Taisheng Li

Reduced Thymic Output Is a Major Mechanism of Immune Reconstitution Failure in HIV-Infected Patients After Long-term Antiretroviral Therapy

BACKGROUND Approximately 20% of human immunodeficiency virus type 1 (HIV-1)--infected adults do not normalize their CD4(+) T lymphocytes after long-term effective highly active antiretroviral therapy (HAART). The mechanistic basis for this failure is unclear. METHODS Seventy-four patients were followed up regularly for 3-7 years. Patients with undetectable plasma viral load (<50 copies/mL) for over 12 months were further classified into 2 groups: (1) immunological nonresponders, whose CD4(+) T-cell count was < 200/μL or <20% compared with baseline; and (2) immunological responders, whose CD4(+) T-cell count was > 300/μL or >30% compared with baseline. RESULTS Compared with 17 immunological responders, 13 immunological nonresponders had a lower magnitude of naive CD4(+) T-cell increase, a lower percentage of recent thymic immigrants (CD31(+)%), and a higher percentage of activated CD8(+) T cells. Furthermore, unlike CD4(+) T cells, which increased along with the decrease of viral load, the percentage of recent thymic immigrants (CD31(+)%) had little change in the majority of patients. These data were fit into a mathematical model, , from which we deduced that the initial rate of CD4(+) T-cell restoration is associated significantly with the percentage of recent thymic immigrants (CD31(+)%). CONCLUSIONS Our data indicate that the failure to restore CD4(+) T-cell count following HAART was associated primarily with a defect in recent thymic immigrants, which suggests the existence of thymus exhaustion.

Significant changes of peripheral T lymphocyte subsets in patients with severe acute respiratory syndrome.

This report demonstrates that a rapid decrease of peripheral T cell subsets is a unique characteristic in patients with SARS during acute infection, although total white blood cell counts, red blood cell counts, and platelet counts remain relatively normal. In recovering patients, a rapid and dramatic restoration of peripheral T cell subsets was seen in the periphery. Although the underlying mechanism of the acute decrease of peripheral T cell subsets observed in patients with SARS during the acute stage remains unknown, this clinical characteristic can facilitate an earlier and more accurate diagnosis of SARS.

Novel Immunodominant Peptide Presentation Strategy: a Featured HLA-A*2402-Restricted Cytotoxic T-Lymphocyte Epitope Stabilized by Intrachain Hydrogen Bonds from Severe Acute Respiratory Syndrome Coronavirus Nucleocapsid Protein

ABSTRACT Antigenic peptides recognized by virus-specific cytotoxic T lymphocytes (CTLs) are presented by major histocompatibility complex (MHC; or human leukocyte antigen [HLA] in humans) molecules, and the peptide selection and presentation strategy of the host has been studied to guide our understanding of cellular immunity and vaccine development. Here, a severe acute respiratory syndrome coronavirus (SARS-CoV) nucleocapsid (N) protein-derived CTL epitope, N1 (QFKDNVILL), restricted by HLA-A*2402 was identified by a series of in vitro studies, including a computer-assisted algorithm for prediction, stabilization of the peptide by co-refolding with HLA-A*2402 heavy chain and β2-microglobulin (β2m), and T2-A24 cell binding. Consequently, the antigenicity of the peptide was confirmed by enzyme-linked immunospot (ELISPOT), proliferation assays, and HLA-peptide complex tetramer staining using peripheral blood mononuclear cells (PBMCs) from donors who had recovered from SARS donors. Furthermore, the crystal structure of HLA-A*2402 complexed with peptide N1 was determined, and the featured peptide was characterized with two unexpected intrachain hydrogen bonds which augment the central residues to bulge out of the binding groove. This may contribute to the T-cell receptor (TCR) interaction, showing a host immunodominant peptide presentation strategy. Meanwhile, a rapid and efficient strategy is presented for the determination of naturally presented CTL epitopes in the context of given HLA alleles of interest from long immunogenic overlapping peptides.

Immunological and virological responses to cART in HIV/HBV co-infected patients from a multicenter cohort.

