Plasmid origin of replication of herpesvirus papio: DNA sequence and enhancer function.

Herpesvirus papio (HVP) is a lymphotropic virus of baboons which is related to Epstein-Barr virus (EBV) and produces latent infection. The nucleotide sequence of the 5,775-base-pair (bp) EcoRI K fragment of HVP, which has previously been shown to confer the ability to replicate autonomously, has been determined. Within this DNA fragment is a region which bears structural and sequence similarity to the ori-P region of EBV. The HVP ori-P region has a 10- by 26-bp tandem array which is related to the 20- by 30-bp tandem array from the EBV ori-P region. In HVP there is an intervening region of 764 bp followed by five partial copies of the 26-bp monomer. Both the EBV and HVP 3' regions have the potential to form dyad structures which, however, differ in arrangement. We also demonstrate that a transcriptional enhancer which requires transactivation by a virus-encoded factor is present in the HVP ori-P

Population uptake of HIV testing, treatment, viral suppression, and male circumcision following a community-based intervention in Botswana (Ya Tsie/BCPP): a cluster-randomised trial

BACKGROUND: In settings with high HIV prevalence and treatment coverage, such as Botswana, it is unknown whether uptake of HIV prevention and treatment interventions can be increased further. We sought to determine whether a community-based intervention to identify and rapidly treat people living with HIV, and support male circumcision could increase population levels of HIV diagnosis, treatment, viral suppression, and male circumcision in Botswana. METHODS: The Ya Tsie Botswana Combination Prevention Project study was a pair-matched cluster-randomised trial done in 30 communities across Botswana done from Oct 30, 2013, to June 30, 2018. 15 communities were randomly assigned to receive HIV prevention and treatment interventions, including enhanced HIV testing, earlier antiretroviral therapy (ART), and strengthened male circumcision services, and 15 received standard of care. The first primary endpoint of HIV incidence has already been reported. In this Article, we report findings for the second primary endpoint of population uptake of HIV prevention services, as measured by proportion of people known to be HIV-positive or tested HIV-negative in the preceding 12 months; proportion of people living with HIV diagnosed and on ART; proportion of people living with HIV on ART with viral suppression; and proportion of HIV-negative men circumcised. A longitudinal cohort of residents aged 16-64 years from a random, approximately 20% sample of households across the 15 communities was enrolled to assess baseline uptake of study outcomes; we also administered an end-of-study survey to all residents not previously enrolled in the longitudinal cohort to provide study end coverage estimates. Differences in intervention uptake over time by randomisation group were tested via paired Student's t test. The study has been completed and is registered with ClinicalTrials.gov (NCT01965470). FINDINGS: In the six communities participating in the end-of-study survey, 2625 residents (n=1304 from standard-of-care communities, n=1321 from intervention communities) were enrolled into the 20% longitudinal cohort at baseline from Oct 30, 2013, to Nov 24, 2015. In the same communities, 10 791 (86%) of 12 489 eligible enumerated residents not previously enrolled in the longitudinal cohort participated in the end-of-study survey from March 30, 2017, to Feb 25, 2018 (5896 in intervention and 4895 in standard-of-care communities). At study end, in intervention communities, 1228 people living with HIV (91% of 1353) were on ART; 1166 people living with HIV (88% of 1321 with available viral load) were virally suppressed, and 673 HIV-negative men (40% of 1673) were circumcised in intervention communities. After accounting for baseline differences, at study end the proportion of people living with HIV who were diagnosed was significantly higher in intervention communities (absolute increase of 9% to 93%) compared with standard-of-care communities (absolute increase of 2% to 88%; prevalence ratio [PR] 1·08 [95% CI 1·02-1·14], p=0·032). Population levels of ART, viral suppression, and male circumcision increased from baseline in both groups, with greater increases in intervention communities (ART PR 1·12 [95% CI 1·07-1·17], p=0·018; viral suppression 1·13 [1·09-1·17], p=0·017; male circumcision 1·26 [1·17-1·35], p=0·029). INTERPRETATION: It is possible to achieve very high population levels of HIV testing and treatment in a high-prevalence setting. Maintaining these coverage levels over the next decade could substantially reduce HIV transmission and potentially eliminate the epidemic in these areas. FUNDING: US President's Emergency Plan for AIDS Relief through the Centers for Disease Control and Prevention

