Evidence of a tolerogenic vaccine against AIDS in the Chinese macaque prefigures a potential human vaccine.

In 2006 we discovered a new type of mucosal vaccine against simian immunodeficiency virus (SIV) in Chinese macaques. Here, we review 15 years of our published work on this vaccine, which consists of inactivated SIVmac239 particles adjuvanted with Bacillus Calmette-Guérin, Lactobacillus plantarum, or Lactobacillus rhamnosus. Without adjuvant, the vaccine administered by the intragastric route induced the usual SIV-specific humoral and cellular immune responses but provided no protection against intrarectal challenge with SIVmac239.

A 30-year journey of trial and error towards a tolerogenic AIDS vaccine.

Since 1985, we have tested several immunological approaches to suppressing HIV replication in HIV-infected patients and to prevent HIV acquisition in uninfected people. Here, after briefly reviewing our studies on immunosuppressive treatments and therapeutic dendritic cell-based therapies, we examine in more detail our work on the tolerogenic vaccines we developed against AIDS in Chinese macaques. The vaccine consisted of inactivated SIVmac239 particles adjuvanted with the Bacillus of Calmette and Guerin (BCG), Lactobacillus plantarum (LP), or Lactobacillus rhamnosus (LR).

Intragastric Administration of Lactobacillus plantarum and 2,2'-Dithiodipyridine-Inactivated Simian Immunodeficiency Virus (SIV) Does Not Protect Indian Rhesus Macaques from Intrarectal SIV Challenge or Reduce Virus Replication after Transmission.

A major obstacle to development of an effective AIDS vaccine is that along with the intended beneficial responses, the immunization regimen may activate CD4 T cells that can facilitate acquisition of human immunodeficiency virus (HIV) by serving as target cells for the virus. Lu et al. (W.

Suppression of HIV Replication by CD8(+) Regulatory T-Cells in Elite Controllers.

We previously demonstrated in the Chinese macaque model that an oral vaccine made of inactivated SIV and Lactobacillus plantarum induced CD8(+) regulatory T-cells, which suppressed the activation of SIV(+)CD4(+) T-cells, prevented SIV replication, and protected macaques from SIV challenges. Here, we sought whether a similar population of CD8(+) T-regs would induce the suppression of HIV replication in elite controllers (ECs), a small population (3‰) of HIV-infected patients with undetectable HIV replication. For that purpose, we investigated the in vitro antiviral activity of fresh CD8(+) T-cells on HIV-infected CD4(+) T-cells taken from 10 ECs.

Evolving molecular epidemiological profile of human immunodeficiency virus 1 in the southwest border of China.

Background: We have previously reported in Xishuangbanna (Banna) Dai Autonomous Prefecture, a well-developed tourist destination in the southwest border of China, that HIV-1 transmitted dominantly through heterosexual contact with less divergent genotypes and few drug resistant mutations. Due to the rapid increase of newly diagnosed HIV-1 cases per year in Banna in recent years, it's important to evaluate the evolution of HIV-1 molecular epidemiology for the better understanding of ongoing HIV-1 outbreak in this region.

Methodology/principal Findings: By sequencing of HIV-1 pol genes and phylogenetic analysis, we conducted a molecular epidemiologic study in 352 HIV-1-seropositive highly active antiretroviral treatment (HAART)-naïve individuals newly diagnosed at the Banna Center for Disease Control and Prevention between 2009 and 2011.

Mucosal SIV Vaccines Comprising Inactivated Virus Particles and Bacterial Adjuvants Induce CD8(+) T-Regulatory Cells that Suppress SIV-Positive CD4(+) T-Cell Activation and Prevent SIV Infection in the Macaque Model.

A new paradigm of mucosal vaccination against human immunodeficiency virus (HIV) infection has been investigated in the macaque model. A vaccine consisting of inactivated simian immunodeficiency virus (SIV)mac239 particles together with a living bacterial adjuvant (either the Calmette and Guerin bacillus, Lactobacillus plantarum or Lactobacillus rhamnosus) was administered to macaques via the vaginal or oral/intragastric route. In contrast to all established human and veterinary vaccines, these three vaccine regimens did not elicit SIV-specific antibodies nor cytotoxic T-lymphocytes but induced a previously unrecognized population of non-cytolytic MHCIb/E-restricted CD8(+) T-regulatory cells that suppressed the activation of SIV-positive CD4(+) T-lymphocytes.

Induction of CD8+ regulatory T cells protects macaques against SIV challenge.

Efforts to develop a vaccine against HIV have so far met with limited success. Given that CD4(+) T cell activation drives the initial burst of viral replication, we explored in macaques whether an oral vaccine comprised of Lactobacillus plantarum, a commensal bacterium that favors immune tolerance, and inactivated simian immunodeficiency virus mac239 (SIVmac239) would induce CD4(+) T cell unresponsiveness/tolerance toward SIV antigens and thereby prevent the establishment of SIV infection. The tolerogenic vaccine induced MHC-Ib/E-restricted CD8(+) regulatory T cells (Tregs) that suppressed SIV-harboring CD4(+) T cell activation and ex vivo SIV replication in 15 of 16 animals without inducing SIV-specific antibodies or cytotoxic T lymphocytes.