Objective:To evaluate the influence of hepatitis B virus (HBV) coinfection on immunological, virological and clinical responses to lamivudine (3TC)-based combined antiretroviral therapy (cART) in Chinese patients. Design and methods:This prospective, multicenter cohort study recruited 529 antiretroviral-naive participants (aged 18–65 years, both sexes) between 2008 and 2010. They were grouped by HBV serostatus. Virological and immunological responses were monitored at baseline and week 4, 8, 12, 24, 36 and 48. cART for all patients was nevirapine, 3TC with either zidovudine or stavudine. Results:First, HIV/HBV coinfection rate in our cohort was 14.6%. Second, among 508 patients with complete baseline information, median CD4 level was significantly lower in the chronic HBV-infected (CHB) group and isolated core group. In the CHB group, hepatitis B e antigen positivity rather than HBV DNA level was associated with lower CD4 cell count. Third, in the isolated core group, occult infection rate was 9.5%. Fourth, at week 48, rate of HIV suppression below 40 copies/ml was 74.2%. Median increase in the CD4 cell count at week 48 was 127 cells/&mgr;l. Of note, HBV serostatus did not influence virological and immunological response to cART at each follow-up time point. Although HBV serostatus was associated with different alanine aminotransferase levels during follow-up, hepatitis and hyperbilirubinemia rates were not significantly different. Fifth, the 3TC-based regimen was efficacious against HBV replication, with median decrease in HBV DNA of 2.87 log copies/ml. However, hepatitis B e antigen positivity was associated with poorer HBV DNA suppression. Conclusion:In our cohort, CHB infection and isolated hepatitis B core antibody positivity were related to faster HIV progression. Despite of this, virological and immunological responses were not affected by HBV serostatus. (ClinicalTrials.gov identifier: NCT00872417)

Three Generic Nevirapine-Based Antiretroviral Treatments in Chinese HIV/AIDS Patients: Multicentric Observation Cohort

Background The purpose of this study was to evaluate the efficacy and safety of three nevirapine-based antiretroviral treatments for adult antiretroviral-naïve Chinese patients with HIV-1 infection. Methodology This was a prospective, multicenter study. 198 antiretroviral-naïve HIV-1 positive subjects with CD4 lymphocyte counts between 100/ul and 350/ul and plasma HIV-1 RNA levels more than 500 copies/ml were randomized to start three NVP-based antiretroviral treatments: group A, NVP+AZT+ddI; group B, NVP+3TC+d4T; group C, NVP+AZT+3TC. Viral responses, immunologic responses, adverse events and drug resistence were monitored at baseline and the end of week 4, 12, 24, 36, 52. Viralogical response and immunological response were also comparaed in different strata of baseline CD4 T lymphocyte counts and plasma HIV-1 RNA concentrations. At baseline, the plasma HIV-1 RNA was 4.44±0.68, 4.52±0.71 and 4.41±0.63 lg copies/ml in group A, B and C respectively (p = 0.628). At the end of the study, the plasma viral load reached 2.54±1.11, 1.89±0.46 and 1.92±0.58 lg copies/ml in group A, B and C respectively (p<0.001). At week 52, suppression of plasma HIV-1 RNA to less than 50 copies/ml was achieved in more patients in group B and C than in group A (68.2%, 69% vs. 39.7%; p<0.001). In planned subgroup analyses, the decrease of viral response rate was seen in group A when CD4 cell count >200/ul (subgroup H). But in subgroup L, viral response rate of three groups has no significant statistic difference. There were no statistically significant differences among three groups in immunological response wthin any of the CD4 or pVL strata. 3 out of 193 patients with available genotype at baseline showed primary drug resistant. Of 26 patients with virologic failure, 17 patients showed secondary drug resistant, 16 subjects in group A and 1 subject in group B. Logistic regression analysis indicated that presence of hepatotoxicity was associated with HCV-Ab positive (OR = 2.096, 95%CI: 1.106–3.973, P = 0.023) and higher CD4 baseline (CD4 count >250/ul)(OR = 2.096, 95%CI: 1.07–4.107, P = 0.031). Conclusion Our findings strongly support the use of 3TC+d4T and 3TC+AZT as the nucleoside analogue combination in NVP-based antiretroviral therapy. The regimen of AZT+ddI+NVP produced poor virological response especially in the stratum of CD4 count more than 200/ul. More patients showed secondary drug resistant in this arm too. Patients with HCV-Ab+ and CD4 count >250/ul appear to have significantly high risk of hepatoxicity. Trial Registration ClinicalTrials.gov NCT00618176

Nevirapine Plasma Concentrations Are Associated with Virologic Response and Hepatotoxicity in Chinese Patients with HIV Infection

Background Limited information is available on the relationship between nevirapine plasma concentrations and virologic response or liver toxicity in Chinese patients with HIV infection. The objective of this prospective study was to test this relationship and to determine the minimal therapeutic trough concentration of nevirapine for Chinese patients. Methods A total of 227 HIV-infected, treatment naïve patients were enrolled into this study. Blood samples were taken at Ctrough (12 hr postdose) and C2 (2 hr postdose) for measurement of nevirapine concentrations 6 months after treatment initiation. Therapeutic outcomes, viral load and CD4 cell count, were assessed at 3 and 6 months after starting therapy, while the evaluation of hepatotoxicity was undertaken 12 months after nevirapine treatment. Results A significant correlation between nevirapine trough concentrations and viral load was noticed after 6 months of treatment, particularly in patients with partial response and viral failure (p<0.01). The therapeutic Ctrough of nevirapine for Chinese patients was determined to be 3.9 µg/ml using the receiver operating characteristic curve. Virologic failure was observed in 21% (6/29) of patients with low nevirapine concentrations (<3.9 µg/ml) versus 5% (4/87) in patients with concentrations higher than 3.9 µg/ml (p = 0.015). Hepatotoxicity was significantly associated with the median nevirapine trough concentrations among male patients (8.20 vs. 5.48 µg/ml, p = 0.015) and hepatitis C virus co-infection (p = 0.039). Conclusions Among Chinese patients with HIV infection, the therapeutic Ctrough of nevirapine was 3.9 µg/ml, higher than the recommended 3.0 µg/ml. The correlation between nevirapine concentrations, efficacy and hepatotoxicity suggests the benefit of dosage adjustment based on therapeutic drug monitoring among Chinese HIV-infected patients to optimize nevirapine containing antiretroviral therapy.

