M Jia

Loss of balance between T helper type 17 and regulatory T cells in chronic human immunodeficiency virus infection

The aim of this study is to characterize the changes of CD4+CD25highforkhead box P3 (FoxP3+) regulatory T cells (Treg), interleukin (IL)‐17 secreting T helper type 17 (Th17) cell frequencies and the balance of these two subsets in a cohort of chronic human immunodeficiency virus type 1 (HIV‐1)‐infected patients in China. A total of 115 untreated chronic HIV‐infected individuals and 32 healthy donors were recruited in this study. Peripheral blood mononuclear cells were isolated from ethylenediamine tetracetic acid (EDTA) anti‐coagulated fresh whole blood and stained to characterize the frequencies of Treg and Th17. Of a total 115 patients, 42 individuals including 10 elite controllers were followed‐up for more than 1 year, and changes of Treg and Th17 frequencies were analysed over time. The continuous loss of Th17 cells was accompanied by a concomitant rise in the frequency of Treg cells, resulting in a loss of Th17/Treg balance during the progressive HIV infection. Meanwhile, the Treg levels, Th17 levels and Th17/Treg ratios of the elite controller group were comparable to those of the HIV‐1 negative controls in the follow‐up study. Additionally, we demonstrated that loss of balance between Th17 and Treg is associated with an earlier CD4 T cell decline during the course of HIV infection. Our results indicate that a loss of immune‐balance of Th17 to Treg during HIV‐1 disease progression and the persistence of such an immune‐balance in the elite controllers may have a critical role in HIV‐1 infection and further shed new light into understanding the pathogenesis of HIV‐1.

P14-15 LB. The safety and immunogenicity of HIV-1 vaccines based on DNA and replication competent vaccinia vector in phase I clinical trial

Methods HIV-1 CN54 gag, pol and env genes were constructed into DNA and rTV vectors. 48 healthy participants were either inoculated with rTV (5 × 104 pfu, skin scratches) or DNA vaccine (2 mg, 4 mg, i.m.) alone, in combination, or placed on the placebo. The participants were monitored up to 36 weeks for clinical symptoms and laboratory tests. Vaccine induced immunogenicity were measured by ELIspot, ICS, and antibody assays.

Human immunodeficiency virus type 1 specific cytotoxic T lymphocyte responses in Chinese infected with HIV-1 B'/C Recombinant (CRF07_BC)

BackgroundThe characterization of HIV-1-specific T cell responses in people infected with locally circulating HIV-1 strain will facilitate the development of HIV-1 vaccine. Sixty intravenous drug users infected with HIV-1 circulating recombinant form 07_BC (CRF07_BC), which has been spreading rapidly in western China from north to south, were recruited from Xinjiang, China to assess the HIV-1-specific T cell responses at single peptide level with overlapping peptides (OLP) covering the whole concensus clades B and C proteome.ResultsThe median of the total magnitude and total number of OLPs recognized by CTL responses were 10925 SFC/million PBMC and 25 OLPs, respectively, when tested by clade C peptides, which was significantly higher than when tested by clade B peptides. The immunodominant regions, which cover 14% (58/413) of the HIV-1 proteome, are widely distributed throughout the HIV-1 proteome except in Tat, Vpu and Pol-PR, with Gag, Pol-RT, Pol-Int and Nef being most frequently targeted. The subdominant epitopes are mostly located in p24, Nef, integrase, Vpr and Vif. Of the responses directed to clade C OLPs, 61.75% (972/1574) can be observed when tested with corresponding clade B OLPs. However, Pol-PR and Vpu tend to be targeted in the clade B sequence rather than the clade C sequence, which is in line with the recombinant pattern of CRF07_BC. Stronger and broader CTL responses in subjects with CD4 cell counts ranging from 200 to 400/mm3 were observed when compared to those with less than 200/mm3 or more than 400/mm3, though there have been no significant correlations identified between the accumulative CTL responses or overall breadth and CD4 cell count or plasma viral load.ConclusionThis is the first study conducted to comprehensively address T cell responses in Chinese subjects infected with HIV-1 CRF07_BC in which subtle differences in cross-reactivity were observed, though similar patterns of overall immune responses were demonstrated with clade B infected populations. The immunodominant regions identified in this population can facilitate future HIV-1 vaccine development in China.

Non-neutralizing epitopes induce robust hepatitis C virus (HCV)-specific antibody-dependent CD56 natural killer cell responses in chronic HCV-infected patients.

