8 research outputs found

    Immunodominant HIV-1 Cd4+ T Cell Epitopes in Chronic Untreated Clade C HIV-1 Infection

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    Background: A dominance of Gag-specific CD8+ T cell responses is significantly associated with a lower viral load in individuals with chronic, untreated clade C human immunodeficiency virus type 1 (HIV-1) infection. This association has not been investigated in terms of Gag-specific CD4+ T cell responses, nor have clade C HIV-1–specific CD4+ T cell epitopes, likely a vital component of an effective global HIV-1 vaccine, been identified. Methodology/Principal Findings: Intracellular cytokine staining was conducted on 373 subjects with chronic, untreated clade C infection to assess interferon-gamma (IFN-γ) responses by CD4+ T cells to pooled Gag peptides and to determine their association with viral load and CD4 count. Gag-specific IFN-γ–producing CD4+ T cell responses were detected in 261/373 (70%) subjects, with the Gag responders having a significantly lower viral load and higher CD4 count than those with no detectable Gag response (p<0.0001 for both parameters). To identify individual peptides targeted by HIV-1–specific CD4+ T cells, separate ELISPOT screening was conducted on CD8-depleted PBMCs from 32 chronically infected untreated subjects, using pools of overlapping peptides that spanned the entire HIV-1 clade C consensus sequence, and reconfirmed by flow cytometry to be CD4+ mediated. The ELISPOT screening identified 33 CD4+ peptides targeted by 18/32 patients (56%), with 27 of the 33 peptides located in the Gag region. Although the breadth of the CD4+ responses correlated inversely with viral load (p = 0.015), the magnitude of the response was not significantly associated with viral load. Conclusions/Significance: These data indicate that in chronic untreated clade C HIV-1 infection, IFN-γ–secreting Gag-specific CD4+ T cell responses are immunodominant, directed at multiple distinct epitopes, and associated with viral control

    Human Immunodeficiency Virus-Specific CD8+ T-Cell Activity Is Detectable from Birth in the Majority of In Utero-Infected Infants▿

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    Human immunodeficiency virus (HIV)-infected infants in sub-Saharan Africa typically progress to AIDS or death by 2 years of life in the absence of antiretroviral therapy. This rapid progression to HIV disease has been related to immaturity of the adaptive immune response in infants. We screened 740 infants born to HIV-infected mothers and tracked development and specificity of HIV-specific CD8+ T-cell responses in 63 HIV-infected infants identified using gamma interferon enzyme-linked immunospot assays and intracellular cytokine staining. Forty-four in utero-infected and 19 intrapartum-infected infants were compared to 45 chronically infected children >2 years of age. Seventy percent (14 of 20) in utero-infected infants tested within the first week of life demonstrated HIV-specific CD8+ T-cell responses. Gag, Pol, and Nef were the principally targeted regions in chronic pediatric infection. However, Env dominated the overall response in one-third (12/36) of the acutely infected infants, compared to only 2/45 (4%) of chronically infected children (P = 0.00083). Gag-specific CD4+ T-cell responses were minimal to undetectable in the first 6 months of pediatric infection. These data indicate that failure to control HIV replication in in utero-infected infants is not due to an inability to induce responses but instead suggest secondary failure of adaptive immunity in containing this infection. Moreover, the detection of virus-specific CD8+ T-cell responses in the first days of life in most in utero-infected infants is encouraging for HIV vaccine interventions in infants

    The majority of the HIV-1 C clade CD4+ epitopes cluster in the Gag region.

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    <p>ELISPOT screening was conducted on 32 randomly selected subjects. (A) 33 CD4+ restricted epitopes were identified, with 27 epitopes located in the Gag region, 3 in the Polymerase region, 1 in the Vpr region and 2 in the Nef region. There were no CD4+ epitopes present in the Vif, Vpu, Rev, Tat, or Envelope proteins. (B) The peptides identified by the ELISPOT assay utilizing CD8+ depleted PBMCs were confirmed by flow cytometry using whole PBMCs to be CD4+ restricted. The dot plot above represents data from the negative control on the left and a CD4+ IFN-γ response to the p24 Gag peptide YVDRFFKTLRAEQATADV.</p

    The total HIV-1–specific CD4+ T cell response is dominated by Gag.

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    <p>Using IFN-γ ELISPOT assay to identify HIV-1 specific CD4+ T cell epitopes in 32 subjects, we found that irrespective of the viral load, the Gag protein is the most commonly targeted and therefore makes the greatest contribution to the overall CD4+ T cell response. Subjects 1–16 had viral loads below the median, while subjects 18–32 had viremia greater than the median (36 550 copies/ml plasma). Acc (accessory) denotes the Vpr, Vpu and Vif proteins pooled together. Subjects 24 and 25 both targeted a single Vpr protein.</p

    Clinical features and prognostic factors of listeriosis: the MONALISA national prospective cohort study

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