Phenotypic hypersusceptibility to multiple protease inhibitors and low replicative capacity in patients who are chronically infected with human immunodeficiency virus type 1

Increased susceptibility to the protease inhibitors saquinavir and amprenavir has been observed in human immunodeficiency virus type 1 (HIV-1) with specific mutations in protease (V82T and N88S). Increased susceptibility to ritonavir has also been described in some viruses from antiretroviral agent-naïve patients with primary HIV-1 infection in association with combinations of amino acid changes at polymorphic sites in the protease. Many of the viruses displaying increased susceptibility to protease inhibitors also had low replication capacity. In this retrospective study, we analyze the drug susceptibility phenotype and the replication capacity of virus isolates obtained at the peaks of viremia during five consecutive structured treatment interruptions in 12 chronically HIV-1-infected patients. Ten out of 12 patients had at least one sample with protease inhibitor hypersusceptibility (change ≤0.4-fold) to one or more protease inhibitor. Hypersusceptibility to different protease inhibitors was observed at variable frequency, ranging from 38% to amprenavir to 11% to nelfinavir. Pairwise comparisons between susceptibilities for the protease inhibitors showed a consistent correlation among all pairs. There was also a significant relationship between susceptibility to protease inhibitors and replication capacity in all patients. Replication capacity remained stable over the course of repetitive cycles of structured treatment interruptions. We could find no association between in vitro replication capacity and in vivo plasma viral load doubling time and CD4(+) and CD8(+) T-cell counts at each treatment interruption. Several mutations were associated with hypersusceptibility to each protease inhibitor in a univariate analysis. This study extends the association between hypersusceptibility to protease inhibitors and low replication capacity to virus isolated from chronically infected patients and highlights the complexity of determining the genetic basis of this phenomenon. The potential clinical relevance of protease inhibitor hypersusceptibility and low replication capacity to virologic response to protease inhibitor-based therapies deserves to be investigated further

R^2 Corrections and Non-perturbative Dualities of N=4 String ground states

We compute and analyse a variety of four-derivative gravitational terms in the effective action of six- and four-dimensional type II string ground states with N=4 supersymmetry. In six dimensions, we compute the relevant perturbative corrections for the type II string compactified on K3. In four dimensions we do analogous computations for several models with (4,0) and (2,2) supersymmetry. Such ground states are related by heterotic-type II duality or type II-type II U-duality. Perturbative computations in one member of a dual pair give a non-perturbative result in the other member. In particular, the exact CP-even R^2 coupling on the (2,2) side reproduces the tree-level term plus NS 5-brane instanton contributions on the (4,0) side. On the other hand, the exact CP-odd coupling yields the one-loop axionic interaction a.R\wedge R together with a similar instanton sum. In a subset of models, the expected breaking of the SL(2,Z)_S S-duality symmetry to a \Gamma(2)_S subgroup is observed on the non-perturbative thresholds. Moreover, we present a duality chain that provides evidence for the existence of heterotic N=4 models in which N=8 supersymmetry appears at strong coupling.Comment: Latex2e, 51 pages, 1 figur

G3-homogeneous gravitational instantons

We provide an exhaustive classification of self-dual four-dimensional gravitational instantons foliated with three-dimensional homogeneous spaces, i.e. homogeneous self-dual metrics on four-dimensional Euclidean spaces admitting a Bianchi simply transitive isometry group. The classification pattern is based on the algebra homomorphisms relating the Bianchi group and the duality group SO(3). New and general solutions are found for Bianchi III.Comment: 24 pages, few correction

Universality properties of N=2 and N=1 Heterotic threshold corrections

In the framework of heterotic compactifications, we consider the one-loop corrections to the gauge couplings, which were shown to be free of any infra-red ambiguity. For a class of N=2 models, namely those that are obtained by toroidal compactification to four dimensions of generic six-dimensional N=1 ground states, we give an explicit formula for the gauge-group independent thresholds, and show that these are equal within this class, as a consequence of an anomaly-cancellation constraint in six dimensions. We further use these results to compute the (N=2)-sector contributions to the thresholds of N=1 orbifolds. We then consider the full contribution of N=1 sectors to the gauge couplings which generically are expected to modify the unification picture. We compute such corrections in several models. We finally comment on the effect of such contributions to the issue of string unification

Ricci flows and expansion in axion-dilaton cosmology

We study renormalization-group flows by deforming a class of conformal sigma-models. We consider overall scale factor perturbation of Einstein spaces as well as more general anisotropic deformations of three-spheres. At leading order in alpha, renormalization-group equations turn out to be Ricci flows. In the three-sphere background, the latter is the Halphen system, which is exactly solvable in terms of modular forms. We also analyze time-dependent deformations of these systems supplemented with an extra time coordinate and time-dependent dilaton. In some regimes time evolution is identified with renormalization-group flow and time coordinate can appear as Liouville field. The resulting space-time interpretation is that of a homogeneous isotropic Friedmann-Robertson-Walker universe in axion-dilaton cosmology. We find as general behaviour the superposition of a big-bang (polynomial) expansion with a finite number of oscillations at early times. Any initial anisotropy disappears during the evolution.Comment: 22 page

