179 research outputs found
P19-16. Potential of an HIV-1 Tat fusion protein expressed in tomato as a plant-based HIV vaccine
Polydisperse fluid mixtures of adhesive colloidal particles
We investigate polydispersity effects on the average structure factor of
colloidal suspensions of neutral particles with surface adhesion. A sticky hard
sphere model alternative to Baxter's one is considered. The choice of
factorizable stickiness parameters in the potential allows a simple analytic
solution, within the ``mean spherical approximation'', for any number of
components and arbitrary stickiness distribution. Two particular cases are
discussed: i) all particles have different sizes but equal stickiness (Model
I), and ii) each particle has a stickiness proportional to its size (Model II).
The interplay between attraction and polydispersity yields a markedly different
behaviour for the two Models in regimes of strong coupling (i.e. strong
adhesive forces and low temperature) and large polydispersity. These results
are then exploited to reanalyze experimental scattering data on sterically
stabilized silica particles.Comment: 9 pages, 2 figures (included), Physica A (2001) to appea
A Two-Zone Model for Type I X-ray Bursts on Accreting Neutron Stars
We construct a two-zone model to describe H and He burning on the surface of
an accreting neutron star and use it to study the triggering of type I X-ray
bursts. Although highly simplified, the model reproduces all of the bursting
regimes seen in the more complete global linear stability analysis of Narayan &
Heyl (2003), including the regime of delayed mixed bursts. The results are also
consistent with observations of type I X-ray bursts. At accretion rates Mdot <
0.1 Mdot_Edd, thermonuclear He burning via the well-known thin-shell thermal
instability triggers bursts. As Mdot increases, however, the trigger mechanism
evolves from the fast thermal instability to a slowly growing overstability
involving both H and He burning. The competition between nuclear heating via
the beta-limited CNO cycle and the triple-alpha process on the one hand, and
radiative cooling via photon diffusion and emission on the other hand, drives
oscillations with a period approximately equal to the H-burning timescale. If
these oscillations grow, the gradually rising temperature at the base of the
helium layer eventually provokes a thin-shell thermal instability and hence a
delayed mixed burst. For Mdot > 0.25 Mdot_Edd, there is no instability or
overstability, and there are no bursts. Nearly all other theoretical models
predict that bursts should occur for all Mdot < Mdot_Edd, in conflict with both
our results and observations. We suggest that this discrepancy arises from the
assumed strength of the hot CNO cycle breakout reaction 15O(alpha,gamma)19Ne in
these other models. That observations agree much better with the results of
Narayan & Heyl and our two-zone model, both of which neglect breakout
reactions, may imply that the true 15O(alpha,gamma)19Ne cross section is much
smaller than assumed in previous investigations.Comment: 13 pages, 8 figures, accepted by Ap
A New Light on the Evolution and Propagation of Prehistoric Grain Pests: The World's Oldest Maize Weevils Found in Jomon Potteries, Japan
Three Sitophilus species (S. granarius L., S. oryzae L., and S. zeamais Mots.) are closely related based on DNA analysis of their endosymbionts. All are seed parasites of cereal crops and important economic pest species in stored grain. The Sitophilus species that currently exist, including these three species, are generally believed to be endemic to Asia's forested areas, suggesting that the first infestations of stored grain must have taken place near the forested mountains of southwestern Asia. Previous archaeological data and historical records suggest that the three species may have been diffused by the spread of Neolithic agriculture, but this hypothesis has only been established for granary weevils in European and southwestern Asian archaeological records. There was little archeological evidence for grain pests in East Asia before the discovery of maize weevil impressions in Jomon pottery in 2004 using the βimpression replicaβ method. Our research on Jomon agriculture based on seed and insect impressions in pottery continued to seek additional evidence. In 2010, we discovered older weevil impressions in Jomon pottery dating to ca. 10 500 BP. These specimens are the oldest harmful insects in the world discovered at archaeological sites. Our results provide evidence of harmful insects living in the villages from the Earliest Jomon, when no cereals were cultivated. This suggests we must reconsider previous scenarios for the evolution and propagation of grain pest weevils, especially in eastern Asia. Although details of their biology or the foods they infested remain unclear, we hope future interdisciplinary collaborations among geneticists, entomologists, and archaeologists will provide the missing details
