A Steady State of CD4(+) T Cell Memory Maturation and Activation Is Established during Primary Subtype C HIV-1 Infection

AIDS Research Unit, National Institute for Communicable Diseases, Johannesburg, Gauteng, South Africa.
The Journal of Immunology (Impact Factor: 4.92). 04/2010; 184(9):4926-35. DOI: 10.4049/jimmunol.0903771
Source: PubMed


The functional integrity of CD4(+) T cells is crucial for well-orchestrated immunity and control of HIV-1 infection, but their selective depletion during infection creates a paradox for understanding a protective response. We used multiparameter flow cytometry to measure activation, memory maturation, and multiple functions of total and Ag-specific CD4(+) T cells in 14 HIV-1- and CMV- coinfected individuals at 3 and 12 mo post HIV-1 infection. Primary HIV-1 infection was characterized by elevated levels of CD38, HLA-DR, and Ki67 in total memory and Gag-specific CD4(+) and CD8(+) T cells. In both HIV-infected and 15 uninfected controls, the frequency of activated cells was uniformly distributed among early differentiated (ED; CD45RO(+)CD27(+)), late differentiated (CD45RO(+)CD27(-)), and fully differentiated effector (CD45RO(-)CD27(-)) memory CD4(+) T cells. In HIV-1-infected individuals, activated CD4(+) T cells significantly correlated with viremia at 3 mo postinfection (r = 0.79, p = 0.0007) and also harbored more gag provirus DNA copies than nonactivated cells (p = 0.04). Moreover, Gag-specific ED CD4(+) T cells inversely associated with plasma viral load (r = -0.87, p < 0.0001). Overall, we show that low copy numbers of gag provirus and plasma RNA copies associated with low CD4 activation as well as accumulation of ED HIV-specific CD4(+) memory. Significant positive correlations between 3 and 12 mo activation and memory events highlighted that a steady state of CD4(+) T cell activation and memory maturation was established during primary infection and that these cells were unlikely to be involved in influencing the course of viremia in the first 12 mo of HIV-1 infection.

