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. In contrast, out of 24 macaques immunized with the adjuvanted vaccine and challenged intrarectally with SIVmac239 or SIVB670, 23 were sterilely protected for up to five years, while all control macaques were infected. This protection was confirmed by an independent group from the Pasteur Institute. During the past 15 years, we have identified the mechanism of action of the vaccine and discovered that the vaccinated macaques produced a previously unrecognized class of MHC-Ib/E-restricted CD8+ T cells (which we refer to as tolerogenic CD8+ T cells) that suppressed the activation of SIV-RNA-infected CD4+ T cells and thereby inhibited the (activation-dependent) reverse transcription of the virus, which in turn prevented the establishment of SIV infection. Importantly, we discovered also that the tolerogenic CD8+ T cell subset observed in vaccinated Chinese macaques could also be found in human elite controllers, a small group of HIV-infected patients in whom these tolerogenic CD8+ T cells were shown to naturally suppress viral replication. Given that SIV and HIV require activated immune cells in which to replicate, the specific prevention of activation of SIV-RNA-containing CD4+ T cells by a tolerogenic vaccine approach offers an exciting new avenue in HIV vaccine research.

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. Lu et al., Cell Rep 2:1736-1746, 2012, https://doi.org/10.1016/j.celrep.2012.11.016) reported that intragastric administration of chemically inactivated simian immunodeficiency virus SIVmac239 and Lactobacillus plantarum (iSIV-L. plantarum) protected 15/16 Chinese-origin rhesus macaques (RMs) from high-dose intrarectal SIVmac239 challenge at 3 months postimmunization. They attributed the observed protection to induction of immune tolerance, mediated by "MHC-Ib/E-restricted CD8+ regulatory T cells that suppressed SIV-harboring CD4+ T cell activation and ex vivo SIV replication in 15/16 animals without inducing SIV-specific antibodies or cytotoxic T." J.-M. Andrieu et al. (Front Immunol 5:297, 2014, https://doi.org/10.3389/fimmu.2014.00297) subsequently reported protection from infection in 23/24 RMs immunized intragastrically or intravaginally with iSIV and Mycobacterium bovis BCG, L. plantarum, or Lactobacillus rhamnosus, which they ascribed to the same tolerogenic mechanism. Using vaccine materials obtained from our coauthors, we conducted an immunization and challenge experiment with 54 Indian RMs and included control groups receiving iSIV only or L. plantarum only as well as unvaccinated animals. Intrarectal challenge with SIVmac239 resulted in rapid infection in all groups of vaccinated RMs as well as unvaccinated controls. iSIV-L. plantarum-vaccinated animals that became SIV infected showed viral loads similar to those observed in animals receiving iSIV only or L. plantarum only or in unvaccinated controls. The protection from SIV transmission conferred by intragastric iSIV-L. plantarum administration reported previously for Chinese-origin RMs was not observed when the same experiment was conducted in a larger cohort of Indian-origin animals.IMPORTANCE Despite an increased understanding of immune responses against HIV, a safe and effective AIDS vaccine is not yet available. One obstacle is that immunization may activate CD4+ T cells that may act as target cells for acquisition of HIV. An alternative strategy may involve induction of a tolerance-inducing response that limits the availability of activated CD4+ T cells, thus limiting the ability of virus to establish infection. In this regard, exciting results were obtained for Chinese-origin rhesus macaques by using a "tolerogenic" vaccine, consisting of intragastric administration of Lactobacillus plantarum and 2,2'-dithiodipyridine-inactivated SIV, which showed highly significant protection from virus transmission. In the present study, we administered iSIV-L. plantarum to Indian-origin rhesus macaques and failed to observe any protective effect on virus acquisition in this experimental setting. This work is important because it contributes to the overall assessment of the clinical potential of a new candidate AIDS vaccine platform based on iSIV-L. plantarum.

