Association of differentiation state of CD4+ T cells and disease progression in HIV-1 perinatally infected children.

Division of Experimental Medicine, Department of Medicine, University of California San Francisco, San Francisco, California, United States of America.
PLoS ONE (Impact Factor: 3.53). 01/2012; 7(1):e29154. DOI: 10.1371/journal.pone.0029154
Source: PubMed

ABSTRACT In the USA, most HIV-1 infected children are on antiretroviral drug regimens, with many individuals surviving through adolescence and into adulthood. The course of HIV-1 infection in these children is variable, and understudied.
We determined whether qualitative differences in immune cell subsets could explain a slower disease course in long term survivors with no evidence of immune suppression (LTS-NS; CD4%≥25%) compared to those with severe immune suppression (LTS-SS; CD4%≤15%). Subjects in the LTS-NS group had significantly higher frequencies of naïve (CCR7+CD45RA+) and central memory (CCR7+CD45RA-) CD4+ T cells compared to LTS-SS subjects (p = 0.0005 and <0.0001, respectively). Subjects in the rapid progressing group had significantly higher levels of CD4+ T(EMRA) (CCR7-CD45RA+) cells compared to slow progressing subjects (p<0.0001).
Rapid disease progression in vertical infection is associated with significantly higher levels of CD4+ T(EMRA) (CCR7-CD45RA+) cells.

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    ABSTRACT: Background: T-cell exhaustion seems to play a critical role in CD8(+) T-cell dysfunction during chronic viral infections. However, up to now little is known about the mechanisms underlying CD4(+) T-cell dysfunction during chronic hepatitis B virus (CHB) infection and the role of inhibitory molecules such as programmed death 1 (PD-1) for CD4(+) T-cell failure. Methods: The expression of multiple inhibitory molecules such as PD-1, CTLA-4, TIM-3, CD244, KLRG1 and markers defining the grade of T-cell differentiation as CCR7, CD45RA, CD57 and CD127 were analyzed on virus-specific CD4(+) T-cells from peripheral blood using a newly established DRB1*01-restricted MHC class II Tetramer. Effects of in vitro PD-L1/2 blockade were defined by investigating changes in CD4(+) T-cell proliferation and cytokine production. Results: CD4(+) T-cell responses during chronic HBV infection was characterized by reduced Tetramer(+)CD4(+) T-cell frequencies, effector memory phenotype, sustained PD-1 but low levels of CTLA-4, TIM-3, KLRG1 and CD244 expression. PD-1 blockade revealed individualized patterns of in vitro responsiveness with partly increased IFN-gamma, IL-2 and TNF-alpha secretion as well as enhanced CD4(+) T-cell expansion almost in treated patients with viral control. Conclusion: HBV-specific CD4(+) T-cells are reliably detectable during different courses of HBV infection by MHC class II Tetramer technology. CD4(+) T-cell dysfunction during chronic HBV is basically linked to strong PD-1 upregulation but absent coregulation of multiple inhibitory receptors. PD-L1/2 neutralization partly leads to enhanced CD4(+) T-cell functionality with heterogeneous patterns of CD4(+) T-cell rejunivation.
    PLoS ONE 08/2014; 9(8):e105703. DOI:10.1371/journal.pone.0105703 · 3.53 Impact Factor

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