Yonghong Zhang

Interferon-induced transmembrane protein-3 genetic variant rs12252-C is associated with severe influenza in Chinese individuals.

The SNP rs12252-C allele alters the function of interferon-induced transmembrane protein-3 increasing the disease severity of influenza virus infection in Caucasians, but the allele is rare. However, rs12252-C is much more common in Han Chinese. Here we report that the CC genotype is found in 69% of Chinese patients with severe pandemic influenza A H1N1/09 virus infection compared with 25% in those with mild infection. Specifically, the CC genotype was estimated to confer a sixfold greater risk for severe infection than the CT and TT genotypes. More importantly, because the risk genotype occurs with such a high frequency, its effect translates to a large population-attributable risk of 54.3% for severe infection in the Chinese population studied compared with 5.4% in Northern Europeans. Interferon-induced transmembrane protein-3 genetic variants could, therefore, have a strong effect of the epidemiology of influenza in China and in people of Chinese descent.

Extensive HLA-driven viral diversity following a narrow-source HIV-1 outbreak in rural China.

Obstacles to developing an HIV-1 vaccine include extensive viral diversity and lack of correlates of protective immunity. High mutation rates allow HIV-1 to adapt rapidly to selective forces such as antiretroviral therapy and immune pressure, including HIV-1-specific CTLs that select viral variants which escape T-cell recognition. Multiple factors contribute to HIV-1 diversity, making it difficult to disentangle the contribution of CTL selection without using complex analytical approaches. We describe an HIV-1 outbreak in 231 former plasma donors in China, where a narrow-source virus that had contaminated the donation system was apparently transmitted to many persons contemporaneously. The genetic divergence now evident in these subjects should uniquely reveal how much viral diversity at the population level is solely attributable to host factors. We found significant correlations between pair-wise divergence of viral sequences and HLA class I genotypes across epitope-length windows in HIV-1 Gag, reverse transcriptase, integrase, and Nef, corresponding to sites of 140 HLA class I allele-associated viral polymorphisms. Of all polymorphic sites across these 4 proteins, 24%-56% were sites of HLA-associated selection. These data confirm that CTL pressure has a major effect on inter-host HIV-1 viral diversity and probably represents a key element of viral control.

High levels of virus-specific CD4+ T cells predict severe pandemic influenza A virus infection.

RATIONALE T-cell responses have been implicated in control and exacerbation of lung injury during influenza A virus (IAV) infection. OBJECTIVES To examine the breadth and magnitude of influenza-specific CD4(+) and CD8(+) T-cell responses during acute phase of infection. METHODS Influenza-specific T-cell response to the entire pandemic H1N1/09 IAV proteome and T cell-related cytokine levels were measured in blood from previously healthy individuals with mild (n = 32) and severe (n = 16) IAV infection during the 2009 influenza pandemic. Virus-specific T-cell response in lung and blood was also performed in two acutely infected, severely ill patients using fluorescent-conjugated pdmH1N1/09 Matrix-MHC-I tetrameric complexes. MEASUREMENTS AND MAIN RESULTS Strong and broad CD4(+) but not CD8(+) T-cell responses were observed in the blood, and were higher in those with severe disease. Antigen-specific CD8(+) T cells in the lungs were on average 45-fold higher compared with blood in severely ill patients. Paradoxically, in patients with severe disease, IL-17, IL-2, IL-4, and IFN-γ levels were significantly decreased. CONCLUSIONS High levels of circulating virus-specific CD4(+) T cells to two viral internal proteins (nucleoprotein and matrix) in the first phase of infection are associated with subsequent development of severe IAV infection. This finding could be an early and specific marker for ensuing clinical deterioration. Contrasting levels of antigen-specific CD8(+) T cells in lungs and blood have implications on design and analysis of clinical trials for T-cell vaccines because measurements of T cells in the periphery may not reflect events in the lungs.

High Frequency of HIV Mutations Associated with HLA-C Suggests Enhanced HLA-C–Restricted CTL Selective Pressure Associated with an AIDS-Protective Polymorphism

Delayed HIV-1 disease progression is associated with a single nucleotide polymorphism upstream of the HLA-C gene that correlates with differential expression of the HLA-C Ag. This polymorphism was recently shown to be a marker for a protective variant in the 3′UTR of HLA-C that disrupts a microRNA binding site, resulting in enhanced HLA-C expression at the cell surface. Whether individuals with “high” HLA-C expression show a stronger HLA-C–restricted immune response exerting better viral control than that of their counterparts has not been established. We hypothesized that the magnitude of the HLA-C–restricted immune pressure on HIV would be greater in subjects with highly expressed HLA-C alleles. Using a cohort derived from a unique narrow source epidemic in China, we identified mutations in HIV proviral DNA exclusively associated with HLA-C, which were used as markers for the intensity of the immune pressure exerted on the virus. We found an increased frequency of mutations in individuals with highly expressed HLA-C alleles, which also correlated with IFN-γ production by HLA-C–restricted CD8+ T cells. These findings show that immune pressure on HIV is stronger in subjects with the protective genotype and highlight the potential role of HLA-C–restricted responses in HIV control. This is, to our knowledge, the first in vivo evidence supporting the protective role of HLA-C–restricted responses in nonwhites during HIV infection.