Molecular epidemiology of human immunodeficiency virus type 1 in Guangdong province of southern China.

Background: Although the outbreak of human immunodeficiency virus type 1 (HIV-1) in Guangdong has been documented for more than a decade, the molecular characteristics of such a regional HIV-1 epidemic remained unknown.

Methodology/principal Findings: By sequencing of HIV-1 pol/env genes and phylogenetic analysis, we performed a molecular epidemiologic study in a representative subset (n  = 200) of the 508 HIV-1-seropositive individuals followed up at the center for HIV/AIDS care and treatment of Guangzhou Hospital of Infectious Diseases. Of 157 samples (54.

Intermediate stage Hodgkin lymphoma in partial remission after three or four courses of doxorubicin, bleomycin, vinblastine dacarbazine: no benefit of one course of intensive chemotherapy before irradiation.

The H97-I trial (1997-2004) for Hodgkin lymphoma at intermediate stage (HL-I) included 269 patients who were randomized to receive three or four cycles of doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD). The 197 patients who reached complete remission (CR) (73.2%, p = 0.

Variability of bio-clinical parameters in Chinese-origin Rhesus macaques infected with simian immunodeficiency virus: a nonhuman primate AIDS model.

Background: Although Chinese-origin Rhesus macaques (Ch RhMs) infected with simian immunodeficiency virus (SIV) have been used for many years to evaluate the efficacy of AIDS vaccines and therapeutics, the bio-clinical variability of such a nonhuman primate AIDS model was so far not established.

Methodology/principal Findings: By randomizing 150 (78 male and 72 female) Ch RhMs with diverse MHC class I alleles into 3 groups (50 animals per group) challenged with intrarectal (i.r.

Neoadjuvant dose-dense gemcitabine plus docetaxel and vinorelbine plus epirubicin for operable breast cancer: improved prognosis in triple-negative tumors.

Background: Neoadjuvant anti-tumor activity of an alternating taxane- and anthracycline-based dose-dense regimen in patients with operable, non-inflammatory large breast cancer was investigated.

Objective: The objective is to study the rate of pathological complete response in patients with breast cancer receiving dose-dense chemotherapy sequentially with gemcitabine plus docetaxel and vinorelbine plus epirubicin.

Methods: Women (n = 74) with clinical stage II or III breast cancer were enrolled in this open-label, multicenter study to receive six 2-weekly courses of gemcitabine 1000 mg/m2 plus docetaxel 75 mg/m2 on days 1 and 15, and vinorelbine 25 mg/m2 plus epirubicin 100 mg/m2 on days 29 and 43.

Reduced versus full doses of irradiation after 3 cycles of combined doxorubicin, bleomycin, vinblastine, and dacarbazine in early stage Hodgkin lymphomas: results of a randomized trial.

Background: The combination of 3 cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) and a tailored, extended irradiation schedule has been used to treat patients with early Hodgkin lymphoma (HL) in the authors' group since 1981. The randomized H97-E trial (1997-2004) was designed to assess the impact of a slightly reduced irradiation dose on the freedom from treatment failure (FFTF) rate.

Methods: Patients with supradiaphragmatic HL at clinical stages I and II who had View Article and Find Full Text PDF

Molecular epidemiological tracing of HIV-1 outbreaks in Hainan island of southern China.

Objectives: To determine the prevalence of HIV in Hainan island and the molecular epidemiological linkages related to risk factors of viral transmission.

Methods: A governmental HIV/AIDS surveillance program, HIV serological study was conducted in volunteers from several high-risk groups between 1991 and 2006 in Hainan province. By phylogenetic reconstruction, we performed a molecular epidemiological tracing in a representative subset of the HIV-1-seropositive individuals diagnosed during this survey.

What is the real impact of bone pain on survival in patients with metastatic hormone-refractory prostate cancer treated with docetaxel?

Objectives: To determine the benefit of starting early chemotherapy with docetaxel (the recommended first-line treatment) for patients with asymptomatic metastatic hormone-refractory prostate cancer (HRPC).

Patients And Methods: Data were analysed from 145 patients with HRPC treated with chemotherapy between February 2000 and June 2002 in one French centre. Eligible patients were categorized into three groups according to the bone pain at baseline, i.

Salvage therapy with bevacizumab-sunitinib combination after failure of sunitinib alone for metastatic renal cell carcinoma: a case series.

We present a case series of seven patients with metastatic renal cell carcinoma treated with bevacizumab (10 mg/kg) in combination with sunitinib 25-50 mg as salvage therapy after disease progression under sunitinib monotherapy. Two patients had a partial response, four had stable disease, and one patient had disease progression. After a median follow-up of 17.

Early versus late intensification for patients with high-risk Hodgkin lymphoma-3 cycles of intensive chemotherapy plus low-dose lymph node radiation therapy versus 4 cycles of combined doxorubicin, bleomycin, vinblastine, and dacarbazine plus myeloablative chemotherapy with autologous stem cell transplantation: five-year results of a randomized trial on behalf of the GOELAMS Group.