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Available from: Catherine Riou, Oct 06, 2015
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    • "An effective CD8 T-cell response is believed to be important in reducing the peak of viral load after PHI (McMichael et al., 2010), and the association of such responses with LTNP and EC status is discussed below. However, there is also a significant CD4 T-cell response to HIV infection as well during PHI (Rosenberg et al., 2000; Oxenius et al., 2001; Gloster et al., 2004; Kaufmann et al., 2004; Zaunders et al., 2005; Maenetje et al., 2010; Riou et al., 2012). We have consistently found that there is a transient, greatly increased rate of activation and proliferation of CD4 T-cells which results in high levels of CD38high, CCR5+, Ki67+, and CD127low cells (Zaunders et al., 1995, 2001, 2005), making ideal targets for highly productive HIV-1 infection. "
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    ABSTRACT: Long-term non-progressors (LTNP) were identified after 10-15 years of the epidemic, and have been the subject of intense investigation ever since. In a small minority of cases, infection with nef/3'LTR deleted attenuated viral strains allowed control over viral replication. A common feature of LTNP is the readily detected proliferation of CD4 T cells in vitro, in response to p24. In some cases, the responding CD4 T cells have cytotoxic effector function and may target conserved p24 epitopes, similar to the CD8 T cells described below. LTNP may also carry much lower HIV DNA burden in key CD4 subsets, presumably resulting from lower viral replication during primary infection. Some studies, but not others, suggest that LTNP have CD4 T cells that are relatively resistant to HIV infection in vitro. One possible mechanism may involve up-regulation of the cell cycle regulator p21/waf in CD4 T cells from LTNP. Delayed progression in Caucasian LTNP is also partly associated with heterozygosity of the ∆32 CCR5 allele, probably through decreased expression of CCR5 co-receptor on CD4 T cells. However, in approximately half of Caucasian LTNP, two host genotypes, namely HLA-B57 and HLA-B27, are associated with viral control. Immunodominant CD8 T cells from these individuals target epitopes in p24 that are highly conserved, and escape mutations have significant fitness costs to the virus. Furthermore, recent studies have suggested that these CD8 T cells from LTNP, but not from HLA-B27 or HLA-B57 progressors, can cross-react with intermediate escape mutations, preventing full escape via compensatory mutations. Humoral immunity appears to play little part in LTNP subjects, since broadly neutralizing antibodies are rare, even amongst slow progressors. Recent genome wide comparisons between LTNP and progressors have confirmed the HLA-B57, HLA-B27 and delta32 CCR5 allelic associations, plus indicated a role for HLA-C/KIR interactions, but have not revealed any new genotypes so far.
    Frontiers in Immunology 04/2013; 4:95. DOI:10.3389/fimmu.2013.00095
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    • "Primary infection with the human immunodeficiency virus type-1 (HIV) is a crucial moment for establishing relationships between virus and host [1], [2], [3]. The high plasma viral load (pVL) causes a relevant and persistent immune activation that can trigger apoptosis [6]–[8], and becomes chronic in the absence of a valid immune response or without efficient antiretroviral therapy. "
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    ABSTRACT: Immune changes occurring after primary HIV infection (PHI) have a pivotal relevance. Our objective was to characterize the polyfunctionality of immune response triggered by PHI, and to characterize immune activation and regulatory T cells, correlating such features to disease progression. We followed 11 patients experiencing PHI for 4 years. By polychromatic flow cytometry, we studied every month, for the first 6 months, T lymphocyte polyfunctionality after cell stimulation with peptides derived from HIV-1 gag and nef. Tregs were identified by flow cytometry, and T cell activation studied by CD38 and HLA-DR expression. An increase of anti-gag and anti-nef CD8+ specific T cells was observed 3 months after PHI; however, truly polyfunctional T cells, also able to produce IL-2, were never found. No gross changes in Tregs were present. T lymphocyte activation was maximal 1 and 2 months after PHI, and significantly decreased in the following period. The level of activation two months after PHI was strictly correlated to the plasma viral load 1 year after infection, and significantly influenced the length of period without therapy. Indeed, 80% of patients with less than the median value of activated CD8+ (15.5%) or CD4+ (0.9%) T cells remained free of therapy for >46 months, while all patients over the median value had to start treatment within 26 months. T cell activation after PHI, more than T cell polyfunctionality or Tregs, is a predictive marker for the control of viral load and for the time required to start treatment.
    PLoS ONE 12/2012; 7(12):e50728. DOI:10.1371/journal.pone.0050728 · 3.23 Impact Factor
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    ABSTRACT: Activated CD4(+) T cells are more susceptible to HIV infection than resting T cells; the reason for this remains unresolved. Induction of CIITA and subsequent expression of the MHC class II isotype HLA-DR are hallmarks of CD4(+) T cell activation; therefore, we investigated the role of CIITA expression in T cells during HIV infection. CIITA-expressing SupT1 cells display enhanced virion attachment in a gp160/CD4-dependent manner, which results in increased HIV infection, virus release, and T cell depletion. Although increased attachment and infection of T cells correlated with HLA-DR surface expression, Ab blocking, transient expression of HLA-DR without CIITA, and short hairpin RNA knockdown demonstrate that HLA-DR does not directly enhance susceptibility of CIITA-expressing cells to HIV infection. Further analysis of the remaining MHC class II isotypes, HLA-DP and HLA-DQ, MHC class I isotypes, HLA-A, HLA-B, and HLA-C, and the class II Ag presentation genes, invariant chain and HLA-DM, demonstrate that these proteins likely do not contribute to CIITA enhancement of HIV infection. Finally, we demonstrate that in activated primary CD4(+) T cells as HLA-DR/CIITA expression increases there is a corresponding increase in virion attachment. Overall, this work suggests that induction of CIITA expression upon CD4(+) T cell activation contributes to enhanced attachment, infection, virus release, and cell death through an undefined CIITA transcription product that may serve as a new antiviral target.
    The Journal of Immunology 11/2010; 185(11):6480-8. DOI:10.4049/jimmunol.1000830 · 4.92 Impact Factor
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