Multilayered defense in HLA-B51-associated HIV viral control

Polymorphism in the HLA region of a chromosome is the major source of host genetic variability in HIV-1 outcome, but there is limited understanding of the mechanisms underlying the beneficial effect of protective class I alleles such as HLA-B57, -B27, and -B51. Taking advantage of a unique cohort infected with clade B’ HIV-1 through contaminated blood, in which many variables such as the length of infection, the infecting viral strain, and host genetic background are controlled, we performed a comprehensive study to understand HLA-B51–associated HIV-1 control. We focused on the T cell responses against three dominant HLA-B51–restricted epitopes: Gag327-345(NI9) NANPDCKTI, Pol743-751(LI9) LPPVVAKEI, and Pol283-289(TI8) TAFTIPSI. Mutations in all three dominant epitopes were significantly associated with HLA-B51 in the cohort. A clear hierarchy in selection of epitope mutations was observed through epitope sequencing. L743I in position 1 of epitope LI9 was seen in most B51+ individuals, followed by V289X in position 8 of the TI8, and then, A328S, in position 2 of the NI9 epitope, was also seen in some B51+ individuals. Good control of viral load and higher CD4+ counts were significantly associated with at least one detectable T cell response to unmutated epitopes, whereas lower CD4+ counts and higher viral loads were observed in patients who had developed escape mutations in all three epitopes or who lacked T cell responses specific to these epitope(s). We propose that patients with HLA-B51 benefit from having multiple layers of effective defense against the development of immune escape mutations.

Interferon-induced transmembrane protein-3 rs12252-C is associated with rapid progression of acute HIV-1 infection in Chinese MSM cohort

Background:The interferon-inducible transmembrane protein-3 (IFITM3) is a protein that restricts multiple pathogenic viruses such as influenza virus. The single-nucleotide polymorphism rs12252-C, which is rare in Caucasian populations, but much more common in the Han Chinese population, has been found in much higher homozygous frequency in patients with severe acute influenza. Until now, there has been no study on the effect of this genetic variant on the clinical control of other viral infections. Objectives:To investigate the impact of IFITM3-rs12252 genotypes on primary HIV-1 infection progression in an acute HIV-1-infected cohort in Beijing (PRIMO), China. Design and methods:We identified IFITM3-rs12252 genotypes of 178 acute HIV-1-infected patients and 196 HIV-negative candidates from the PRIMO cohort. HIV-1 viral load and CD4+ T-cell counts were monitored at multiple time points during the first year of infection, and the association between IFITM3-rs12252 genotype and disease progression was evaluated. Results:The current study shows that the IFITM3-rs12252 genetic variant affects the progression of HIV-1 infection, but not the acquisition. A significantly higher frequency of the CC/CT genotypes was found in rapid progressors compared to nonprogressors. Patients with CC/CT genotypes showed an elevated peak viremia level and significantly lower CD4+ T-cell count at multiple time points during the first year of primary infection, and a significantly higher risk of rapid decline of the CD4+ T-cell count to below 350 cells/&mgr;l. Conclusion:A novel association between IFITM3 gene polymorphism and rapid disease progression is reported in an acute HIV-1-infected MSM cohort in China.

Potent hepatitis B surface antigen response to treatment of hepatitis-B-e-antigen-positive chronic hepatitis B with α-interferon plus a nucleos(t)ide analog.

Background and Aim:  Hepatitis B surface antigen (HBsAg) clearance is the closest cure outcome in hepatitis B. The goal of this study was to investigate clinical features in chronic hepatitis B patients achieving seroconversion of HBsAg after treatment with α‐interferon (IFN‐α) and a nucleos(t)ide analog.

HIV burden in men who have sex with men: a prospective cohort study 2007–2012

We conducted a prospective cohort study among HIV-negative MSM aged 18 years or older between 2007 and 2012 in Beijing, China to measure the rates of incident HIV and identify risk factors for infection. Among 5,800 participants evaluated at enrollment, we identified 486 prevalent cases of HIV (8.4%). Among the 3,625 enrollees who were HIV-negative at enrollment and completed at least one follow-up interview, we identified 440 incident cases of HIV in the follow up period: this constituted an HIV incidence rate of 7.1 per 100 person-years (95% CI: 6.4–7.7). Early treatment of syphilis may have significantly reduced risk of HIV infection (RR: 1.45, 95% CI: 1.11–1.93), while MSM presenting perfect compliance in the cohort did not show reduction in HIV infection. Our study suggested that HIV incidence has been remained high in this sample of Chinese MSM during the intensive preventive intervention, suggesting that we need to find new strategies to prevent HIV infection in this population.

MicroRNA panels as disease biomarkers distinguishing hepatitis B virus infection caused hepatitis and liver cirrhosis

An important unresolved clinical issue is to distinguish hepatitis B virus (HBV) infection caused chronic hepatitis and their corresponding liver cirrhosis (LC). Recent research suggests that circulating microRNAs are useful biomarkers for a wide array of diseases. We analyzed microRNA profiles in the plasmas of a total of 495 chronic hepatitis B (CHB) patients, LC patients and healthy donors and identified 10 miRNAs that were differentially expressed between CHB and LC patients. Our logistic models show that three panels of miRNAs have promising diagnostic performances in discriminating CHB from LC. Blinded tests were subsequently conducted to evaluate the diagnostic performances in clinical practice and a sensitivity of 85% and specificity of 70% have been achieved in separating CHB from LC pateints. The expression levels of some circulating miRNAs were significantly correlated with HBV DNA load and liver function, such as prothrombin activity (PTA) and levels of alanin aminotransferase (ALT), albumin (ALB) and cholinesterase (CHE). Our results provide important information for developing novel diagnostic tools for distinguishing chronic HBV hepatitis and their corresponding cirrhosis.

Identification of T cell epitopes on soluble liver antigen in Chinese patients with auto‐immune hepatitis

Aim: To identify soluble liver antigen (SLA)‐specific dominant epitopes and analyse the correlation between SLA‐specific T cell response and the status of the disease.