Contributions of Mamu-A*01 Status and TRIM5 Allele Expression, But Not CCL3L Copy Number Variation, to the Control of SIVmac251 Replication in Indian-Origin Rhesus Monkeys
CCL3 is a ligand for the HIV-1 co-receptor CCR5. There have recently been conflicting reports in the literature concerning whether CCL3-like gene (CCL3L) copy number variation (CNV) is associated with resistance to HIV-1 acquisition and with both viral load and disease progression following infection with HIV-1. An association has also been reported between CCL3L CNV and clinical sequelae of the simian immunodeficiency virus (SIV) infection in vivo in rhesus monkeys. The present study was initiated to explore the possibility of an association of CCL3L CNV with the control of virus replication and AIDS progression in a carefully defined cohort of SIVmac251-infected, Indian-origin rhesus monkeys. Although we demonstrated extensive variation in copy number of CCL3L in this cohort of monkeys, CCL3L CNV was not significantly associated with either peak or set-point plasma SIV RNA levels in these monkeys when MHC class I allele Mamu-A*01 was included in the models or progression to AIDS in these monkeys. With 66 monkeys in the study, there was adequate power for these tests if the correlation of CCL3L and either peak or set-point plasma SIV RNA levels was 0.34 or 0.36, respectively. These findings call into question the premise that CCL3L CNV is important in HIV/SIV pathogenesis
Insect spiracle as the main penetration route of pyrethroids
The penetration route of adhered pyrethroids following direct aerosol spraying was studied in the German cockroach (Blattella germanica) by investigating the relationship between the application site of insecticide and knockdown efficacy. In direct spray, KT50 was 26.4 s and the adhered amount of pyrethroid was 0.745 ΞΌg. On the contrary, required amount of pyrethroid to obtain the same KT50 was one-eighth in topical application to the mesothoracic spiracle, while 2.6 times to the ventral mesothorax. KT50 of cockroaches with blocked mesothoracic spiracles was greater than those with unblocked spiracles by 1.8-fold. The amount of directly sprayed pyrethroid penetrating through the inner wall of the mesothoracic trachea was significantly higher than the amount penetrating through the body wall of the ventral mesothorax. Therefore, the knockdown effect of the direct spray was believed to be caused by the flow of pyrethroids into the mesothoracic spiracles and its subsequent penetration through the inner wall of the mesothoracic trachea
Immunization with Cocktail of HIV-Derived Peptides in Montanide ISA-51 Is Immunogenic, but Causes Sterile Abscesses and Unacceptable Reactogenicity
BACKGROUND: A peptide vaccine was produced containing B and T cell epitopes from the V3 and C4 Envelope domains of 4 subtype B HIV-1 isolates (MN, RF, CanO, & Ev91). The peptide mixture was formulated as an emulsion in incomplete Freund's adjuvant (IFA). METHODS: Low-risk, healthy adult subjects were enrolled in a randomized, placebo-controlled dose-escalation study, and selected using criteria specifying that 50% in each study group would be HLA-B7+. Immunizations were scheduled at 0, 1, and 6 months using a total peptide dose of 1 or 4 mg. Adaptive immune responses in16 vaccine recipients and two placebo recipients after the 2nd immunization were evaluated using neutralization assays of sera, as well as ELISpot and ICS assays of cryopreserved PBMCs to assess CD4 and CD8 T-cell responses. In addition, (51)Cr release assays were performed on fresh PBMCs following 14-day stimulation with individual vaccine peptide antigens. RESULTS: 24 subjects were enrolled; 18 completed 2 injections. The study was prematurely terminated because 4 vaccinees developed prolonged pain and sterile abscess formation at the injection site-2 after dose 1, and 2 after dose 2. Two other subjects experienced severe systemic reactions consisting of headache, chills, nausea, and myalgia. Both reactions occurred after the second 4 mg dose. The immunogenicity assessments showed that 6/8 vaccinees at each dose level had detectable MN-specific neutralizing (NT) activity, and 2/7 HLA-B7+ vaccinees had classical CD8 CTL activity detected. However, using both ELISpot and ICS, 8/16 vaccinees (5/7 HLA-B7+) and 0/2 controls had detectable vaccine-specific CD8 T-cell responses. Subjects with moderate or severe systemic or local reactions tended to have more frequent T cell responses and higher antibody responses than those with mild or no reactions. CONCLUSIONS: The severity of local responses related to the formulation of these four peptides in IFA is clinically unacceptable for continued development. Both HIV-specific antibody and T cell responses were induced and the magnitude of response correlated with the severity of local and systemic reactions. If potent adjuvants are necessary for subunit vaccines to induce broad and durable immune responses, careful, incremental clinical evaluation is warranted to minimize the risk of adverse events. TRIAL REGISTRATION: ClinicalTrials.gov NCT00000886