Background: The 5-year freedom from treatment failure (FFTF) rate, with treatment failure defined as the lack of post-treatment complete remission (CR), recurrence, or death, ranges from 60% to 70% after 6 to 8 cycles of combined doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD), which is the reference treatment for patients with advanced Hodgkin lymphoma (HL). In this randomized, phase 2 study, the authors tested 2 intensive chemotherapy regimens in 158 patients with clinical stage (CS) IIB through IV HL accompanied by high-risk factors who were recruited between May 1997 and December 2004.

Methods: High-risk CS IIB, III, and IV were defined by the presence of > or =5 involved lymphoid areas, and/or a mediastinal mass ratio > or =0.

Molecular tracing of sexual HIV Type 1 transmission in the southwest border of China.

Since the first outbreak of HIV-1 was reported in heroin users in China in 1989, HIV-1 has spread steadily among injection drug users, leading to an exponential growth of nationwide outbreaks from 1998 to 2004. However, the impact of sexual transmission on outbreaks of HIV in China's general population is still unclear. Through a governmental HIV/AIDS surveillance program, an HIV serological study was conducted in volunteers between 1996 and 2005 in Xishuangbanna Dai Autonomous Prefecture of Yunnan province.

The human spleen is a major reservoir for long-lived vaccinia virus-specific memory B cells.

The fact that you can vaccinate a child at 5 years of age and find lymphoid B cells and antibodies specific for this vaccination 70 years later remains an immunologic enigma. It has never been determined how these long-lived memory B cells are maintained and whether they are protected by storage in a special niche. We report that, whereas blood and spleen compartments present similar frequencies of IgG(+) cells, antismallpox memory B cells are specifically enriched in the spleen where they account for 0.

Matched case-control phase 2 study to evaluate the use of a frozen sock to prevent docetaxel-induced onycholysis and cutaneous toxicity of the foot.

Background: Onycholysis occurs in approximately 30% of patients treated with docetaxel. The efficacy and safety of an Elasto-Gel frozen sock (FS) was investigated for the prevention of docetaxel-induced nail and skin toxicity of the feet.

Methods: Patients receiving docetaxel at a dose of 70 to 100 mg/m(2) every 3 weeks were eligible for this matched case-control study.

Twenty-year disease and treatment-associated mortality rates of patients with Hodgkin lymphoma of clinical stages IIIB and IV prospectively treated with 3-month anthracycline-based chemotherapy followed by extended high-dose radiation.

Background: In 1981, the authors developed an original strategy combining 3 cycles of doxorubicin (adriamycin), bleomycin, vinblastine, and dacarbazine (ABVD) or ABVD-like chemotherapy and extended high-dose radiation for treating patients with clinical stages IIIB and IV Hodgkin lymphoma (HL). In the current study, the authors analyzed the 20-year results of this treatment as applied to 213 patients according to 2 successive trials.

Methods: All patients who responded to chemotherapy received extended high-dose radiation.

Meta-analysis of randomised trials comparing gemcitabine-based doublets versus gemcitabine alone in patients with advanced and metastatic pancreatic cancer.

Objective: To evaluate the impact on overall survival at 6, 12 and 18 months of gemcitabine-based doublets compared with gemcitabine alone in patients with advanced and metastatic pancreatic cancer.

Methods: We conducted a systematic review and meta-analysis of published data on the use of gemcitabine-based doublets compared with gemcitabine alone in chemotherapy-naive patients with advanced and metastatic pancreatic cancer treated in randomised controlled phase II-III trials with overall survival as the principal or secondary endpoint. To this end, a literature search was performed using Cochrane methodology.

Serum PSA half-life as a predictor of survival for hormone-refractory prostate cancer patients: modelization using a standardized set of response criteria.

Objective: Changes of serum prostate-specific antigen (PSA) during chemotherapy have been validated as a marker of response for hormone-refractory prostate cancer (HRPC) patients. We retrospectively established new response criteria to assess the risk of death.

Methods: Two hundred fifty-six chemonaive HRPC patients treated with chemotherapy were included in the analysis.

Predictive and discriminating three-risk-group prognostic scoring system for staging Hodgkin lymphomas.

Background: Several 3-stage Ann Arbor classification-derived prognostic systems were constructed since 1980 to identify the prognosis of Hodgkin lymphoma (HL). Modern statistical tools were applied to 955 patients treated between 1981 and 1996 to build a 3-stage prognostic scoring system (PSS).

Methods: Each variable associated with 10-year overall survival (10-year OS) was assigned to 2 (0 or 1) or 3 (0, 1 or 3) values.

Multicenter study of a frozen glove to prevent docetaxel-induced onycholysis and cutaneous toxicity of the hand.

Purpose: Onycholysis and skin toxicity occur in approximately 30% of patients treated with docetaxel. We investigated the efficacy and safety of an Elasto-Gel (84400 APT Cedex, Akromed, France) frozen glove (FG) for the prevention of docetaxel-induced onycholysis and skin toxicity.

Patients And Methods: Patients receiving docetaxel 75 mg/m2 alone or in combination chemotherapy were eligible for this case-control study.