String Threshold corrections in models with spondaneously broken supersymmetry

We analyse a class of four-dimensional heterotic ground states with N=2 space-time supersymmetry. From the ten-dimensional perspective, such models can be viewed as compactifications on a six-dimensional manifold with SU(2) holonomy, which is locally but not globally K3 x T^2. The maximal N=4 supersymmetry is spontaneously broken to N=2. The masses of the two massive gravitinos depend on the (T,U) moduli of T^2. We evaluate the one-loop threshold corrections of gauge and R^2 couplings and we show that they fall in several universality classes, in contrast to what happens in usual K3 x T^2 compactifications, where the N=4 supersymmetry is explicitly broken to N=2, and where a single universality class appears. These universality properties follow from the structure of the elliptic genus. The behaviour of the threshold corrections as functions of the moduli is analysed in detail: it is singular across several rational lines of the T^2 moduli because of the appearance of extra massless states, and suffers only from logarithmic singularities at large radii. These features differ substantially from the ordinary K3 x T^2 compactifications, thereby reflecting the existence of spontaneously-broken N=4 supersymmetry. Although our results are valid in the general framework defined above, we also point out several properties, specific to orbifold constructions, which might be of phenomenological relevance

Improved shaping approach to the preliminary design of low-thrust trajectories

This paper presents a general framework for the development of shape-based approaches to low-thrust trajectory design. A novel shaping method, based on a three-dimensional description of the trajectory in spherical coordinates, is developed within this general framework. Both the exponential sinusoid and the inverse polynomial shaping are demonstrated to be particular two-dimensional cases of the spherical one. The pseudoequinoctial shaping is revisited within the new framework, and the nonosculating nature of the pseudoequinoctial elements is analyzed. A two step approach is introduced to solve the time of flight constraint, related to the design of low-thrust arcs with boundary constraints for both spherical and pseudoequinoctial shaping. The solution derived from the shaping approach is improved with a feedback linear-quadratic controller and compared against a direct collocation method based on finite elements in time. The new shaping approach and the combination of shaping and linear-quadratic controller are tested on three case studies: a mission to Mars, a mission to asteroid 1989ML, a mission to comet Tempel-1, and a mission to Neptune

Symplectic structure of N=1 supergravity with anomalies and Chern-Simons terms

The general actions of matter-coupled N=1 supergravity have Peccei-Quinn terms that may violate gauge and supersymmetry invariance. In addition, N=1 supergravity with vector multiplets may also contain generalized Chern-Simons terms. These have often been neglected in the literature despite their importance for gauge and supersymmetry invariance. We clarify the interplay of Peccei-Quinn terms, generalized Chern-Simons terms and quantum anomalies in the context of N=1 supergravity and exhibit conditions that have to be satisfied for their mutual consistency. This extension of the previously known N=1 matter-coupled supergravity actions follows naturally from the embedding of the gauge group into the group of symplectic duality transformations. Our results regarding this extension provide the supersymmetric framework for studies of string compactifications with axionic shift symmetries, generalized Chern-Simons terms and quantum anomalies.Comment: 27 pages; v2: typos corrected; version to be published in Class.Quantum Gra

D-branes in Lorentzian AdS(3)

We study the exact construction of D-branes in Lorentzian AdS(3). We start by defining a family of conformal field theories that gives a natural Euclidean version of the SL(2,R) CFT and does not correspond to H(3)+, the analytic continuation of AdS(3). We argue that one can recuperate the exact CFT results of Lorentzian AdS(3), upon an analytic continuation in the moduli space of these conformal field theories. Then we construct exact boundary states for various symmetric and symmetry-breaking D-branes in AdS(3).Comment: JHEP style;21 pages, no figures; v2:some corrections, comments and references adde

From the WZWN Model to the Liouville Equation: Exact String Dynamics in Conformally Invariant AdS Background

It has been known for some time that the SL(2,R) WZWN model reduces to Liouville theory. Here we give a direct and physical derivation of this result based on the classical string equations of motion and the proper string size. This allows us to extract precisely the physical effects of the metric and antisymmetric tensor, respectively, on the {\it exact} string dynamics in the SL(2,R) background. The general solution to the proper string size is also found. We show that the antisymmetric tensor (corresponding to conformal invariance) generally gives rise to repulsion, and it precisely cancels the dominant attractive term arising from the metric. Both the sinh-Gordon and the cosh-Gordon sectors of the string dynamics in non-conformally invariant AdS spacetime reduce here to the Liouville equation (with different signs of the potential), while the original Liouville sector reduces to the free wave equation. Only the very large classical string size is affected by the torsion. Medium and small size string behaviours are unchanged. We also find illustrative classes of string solutions in the SL(2,R) background: dynamical closed as well as stationary open spiralling strings, for which the effect of torsion is somewhat like the effect of rotation in the metric. Similarly, the string solutions in the 2+1 BH-AdS background with torsion and angular momentum are fully analyzed.Comment: 24 pages including 4 postscript figures. Enlarged version including a section on string solutions in 2+1 black hole background. To be published in Phys. Rev. D., December 199