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). Without adjuvant, the vaccine administered by the intragastric route induced the usual simian immunodeficiency virus (SIV)-specific humoral immune responses but no post-challenge protection. In contrast, out of 24 macaques that were immunized with the adjuvanted vaccine and challenged intrarectally with SIVmac239 or SIVB670, 23 were sterilely protected for up to 5 years, while all control macaques were infected. On the other hand, all macaques of Indian origin that were immunized with the same adjuvanted vaccine were not protected. We then discovered that vaccinated Chinese macaques developed a previously unrecognized class of non-cytolytic MHC-Ib/E-restricted CD8+ T cells (or CD8+ T-Regs) that suppressed the activation of SIV RNA-infected CD4+ T cells and thereby inhibited the (activation-dependent) reverse transcription of the virus and prevented the establishment of SIV infection. Finally, we found a similar population of HLA-E-restricted CD8+ T-Regs in human elite controllers (a small group of HIV-infected patients whose viral replication is naturally inhibited). Ex vivo, their CD8+ T-Regs suppressed viral replication in the same manner as those of vaccinated Chinese macaques. It is noteworthy that all of these elite controllers had a homo- or heterozygous HLA-Bw4-80I genotype. Taking into account the longevity and the high percentage of vaccine-protected Chinese macaques together with the concomitant identification of a robust ex vivo correlate of protection and the discovery of similar CD8+ T-Regs in human elite controllers, preventive and therapeutic HIV vaccines should be envisaged in humans.

Therapeutic dendritic-cell vaccine for chronic HIV-1 infection.

We present the results of a preliminary investigation of the efficacy of a therapeutic dendritic cell (DC)-based vaccine for HIV-1. We immunized 18 chronically HIV-1-infected and currently untreated individuals showing stable viral loads for at least 6 months with autologous monocyte-derived DCs loaded with autologous aldrithiol-2-inactivated HIV-1. Plasma viral load levels were decreased by 80% (median) over the first 112 d following immunization. Prolonged suppression of viral load of more than 90% was seen in 8 individuals for at least 1 year. The suppression of viral load was positively correlated with HIV-1-specific interleukin-2 or interferon-gamma-expressing CD4(+) T cells and with HIV-1 gag-specific perforin-expressing CD8(+) effector cells, suggesting that a robust virus-specific CD4(+) T-helper type 1 (T(H)1) response is required for inducing and maintaining virus-specific CD8(+) effectors to contain HIV-1 in vivo. The results suggest that inactivated whole virus-pulsed DC vaccines could be a promising strategy for treating people with chronic HIV-1 infection.

Therapeutic dendritic-cell vaccine for simian AIDS.

An effective immune response against human immunodeficiency virus or simian immunodeficiency virus (SIV) is critical in achieving control of viral replication. Here, we show in SIV-infected rhesus monkeys that an effective and durable SIV-specific cellular and humoral immunity is elicited by a vaccination with chemically inactivated SIV-pulsed dendritic cells. After three immunizations made at two-week intervals, the animals exhibited a 50-fold decrease of SIV DNA and a 1,000-fold decrease of SIV RNA in peripheral blood. Such reduced viral load levels were maintained over the remaining 34 weeks of the study. Molecular and cellular analyses of axillary and inguinal node lymphocytes of vaccinated monkeys revealed a correlation between decreased SIV DNA and RNA levels and increased SIV-specific T-cell responses. Neutralizing antibody responses were augmented and remained elevated. Inactivated whole virus-pulsed dendritic cell vaccines are promising means to control diseases caused by immuno- deficiency viruses.

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 0.24% of all IgG(+) cells (ie, 10-20 million cells) more than 30 years after vaccination. They represent, in contrast, only 0.07% of circulating IgG(+) B cells in blood (ie, 50-100,000 cells). An analysis of patients either splenectomized or rituximab-treated confirmed that the spleen is a major reservoir for long-lived memory B cells. No significant correlation was observed between the abundance of these cells in blood and serum titers of antivaccinia virus antibodies in this study, including in the contrasted cases of B cell-depleting treatments. Altogether, these data provide evidence that in humans, the two arms of B-cell memory--long-lived memory B cells and plasma cells--have specific anatomic distributions--spleen and bone marrow--and homeostatic regulation.