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Hydrography shapes bacterial biogeography of the Deep Arctic Ocean

13 páginas, 5 figuras, 2 tablas.It has been long debated as to whether marine microorganisms have a ubiquitous distribution or patterns of biogeography, but recently a consensus for the existence of microbial biogeography is emerging. However, the factors controlling the distribution of marine bacteria remain poorly understood. In this study, we combine pyrosequencing and traditional Sanger sequencing of the 16S rRNA gene to describe in detail bacterial communities from the deep Arctic Ocean. We targeted three separate water masses, from three oceanic basins and show that bacteria in the Arctic Ocean have a biogeography. The biogeographical distribution of bacteria was explained by the hydrography of the Arctic Ocean and subsequent circulation of its water masses. Overall, this first taxonomic description of deep Arctic bacteria communities revealed an abundant presence of SAR11 (Alphaproteobacteria), SAR406, SAR202 (Chloroflexi) and SAR324 (Deltaproteobacteria) clusters. Within each cluster, the abundance of specific phylotypes significantly varied among water masses. Water masses probably act as physical barriers limiting the dispersal and controlling the diversity of bacteria in the ocean. Consequently, marine microbial biogeography involves more than geographical distances, as it is also dynamically associated with oceanic processes. Our ocean scale study suggests that it is essential to consider the coupling between microbial and physical oceanography to fully understand the diversity and function of marine microbes.Financial and ship time support from Fisheries and Oceans Canada and the Canadian International Polar Year Program’s Canada’s Three Oceans project and the Nansen and Amundsen Basins Observational System project. PE Galand was supported by a Marie Curie Grant (CRENARC MEIF-CT-2007-040247) and EO Casamayor by the Spanish Grant CGL2006-12058-BOS. C Lovejoy would like to acknowledge the support of the Natural Sciences and Engineering Council, Canada (NSERC) Special Research Opportunity Fund and ArcticNet. Deep Arctic samples were collected by K Scarcella, E Didierjean and M-E´ Garneau. Pyrosequencing was supported by a Keck foundation grant to M Sogin and L Ameral Zettler. This is a contribution to the International Census of Marine Microbes (ICOMM).Peer reviewe

Treatment of sexually transmitted infections for HIV prevention: end of the road or new beginning?

Observational and biological data provide compelling evidence of the importance of sexually transmitted infections (STIs) in HIV transmission, but only one of nine intervention trials has shown an effect. This article reviews the observational studies, critically examines the nine randomized controlled trials evaluating the impact of STI treatment interventions on HIV incidence, and discusses implications for HIV prevention policy, programs and future research. The role of other vaginal infections is also briefly considered. In aggregate, the evidence strongly supports the concept that STI treatment prevents HIV infection. However, issues in trial design and conduct, including HIV epidemic phase, STI prevalence, intervention in comparison groups, and power have affected five of the six trials of treatment of curable STIs. In the three herpes intervention trials, antivirals for HSV suppression were insufficiently potent to alleviate persistent genital inflammation in HIV-negative HSV2-positive persons, and the reduction in HIV levels in HIV-positive persons was insufficient to reduce HIV transmission. It is time for a new phase of exploration of how, when, and in whom to include STI control as a key component of HIV prevention, driven by basic research to elucidate the mechanisms by which STIs and vaginal infections facilitate HIV transmission. From a policy perspective, treatment of curable STIs is an essential part of primary healthcare and is a cheap, simple, and effective intervention when appropriately targeted and delivered. It should be promoted as an essential component of HIV control programs in communities in which the burden of STIs is substantial