TRIM5Ξ± Modulates Immunodeficiency Virus Control in Rhesus Monkeys
The cytoplasmic TRIM5Ξ± proteins of certain mammalian lineages efficiently recognize the incoming capsids of particular retroviruses and potently restrict infection in a species-specific manner. Successful retroviruses have evolved capsids that are less efficiently recognized by the TRIM5Ξ± proteins of the natural hosts. To address whether TRIM5Ξ± contributes to the outcome of retroviral infection in a susceptible host species, we investigated the impact of TRIM5 polymorphisms in rhesus monkeys on the course of a simian immunodeficiency virus (SIV) infection. Full-length TRIM5Ξ± cDNAs were derived from each of 79 outbred monkeys and sequenced. Associations were explored between the expression of particular TRIM5 alleles and both the permissiveness of cells to SIV infection in vitro and clinical sequelae of SIV infection in vivo. Natural variation in the TRIM5Ξ± B30.2(SPRY) domain influenced the efficiency of SIVmac capsid binding and the in vitro susceptibility of cells from the monkeys to SIVmac infection. We also show the importance in vivo of the interaction of SIVmac with different allelic forms of TRIM5, demonstrating that particular alleles are associated with as much as 1.3 median log difference in set-point viral loads in SIVmac-infected rhesus monkeys. Moreover, these allelic forms of TRIM5 were associated with the extent of loss of central memory (CM) CD4+ T cells and the rate of progression to AIDS in the infected monkeys. These findings demonstrate a central role for TRIM5Ξ± in limiting the replication of an immunodeficiency virus infection in a primate host
Association of Activating KIR Copy Number Variation of NK Cells with Containment of SIV Replication in Rhesus Monkeys
While the contribution of CD8+ cytotoxic T lymphocytes to early containment of HIV-1 spread is well established, a role for NK cells in controlling HIV-1 replication during primary infection has been uncertain. The highly polymorphic family of KIR molecules expressed on NK cells can inhibit or activate these effector cells and might therefore modulate their activity against HIV-1-infected cells. In the present study, we investigated copy number variation in KIR3DH loci encoding the only activating KIR receptor family in rhesus monkeys and its effect on simian immunodeficiency virus (SIV) replication during primary infection in rhesus monkeys. We observed an association between copy numbers of KIR3DH genes and control of SIV replication in Mamu-A*01β rhesus monkeys that express restrictive TRIM5 alleles. These findings provide further evidence for an association between NK cells and the early containment of SIV replication, and underscore the potential importance of activating KIRs in stimulating NK cell responses to control SIV spread
Dual Neonate Vaccine Platform against HIV-1 and M. tuberculosis
Acquired immunodeficiency syndrome and tuberculosis (TB) are two of the
world's most devastating diseases. The first vaccine the majority of
infants born in Africa receive is Mycobacterium bovis bacillus
Calmette-GuΓ©rin (BCG) as a prevention against TB. BCG protects against
disseminated disease in the first 10 years of life, but provides a variable
protection against pulmonary TB and enhancing boost delivered by recombinant
modified vaccinia virus Ankara (rMVA) expressing antigen 85A (Ag85A) of
M. tuberculosis is currently in phase IIb evaluation in
African neonates. If the newborn's mother is positive for human
immunodeficiency virus type 1 (HIV-1), the baby is at high risk of acquiring
HIV-1 through breastfeeding. We suggested that a vaccination consisting of
recombinant BCG expressing HIV-1 immunogen administered at birth followed by a
boost with rMVA sharing the same immunogen could serve as a strategy for
prevention of mother-to-child transmission of HIV-1 and rMVA expressing an
African HIV-1-derived immunogen HIVA is currently in phase I trials in African
neonates. Here, we aim to develop a dual neonate vaccine platform against HIV-1
and TB consisting of BCG.HIVA administered at birth followed by a boost with
MVA.HIVA.85A. Thus, mMVA.HIVA.85A and sMVA.HIVA.85A vaccines were constructed,
in which the transgene transcription is driven by either modified H5 or short
synthetic promoters, respectively, and tested for immunogenicity alone and in
combination with BCG.HIVA222. mMVA.HIVA.85A was produced markerless
and thus suitable for clinical manufacture. While sMVA.HIVA.85A expressed higher
levels of the immunogens, it was less immunogenic than mMVA.HIVA.85A in BALB/c
mice. A BCG.HIVA222βmMVA.HIVA.85A prime-boost regimen induced
robust T cell responses to both HIV-1 and M. tuberculosis.
Therefore, proof-of-principle for a dual anti-HIV-1/M.
tuberculosis infant vaccine platform is established. Induction of
immune responses against these pathogens soon after birth is highly desirable
and may provide a basis for lifetime protection maintained by boosts later in
life
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