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.e. minimal/no pain, mild, and moderate/severe pain. The primary endpoint was the effect of bone pain on overall survival (OS). RESULTS: Docetaxel was administered to 67% of patients. The risk of death was 1.56 and 2.11 times higher for patients with mild or moderate/severe pain than for those with minimal/no pain (P = 0.027). The median (95% confidence interval (CI)) OS was 23.1 (18.5-27.6) and 14.1 (8.9-19.2) months (P = 0.001, log-rank-test) for patients with minimal pain or no pain treated with docetaxel-based chemotherapy compared with mitoxantrone, respectively. The prostate-specific antigen doubling time (PSA-DT) had a significant effect on OS in patients with minimal/no pain, with a median of 32.4 and 16.5 months for a PSA-DT of >or=45 and <45 days, respectively (P < 0.001). CONCLUSIONS: Our results suggest that patients with HRPC and minimal or no bone pain could have better survival than those with mild pain or moderate to severe pain, independent of the treatment administered. In addition, patients with HRPC and minimal or no bone pain treated with docetaxel-based chemotherapy have a significantly better OS than those treated with mitoxantrone. The PSA-DT can be useful to identify asymptomatic patients who are candidates for early treatment.

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. The relative risks with 95% confidence intervals were estimated based on adjusted number of deaths and patients at risk according to the extent of follow-up and censoring. Twenty-three randomised clinical trials including 5886 patients met the inclusion criteria. In these trials, 2932 patients were randomly assigned to receive gemcitabine-based doublets and 2954 patients to receive gemcitabine alone. RESULTS: Gemcitabine-based doublets were associated with small but significant reductions in the risk of death at 6, 12 and 18 months of 8% (95% CI 3, 13), 4% (95% CI 2, 7) and 3% (95% CI 1, 5), respectively (p<0.005 for all timepoints). No heterogeneity between studies was observed. Subgroup analyses showed an overall survival benefit for gemcitabine-based doublets in clinical trials testing the same planned dose intensity of gemcitabine in comparative arms, using platinum salt-based protocols and with survival as the primary endpoint. CONCLUSION: This meta-analysis of data obtained from randomised controlled phase II-III trials of patients with advanced pancreatic cancer showed a small but significant improvement in overall survival for patients receiving gemcitabine-based doublets compared with gemcitabine alone.

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. Each patient wore an FG for a total of 90 minutes on the right hand. The left hand was not protected and acted as the control. Onycholysis and skin toxicity were assessed at each cycle by National Cancer Institute Common Toxicity Criteria and documented by photography. Wilcoxon matched-pairs rank test was used. RESULTS: Between August 2002 and September 2003, 45 patients were evaluated. Onycholysis and skin toxicity were significantly lower in the FG-protected hand compared with the control hand (P = .0001). Onycholysis was grade (G) 0 in 89% v 49% and G1 to 2 in 11% v 51% for the FG-protected hand and the control hand, respectively. Skin toxicity was G0 in 73% v 41% and G1 to 2 in 27% v 59% for the FG-protected and the control hand, respectively. Median time to nail and skin toxicity occurrence was not significantly different between the FG-protected and the control hand, respectively (106 v 58 days for nail toxicity; 57 v 58 days for skin toxicity). Five patients (11%) experienced discomfort due to cold intolerance. CONCLUSION: FG significantly reduces the nail and skin toxicity associated with docetaxel and provides a new tool in supportive care management to improve a patient's quality of life.

Multicenter randomized phase II study of two schedules of docetaxel, estramustine, and prednisone versus mitoxantrone plus prednisone in patients with metastatic hormone-refractory prostate cancer.

