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.

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.

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.

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. We performed the transmission reconstruction by molecular epidemiological tracing in a subset of the HIV-1-seropositive individuals diagnosed during this survey. Neighbor joining and maximum likelihood trees based on the HIV-1 pol and env genes were implemented to provide information on putative epidemiological links, which were then confirmed by contact tracing. Of 25,390 volunteers, 501 (2%) accumulated cases of HIV-1 infection (21.1% in needle-sharing drug users, 77.3% in heterosexual adults, 0.4% in homosexual adults, and 1.2% in children born from infected mothers) were diagnosed. Among 44 heterosexually infected and antiretroviral-naive local-traceable individuals (27 infected with HIV-1 subtype CRF01_AE, 15 with CRF08_BC, 1 with G, and 1 with a new B/C recombinant), 18 (40.9%) were coclustered into 8 transmission chains with an average size of 2.25 infections per chain. Phylogenetic and epidemiological linkages confirmed eight heterosexual transmission events. This is the first report providing molecular epidemiological evidence of heterosexual transmission of HIV-1 in China's general population. The reconstruction of transmission of current HIV-1 outbreaks by molecular epidemiological tracing is instrumental in identifying sources of the epidemic and in defining prevention strategies.

High temperature and humidity (HTH) can cause diarrhea owing to food and drinking water contamination. However, their direct effects on gut microbiota and gastrointestinal inflammation are unknown. This study aimed to investigate the effects of HTH and probiotics on the microbiome. Twenty-one male mice were randomly assigned to normal control (NC), HTH, and broad-spectrum probiotic-treated (PR) groups. HTH and PR groups were regularly housed at 30 ± 0.5 °C with humidity of 85–90% for eight consecutive weeks. A broad-spectrum probiotic was administrated to PR-group mice from day 50 to 56. Clinical signs were observed and gut microbiota were analyzed via 16 S rRNA-based functional metagenomics. Intestinal pathology and the expression of defensins and pro-inflammatory cytokines were also assessed. Mice in the HTH and PR groups gradually developed sticky or loose feces. The HTH group developed a distinct microbiota profile associated with augmented metabolism and human-like pathophysiologies upon suppression of environmental sensing. Pathological assays indicated minimal enteritis, increased bacterial translocation, and elevated intestinal pro-inflammatory cytokine levels. Thus, ambient HTH directly contributes to gut dysbiosis and minimal enteritis, whereas probiotics partially normalized the microbiota and ameliorated gut inflammation. This study provides novel insights into the pathogenesis of environment-associated diseases and offers a potential therapeutic approach.