells (PDCs) and myeloid DCs-1 in 38 HIV-1-infected patients with impaired restoration of CD4 T cell counts despite prolonged suppression of plasma viremia (discordant) and compared them with 42 patients showing good immunological and virological responses following highly active antiretroviral therapy (HAART). While myeloid DCs showed spontaneous recovery following HAART in both the groups, the discordant patients demonstrated poor peripheral reconstitution of PDCs as compared with concordant patients. The ability of PDCs to produce IFN-α following stimulation with TLR7 ligand imiquimod and TLR9 ligand CpG ODN-2216 was also impaired in discordant patients even after 2 years following initiation of HAART. Lower IFN-α expression in the PDCs following TLR stimulation was further associated with lower expression of transcription factor, IFN regulatory factor-7. In contrast, production of TNF-α and IL-6 following TLR stimulation was comparable in both groups of patients, indicating that impaired reconstitution characteristics do not affect the capacity of PDCs to produce proinflammatory cytokines. The discordant patients had significantly lower baseline CD4 T cell counts and higher baseline viral load at the initiation of HAART implying that lower baseline CD4 T cell counts and higher plasma viral load are associated with impaired restoration of CD4 T cells and PDCs, thus, increasing the susceptibility of discordant patients toward opportunistic infections despite virological control.

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“…Two main subsets of peripheral blood DC have been described in humans, CDllc-positive DC (myeloid DC, roDC) associated with antigen uptake, T cell activation and the ability to secrete IL-12 in response to microbes stimuli, and CDllc-negative DC (plasmacytoid DC, pDC) with lymphoid morphology, modest antigen presenting potential, but with a very high virus-induced IFN-a secretion (12). A decrease in the proportion of both subsets ofblood DC has been observed in HIV infected subjects with active viral replication or with AIDS, suggesting a possible important role of DC in the control of HIV replication (13). In the present study, performed on HIV-infected patients with HAARTdriven suppressed HIV viremia, we extend previous observations on the GBV-C-associated enhancement of the activation of the IFN system in vivo, identify IFN-yas the main factor promoting downstream IRG expression cascade, and describe -enhanced activation of circulating pDC, correlating with GBV-C viral load.…”

mentioning

confidence: 98%

Activation of Interferon Response Genes and of Plasmacytoid Dendritic Cells in HIV-1 Positive Subjects with GB Virus C Co-Infection

Lalle

Sacchi

Abbate

et al. 2008

Int J Immunopathol Pharmacol

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GB virus C (GBV-C) coinfection has a protective role in Human Immunodeficiency Virus (HIV) infection, and increases the duration of suppression of HIV-1 viremia in patients under Highly Active Anti-Retroviral Therapy (HAART). Since innate antiviral response may be involved in the protection, we analyzed the possible role of GBV-C as activator of innate immunity. To this aim, we measured the extent of activation of the interferon (IFN) system and of circulating Dendritic Cells (DC) in vivo, and the ability of GBV-C to activate these functions in vitro. Activation of IFN system and of circulating DC was compared in GBV-positive and -negative HIV-1 co-infected patients with HAART-driven suppression of HIV-1 viremia. Endogenous levels of IFN-γ and RNA-dependent protein kinase (PKR) mRNA were significantly higher in peripheral blood mononuclear cells (PBMC) from GBV-C-positive when compared to GBV-C-negative patients. IFN-γ expression was correlated with all the Interferon response genes (IRGs) and with GBV-C viremia. The frequency of circulating plasmacytoid DC (pDC) expressing the CD80 activation marker was increased in GBV-C-positive patients, and was correlated with GBV-C viral load. In vitro experiments indicated that GBV-C is able to induce IFN-γ expression in PBMC. In addition, in PBMC cultures GBV-C induced an increase of CD80 expression by pDC, that was reduced by antibody to IFN-γ. Our data indicate that in HIV-positive patients GBV-C coinfection promotes the activation of IFN-γ and downstream IRG expression, as well as with the activation/maturation of circulating pDC. GBV-C-driven IFN-γ activation is, at least in part, responsible for the increased maturation of pDC. This crosstalk may suggest a role for GBV-C coinfection in boosting the innate antiviral response to HIV infection.

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Early Plasmacytoid Dendritic Cell Changes Predict Plasma HIV Load Rebound during Primary Infection

Cited by 42 publications

References 13 publications

Baseline Viral Load and Immune Activation Determine the Extent of Reconstitution of Innate Immune Effectors in HIV-1-Infected Subjects Undergoing Antiretroviral Treatment

Baseline Viral Load and Immune Activation Determine the Extent of Reconstitution of Innate Immune Effectors in HIV-1-Infected Subjects Undergoing Antiretroviral Treatment

Impaired Restoration of Plasmacytoid Dendritic Cells in HIV-1-Infected Patients with Poor CD4 T Cell Reconstitution Is Associated with Decrease in Capacity to Produce IFN-α but Not Proinflammatory Cytokines

Activation of Interferon Response Genes and of Plasmacytoid Dendritic Cells in HIV-1 Positive Subjects with GB Virus C Co-Infection

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