PURPOSE: Mitoxantrone-corticosteroid is currently the standard palliative treatment in hormone-refractory prostate cancer (HRPC) patients. Recent clinical trials documented the high activity of the docetaxel-estramustine combination. We conducted a randomized phase II study to evaluate prostate-specific antigen (PSA) response (primary end point) and safety of two docetaxel-estramustine-prednisone (DEP) regimens and mitoxantrone-prednisone (MP). PATIENTS AND METHODS: One hundred thirty metastatic HRPC patients were randomly assigned to receive docetaxel (70 mg/m2 on day 2 or 35 mg/m2 on days 2 and 9 of each 21-day cycle) and estramustine (280 mg p.o. tid on days 1 through 5 and 8 through 12) or mitoxantrone 12 mg/m2 every 3 weeks; all patients received prednisone (10 mg daily). RESULTS: One hundred twenty-seven patients were assessable for PSA response and safety. A > or = 50% PSA decline was found in a greater percentage of patients in the docetaxel arms (67% and 63%) compared with MP (18%; P = .0001). Median time to PSA progression was five times longer with DEP than with MP (8.8 and 9.3 v 1.7 months, respectively; P = .000001). Overall survival was better in the docetaxel arms (18.6 and 18.4 months) compared with the MP arm (13.4 months), but not significantly so (P = .3). Crossover rates differed significantly among treatment arms (16%, 10%, and 48% in arms A, B, and C, respectively; P = .00001). Treatment-related toxicities were mild and mainly hematologic. CONCLUSION: The results of this randomized phase II study showed significantly higher PSA decline < or = 50% and longer times to progression in HRPC patients receiving DEP-based chemotherapy than MP, and that DEP could be proposed in this setting.

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. The 10 ECs had a classical genomic profile: all of them carried the KIR3DL1 gene and 9 carried at least 1 allele of HLA-B:Bw4-80Ile (i.e., with an isoleucine residue at position 80). In the nine HLA-B:Bw4-80Ile-positive patients, we demonstrated a strong viral suppression by KIR3DL1-expressing CD8(+) T-cells that required cell-to-cell contact to switch off the activation signals in infected CD4(+) T-cells. KIR3DL1-expressing CD8(+) T-cells withdrawal and KIR3DL1 neutralization by a specific anti-killer cell immunoglobulin-like receptor (KIR) antibody inhibited the suppression of viral replication. Our findings provide the first evidence for an instrumental role of KIR-expressing CD8(+) regulatory T-cells in the natural control of HIV-1 infection.

Long-term clinical, immunologic and virologic impact of glucocorticoids on the chronic phase of HIV infection.

BACKGROUND: To test the hypothesis of down-regulating the increased immune system activation/destruction process associated with chronic HIV infection, we focused our interest on prednisolone (PDN), because we had showed that, in vitro, PDN had a strong anti-apoptotic activity on activated T cells of HIV-infected patients and no effect on viral replication. We thus designed in 1992 a pilot study to evaluate the clinical, immunologic and virologic effects of PDN. The drug was given to a group of 44 patients with CD4 T cells over 200/microl. After one year, no patient had developed clinical AIDS and the mean CD4 T cell count of the group had increased from 441 +/- 21 cells/microl to 553 +/- 43 cells/microl. Moreover, markers of immune activation had dropped back to normal levels while the mean viral load of the group had remained unchanged. Here we explore the long-term clinical, immunologic, and virologic impact of prednisolone on the chronic phase of HIV infection. METHODS: Retrospective study over 10 years starting between July 1992 and February 1993. A total of 44 patients with CD4 cells/microl ranging from 207 to 775 were treated with prednisolone, 0.5 mg/kg/d, over 6 months and 0.3 mg/kg/d thereafter. RESULTS: No clinical AIDS developed under prednisolone; side effects of the drug were mild. CD4 cells which increased from 421 cells/microl at entry to 625 cells/microl at day 15, slowly decreased to reach 426 cells/microl after two years; T cell apoptosis and activation markers dropped within 15 days to normal levels and reincreased slowly thereafter. Serum viral loads remained stable. The percentage of patients maintaining CD4 cells over entry was 43.2% at two years, 11.4% at five years and 4.6% at 10 years. Initial viral load was highly predictive of the rate of CD4 decrease under prednisolone. CONCLUSIONS: Prednisolone postponed CD4 cell decrease in a viral load dependent manner for a median of two years and for up to 10 years in a fraction of the patients with a low viral load. These findings might stimulate clinical trials as well as biological research on the role of antiapoptotic drugs in HIV infection.