Natural killer (NK) cell‐mediated antibody‐dependent cellular cytotoxicity (NK‐ADCC) is of considerable interest in viral infection. However, little is known about NK‐ADCC responses in chronic hepatitis C virus (HCV) infection. In this study, impaired non‐specific antibody‐dependent CD56+ NK cell responses were observed in chronic HCV infection, as shown by decreased degranulation (extracellular CD107a expression) and interferon (IFN)‐γ production in response to antibody‐bound P815 cells. A peptide pool composed of epitopes recognized by anti‐HCV‐E1/E2 antibodies could induce pronounced HCV‐specific antibody‐dependent NK cell responses in sera from approximately half the chronic HCV carriers. Additionally, HCV‐specific epitopes with the capacity to induce robust NK‐ADCC activity were identified. Five linear NK‐ADCC epitopes (aa211‐aa217, aa384‐aa391, aa464‐aa475, aa544‐aa551 and aa648‐aa659 of the HCV envelope) were identified and do not overlap with putative linear neutralizing epitopes. This study revealed the dysfunctional characteristics of antibody‐dependent CD56+ NK cell responses in chronic HCV carriers. The key non‐neutralizing NK‐ADCC epitopes identified in this study may act as new targets for immunological intervention.

MicroRNA 31 inhibits CD8 + T-cell function by increasing its sensitivity to type I interferon signaling in chronic viral infection

MicroRNA 31 inhibits CD8 + T-cell function by increasing its sensitivity to type I interferon signaling in chronic viral infection

Highly expression of Tim-3 on HIV-specific T cells associated with disease progression and T-cell exhaustion in HIV-1 infected Chinese

Methods 72 HIV-1 infected individuals with different disease outcomes were recruited in this study. Tim-3 expression and the profile of cellular immune response were measured by using Multicolor Intracellular Cytokine Staining (ICS) assay. Association between Tim-3 expression levels and disease progression was analyzed. And the potential role of Tim-3 on immune regulation during HIV-1 infection was investigated through assessment of CTL response with frequencies of Tim-3 expression and blocking effect.

Human leukocyte antigen class I supertypes and viral control in HIV-1 infected former plasma donors from China

Background The role of human leukocyte antigen (HLA) class I supertypes in controlling human immunodeficiency virus type 1 (HIV-1) infection in Chinese has not been established. The aim of this study is to examine the frequency of HLA-A and HLA-B alleles and supertypes of 222 HIV-1 infected former plasma donors in central China and to investigate their impact on HIV-1 viral control. Methods HLA-A and HLA-B alleles were genotyped with PCR-SSP and sequence-based typing assay to four-digit resolution. The HLA alleles were classified functionally to 4 HLA-A supertypes and 6 HLA-B supertypes according to their shared peptide binding properties. Plasma viral load was determined using the Roche Amplicor ultrasensitive assay which has a lower detection limit of 50 copies HIV-1 RNA per ml. Results HLA-A03 supertypes(A03s) and HLA-B62 supertypes (B62s) were associated with lower viral load (P=0.0206, P=0.0483), whereas HLA- A24 supertypes(A24s) appeared to have an association with higher viral load (P=0.0483). There was ah ighly significant correlation between the genotypic supertypes(GS) and viral load (Kendall’s tau b = 0.180, P=0.000). The median viral load was lower among A*3001(P=0.0139), A*1101(P=0.0096), B*5101(P=0.0025), B*3501(P=0.0091) or B*4601(P=0.001) carriers and higher in A*2301(P=0.0106) carriers. Conclusion

P16-12. Relative Dominance of Gag-Specific Cytotoxic T Lymphocytes Is Associated with Viral Load Inversely in HIV-1 Clade B' Infected Chinese

Background The role of CD8+ T cells with cytotoxic (CTL) activity of different HIV proteins in controlling HIV-1 infection is still controversial, though a number of studies have suggested that gag-specific CTLs could play a superior role in viral control. The characterization of HIV-1-specific CTLs in genetic diverse individuals infected with locally prevalent HIV-1 strains will provide useful information in elucidating the mechanism of HIV-1 pathogenesis.

P16-14. Loss of balance between CD4+ regulatory T cell and Th17 population in chronic HIV infection

Background Cumulative data indicate that CD4+ Treg and Th17 cells are reciprocally regulated during differentiation and play couter balance role in inflammatory diseases, suggesting the balance of them is critical in maintaining effective immune function. Loss of such an immuno-balance has recently been documented in tumors and SIV infection. However, little data is available on the balance between Treg and Th17 in chronic HIV-1 infection.