The desire to induce HIV-1-specific responses soon after birth to prevent breast milk transmission of HIV-1 led us to propose a vaccine regimen which primes HIV-1-specific T cells using a recombinant Mycobacterium bovis bacillus Calmette-Gué rin (rBCG) vaccine. Because attenuated live bacterial vaccines are typically not sufficiently immunogenic as stand-alone vaccines, rBCG-primed T cells will likely require boost immunization(s). Here, we compared modified Danish (AERAS-401) and Pasteur lysine auxotroph (222) strains of BCG expressing the immunogen HIVA for their potency to prime HIV-1-specific responses in adult BALB/c mice and examined four heterologous boosting HIVA vaccines for their immunogenic synergy. We found that both BCG.HIVA 401 and BCG.HIVA 222 primed HIV-1-specific CD8 1 T-cell-mediated responses. The strongest boosts were delivered by human adenovirus-vectored HAdV5.HIVA and sheep atadenovirus-vectored OAdV7.HIVA vaccines, followed by poxvirus MVA.HIVA; the weakest was plasmid pTH.HIVA DNA. The prime-boost regimens induced T cells capable of efficient in vivo killing of sensitized target cells. We also observed that the BCG.HIVA 401 and BCG.HIVA 222 vaccines have broadly similar immunologic properties, but display a number of differences mainly detected through distinct profiles of soluble intercellular signaling molecules produced by immune splenocytes in response to both HIV-1-and BCG-specific stimuli. These results encourage further development of the rBCG prime-boost regimen.Key words: BCG . HIV . Mother-to-child transmission . Prime-boost . T cells . Vaccines Supporting Information available online IntroductionIt is 30 years since the first cases of AIDS were described, yet HIV-1 infection continues to take its toll particularly in resourcepoor areas such as many parts of sub-Saharan Africa [1]. About half of the infected adults are women of childbearing age, who will expose their babies to HIV-1 during pregnancy, delivery and breastfeeding [2]. Although antiretroviral treatment substantially decreases mother-to-child transmission (MTCT) of HIV-1 [3], it is not ideal due to the cost, requirement for daily compliance, side effects and possible development of drug resistance. Because breast milk provides essential nutrients and protection against 3542other diseases in the early days of life [4,5], formula as an HIV-1-free alternative is recommended only if it is acceptable, feasible, affordable, sustainable and safe (AFASS) and thus it is not an option for many HIV-1-positive mothers in Africa. The best hope for protecting newborns and infants in the 'South' (and in the 'North') against acquiring HIV-1 from their infected mothers while breastfeeding remains the development of safe, effective and accessible adult and pediatric vaccines [6]. For babies born to HIV-1-positive mothers, induction of anti-HIV-1 immunity as soon as possible after birth is highly desirable and may provide a basis for lifetime protection, which can be maintained by boosts later in life.A successful HIV-1 vaccine may ...
Although major inroads into making antiretroviral therapy available in resource-poor countries have been made, there is an urgent need for an effective vaccine administered shortly after birth, which would protect infants from acquiring human immunodeficiency virus type 1 (HIV-1) through breast-feeding. Bacillus Calmette-Guérin (BCG) is given to most infants at birth, and its recombinant form could be used to prime HIV-1-specific responses for a later boost by heterologous vectors delivering the same HIV-1-derived immunogen. Here, two groups of neonate Indian rhesus macaques were immunized with either novel candidate vaccine BCG.HIVA 401 or its parental strain AERAS-401, followed by two doses of recombinant modified vaccinia virus Ankara MVA.HIVA. The HIVA immunogen is derived from African clade A HIV-1. All vaccines were safe, giving local reactions consistent with the expected response at the injection site. No systemic adverse events or gross abnormality was seen at necropsy. Both AERAS-401 and BCG.HIVA 401 induced high frequencies of BCG-specific IFN-␥-secreting lymphocytes that declined over 23 weeks, but the latter failed to induce detectable HIV-1-specific IFN-␥ responses. MVA.HIVA elicited HIV-1-specific IFN-␥ responses in all eight animals, but, except for one animal, these responses were weak. The HIV-1-specific responses induced in infants were lower compared to historic data generated by the two HIVA vaccines in adult animals but similar to other recombinant poxviruses tested in this model. This is the first time these vaccines were tested in newborn monkeys. These results inform further infant vaccine development and provide comparative data for two human infant vaccine trials of MVA.HIVA.
The amino acid changes between different strains of HBV affect biological properties [1] and crystallization [2]. We hypothesize that these differences manifest as capsid polymorphism within an icosohedral framework.We have crystallized strain adyw HBV T=4 capsids for comparison to the previously determined adw-like HBV capsid [1]. To obtain this structure we engineered disulfide cross-links between the dimer building blocks, resulting in a stabalization of the capsid within the crystallographic lattice. To asses the role of this cross-link, data was also collected on a crystal without cross-linking. A critical advance for our structures was the ability to cryo-cool them, which was only possible when free capsid was included in the artificial mother liquor.Data were collected at the APS synchrotron, beamline 14BMC. The data sets were isomorphous in C2 space group with one capsid per asymmetric unit. The cross-linked capsid data set is 81% complete overall to 3.95Å, while the non-cross-linked capsid is 94.9% complete to 3.95Å.Current efforts are focused on phasing these structures with molecular replacement methods and refinement of the solution. This will allow us to visualize structural polymorphism between strains of HBV capsid and the effect of cross-linking capsid subunits.[1] Ceres P., Stray S., Zlotnick A., J. Virol., 2004, 78 Over 99% of human mitochondrial proteins are synthesised from nuclear DNA and must be imported as immature precursors via a coordinated series of specific, tightly regulated events. Encoded topological signals ensure nascent proteins are ushered to their correct mitochondrial destination. Proteins destined for the inner or outer mitochondrial membranes contain internal targeting information. After transfer through the outer membrane's general import pore, preproteins encounter TIM10, a hetero-hexamer of two homologous polypeptides, Tim9 and Tim10. TIM10 mediates preprotein passage across and within the intermembrane space (IMS). Inner membrane carrier proteins (e.g.AAC) are transferred to the inner membrane translocase, Tim22, for insertion, whereas -barrel proteins of the outer membrane are transferred to the sorting and assembly machinery, SAM[1]. Tim9 and Tim10 share a twin CX 3 C consensus sequence, similar to a zinc finger motif. Whilst disulphide formation appears to be necessary for hexamer formation and function, there is evidence that zinc binding occurs in the cytosol prior to import, oxidation occurring later in the IMS [2].Initial electron density maps have been calculated using SAD phasing, and I am on the way to determining the structure of the human TIM10 complex. The structure will illuminate how this key intermediate functions in the context of translocation.[1] Koehler C.M., Annu. Rev. Cell Dev. Biol., 2004, 20 The activities of the photosynthetic apparatus are highly controlled by the environment. Environmental parameters such as light quality, light intensity, temperature, water availability, and nutrient status play critical roles in photosynthetic complexes act...
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