Expression of genes involved in chemoresistance, proliferation and apoptosis in clinical samples of renal cell carcinoma and correlation with clinical outcome.

This study investigated the multidrug resistance, proliferation and apoptosis expression in renal cell carcinomas compared to adjacent normal kidney (ANK) tissues. Multidrug resistance (MDR1), multidrug resistance-associated protein (MRP), glutathione-S-transferase-pi (GST-pi), Topoisomerase-II alpha (TOPO-IIalpha), thymidylate synthase (TS), thymidine kinase (TK), Ki67, BAX and BCL-2 genes were analysed in a series of 30 renal cell carcinomas (RCC) and 16 biopsies from adjacent normal kidney (ANK) tissue using reverse-transcription-PCR (rt-PCR). The mean MDR1 expression was significantly lower in RCC than that of ANK (0.4 +/- 0.2 sd versus 0.75 +/- 0.19, p = 0.0008). The expression of MRP, GST-pi and TOPO-IIalpha was not significantly different in RCC as compared with ANK. The mean TK expression in RCC was significantly higher than in ANK (0.31 +/- 0.15 versus 0.09 +/- 0.08, p = 0.002). The TS and Ki67 expression in RCC was significantly higher than in ANK (87.5%, IC95% 71-100% versus 0%, p = 0.001; 56% IC95% 32-81% versus 0%, p = 0.004, respectively). BAX and BCL-2 expression in RCC was significantly higher than that of ANK (0.51 +/- 0.08 versus 0.18 +/- 0.12, p = 0.0001; 0.73 +/- 0.16 versus 0.5 +/- 0.22, p = 0.01, respectively). No significant correlation was found between MDR1, MRP, GST-pi, TOPO-IIalpha, TS, TK and BAX expression with the grade and the clinical stage in RCC.

The biological meaning of anti-HBC positive result in blood donors: relation to HBV-DNA and to other serological markers.

In order to assess the potential risk of anti-HBc-positive blood donors for post-transfusional hepatitis and to investigate whether other HBV serological markers are capable of identifying the presence of the virus, 1000 first-time blood donors were enrolled between June and July 1997. These donors were screened using routine Brazilian blood center tests (HIV 1 and 2, HTLV 1 and 2, Chagas disease, Syphilis, HCV, HBsAg, anti-HBc and ALT ). The 120 (12%) found to be anti-HBc-positive underwent further tests: HBe, anti-HBe, anti-HBs and HBV-DNA by PCR. Ten cases were HBsAg positive and all were HBV-DNA positive by PCR. Three HBsAg-negative donors were HBV-DNA-positive. Two HBV-DNA-positive donors were also anti-HBs-positive. All the HBV-positive donors had at least one HBV marker other than anti-HBc. Anti-HBc is an important cause of blood rejection. Testing for HBsAg alone is not fully protective and anti-HBc remains necessary as a screening test. The presence of anti-HBs is not always indicative of absence of the virus. The addition of other HBV serological markers could represent an alternative in predicting the presence of the virus when compared with PCR. It is recommended that other studies should be carried out to confirm this finding.

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. SIV reverse transcription was thereby blocked in inactivated CD4(+) T-cells; the initial burst of virus replication was prevented and the vaccinated macaques were protected from a challenge infection. For 3-14 months after intragastric immunization, 24 macaques were challenged intrarectally with a high dose of SIVmac239 or with the heterologous strain SIV B670 (both strains grown on macaques PBMC). Twenty-three of these animals were found to be protected for up to 48 months while all 24 control macaques became infected. This protective effect against SIV challenge together with the concomitant identification of a robust ex vivo correlate of protection suggests a new approach for developing an HIV vaccine in humans. The induction of this new class of CD8(+) T-regulatory cells could also possibly be used therapeutically for suppressing HIV replication in infected patients and this novel tolerogenic vaccine paradigm may have potential applications for treating a wide range of immune disorders and is likely to may have profound implications across immunology generally.