Impact of a tenofovir disoproxil fumarate plus ritonavir-boosted protease inhibitor-based regimen on renal function in HIV-infected individuals: a prospective, multicenter study

BackgroundThe aim of this study was to investigate the impact of a tenofovir disoproxil fumarate (TDF) plus ritonavir-boosted protease inhibitor (PI/r) regimen on renal function in Chinese HIV-infected patients.MethodsSeventy-five HIV-1 infected patients failing first-line antiretroviral therapy (ART) comprised the TDF+PI/r group. Seventy-five HIV-1 infected patients matched for gender, age, and renal function made up the control. All subjects completed follow-up visits over 48 weeks. CD4 cell count, plasma HIV-1 viral load, and urine protein level were assessed at the trial start (baseline, week 0) and at week 48. The serum creatinine and estimated glomerular filtration rate (eGFR) were monitored at each follow-up point. Change in eGFR from baseline to week 48 was also compared.ResultsCompared to control, the TDF+PI/r group exhibited higher levels of serum creatinine (79 vs. 69.7 μmol/L, P<0.001) and a lower rate of eGFR (93.0 vs. 101.6 ml/min/1.73m2, P=0.009) at the end of week 48. Patients treated with TDF+PI/r showed greater decline in eGFR than control (−8.8 vs. 6.4ml/min/1.73m2, P<0.001). Compared to baseline renal function of the control group, the TDF+PI/r group exhibited a greater median decline in eGFR at the end of week 48 (P<0.001).ConclusionsWe found that a TDF+PI/r based ART regimen resulted in greater renal function decline over 48 weeks. Therefore, renal function should be monitored especially when TDF is used in combination with PI/r.Trial registrationClinicalTrials.gov identifier: NCT00872417

Detection of Hiv-1 viruses in tears of patients even under long-term Haart

To determine whether HIV-1 viruses exist in tears of patients under HAART, a cross-sectional study was designed. All participants who underwent long-term HAART with undetectable plasma viral load had detectable HIV-1 viral load in tears (n = 16) and had no difference from the controls (n = 5). Our data suggested that the lacrimal gland and/or other tear-associated tissues could be new reservoirs for HIV-1 and precautions should be taken when doing eye examinations.

Aging of immune system: Immune signature from peripheral blood lymphocyte subsets in 1068 healthy adults

Aging is a major risk factor for several conditions including neurodegenerative, cardiovascular diseases and cancer. Functional impairments in cellular pathways controlling genomic stability, and immune control have been identified. Biomarker of immune senescence is needed to improve vaccine response and to develop therapy to improve immune control. To identify phenotypic signature of circulating immune cells with aging, we enrolled 1068 Chinese healthy volunteers ranging from 18 to 80 years old. The decreased naïve CD4+ and CD8+ T cells, increased memory CD4+ or CD8+ T cells, loss of CD28 expression on T cells and reverse trend of CD38 and HLA-DR, were significant for aging of immune system. Conversely, the absolute counts and percentage of NK cells and CD19+B cells maintained stable in aging individuals. The Chinese reference ranges of absolute counts and percentage of peripheral lymphocyte in this study might be useful for future clinical evaluation.

Potent and persistent antibody responses against the receptor-binding domain of SARS-CoV spike protein in recovered patients

BackgroundThe spike (S) protein of SARS-CoV not only mediates receptor-binding but also induces neutralizing antibodies. We previously identified the receptor-binding domain (RBD) of S protein as a major target of neutralizing antibodies in animal models and thus proposed a RBD-based vaccine. However, the antigenicity and immunogenicity of RBD in humans need to be characterized.ResultsTwo panels of serum samples from recovered SARS patients were included and the antibody responses against the RBD were measured by ELISA and micro-neutralization assays. We found that the RBD of S protein induced potent antibody responses in the recovered SARS patients and RBD-specific antibodies could persist at high titers over three year follow-up. Furthermore, affinity purified anti-RBD antibodies possessed robust neutralizing activity.ConclusionThe RBD of SARS-CoV is highly immunogenic in humans and mediates protective responses and RBD-based vaccines and diagnostic approaches can be further developed.