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. Of 283 samples (84.1% taken from heterosexually acquired adults, 10.6% from needle-sharing drug users, 2.8% from men who have sex with men, 0.4% from children born from HIV-1-infected mothers, and 2.1% remained unknown) with successful sequencing for pol gene, we identified 108 (38.2%) HIV-1 subtype CRF08_BC, 101 (35.7%) CRF01_AE, 49 (17.3%) CRF07_BC, 5 (1.8%) C/CRF57_BC, 3 (1.1%) B', 1 (0.4%) B/CRF51_01B, and 16 (5.7%) unique recombinants forms. Among these infected individuals, 104 (36.7%) cases showed drug resistant or resistance-relevant mutations, and 4 of them conferring high-level resistance to 3TC/FTC, EFV/NVP or NFV. Phylogenetic analysis revealed 21 clusters (2-7 sequences) with only 21.2% (60/283) sequences involved. CONCLUSION/SIGNIFICANCE: In contrast to our previous findings, CRF08_BC, replaced CRF01_AE, became the dominant genotype of HIV-1 in Banna prefecture. The viral strains with drug resistance mutations were detected frequently in newly diagnosed HIV-1-infected individuals in this region.

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 = 0.41 between arms) received radiotherapy (RT); their 10-year progression-free survival (PFS) rate was 87.7 ± 3.0%, similar to that of the 180 patients of a historical control group (HCG) in CR after three ABVD cycles before RT. The 59 patients who reached post-ABVD partial remission (PR) received one course of intensive chemotherapy (i.v., mg/m(2), vindesine 5, adriamycin 90, BCNU 140, etoposide 600, methylprednisolone 600) before RT. In spite of this additional intensive chemotherapy, their PFS rate (78.4 ± 6.3%) remained significantly lower (p = 0.03) than that of the 197 patients who reached post-ABVD CR, and was similar to that of the 60 patients of the HCG in PR after three ABVD cycles who did not receive additional chemotherapy before RT.

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. Of 16 macaques that were intrarectally challenged with SIVmac239 or heterologous strain SIVB670, 15 were sterilely protected. In four macaques that were rechallenged intravenously, plasma SIV levels peaked slightly and then dropped to undetectable levels, although the animals subsequently harbored intracellular SIV DNA. Infusion of CD8 antibodies confirmed the role of CD8(+) Tregs in preventing/suppressing SIV in vivo. These findings suggest a new avenue of research toward developing an HIV-1 vaccine.

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 (54.1% heterosexual acquired adults, 20.4% needle-sharing drug users, 5.7% receivers of blood transfusion, 1.3% men who have sex with men, and 18.5% remained unknown) with successful sequencing for both pol and env genes, 105 (66.9%) HIV-1 subtype CRF01_AE and 24 (15.3%) CRF07_BC, 9 (5.7%) B', 5 (3.2%) CRF08_BC, 5 (3.2%) B, 1 (0.6%) C, 3 (1.9%) CRF02_AG, and 5 (3.2%) inter-region recombinants were identified within pol/env sequences. Thirteen (8.3%) samples (3 naïves, 6 and 5 received with antiretroviral treatment [ART] 1-21 weeks and ≥24 weeks respectively) showed mutations conferring resistance to nucleoside/nonnucleoside reverse transcriptase inhibitors or protease inhibitors. Among 63 ART-naïve patients, 3 (4.8%) showed single or multiple drug resistant mutations. Phylogenetic analysis showed 8 small clusters (2-3 sequences/cluster) with only 17 (10.8%) sequences involved. CONCLUSION/SIGNIFICANCE: This study confirms that sexual transmission with dominant CRF01_AE strain is a major risk for current HIV-1 outbreak in the Guangdong's general population. The transmission with drug-resistant variants is starting to emerge in this region.