ABSTRACT Here we report the results of studies in the simian immunodeficiency virus (SIV)-rhesus macaque model of intravaginal transmission of human immunodeficiency virus type 1 in the setting of genital ulcerative diseases. We document preferential association of vRNA with induced ulcers during the first days of infection and show that allogeneic cells of the inoculum traffic from the vaginal lumen to lymphatic tissues. This surprisingly rapid systemic dissemination in this cell-associated SIV challenge model thus reveals the challenges of preventing transmission in the setting of genital ulcerative diseases and illustrates the utility of this animal model in tests of strategies aimed at reducing transmission under these conditions.
ZusammenfassungRiemannsche Geometrie ist die Geometrie einer symmetrischen, vom Punkt einer Mannigfaltigkeit abhängenden Bilinearform. Die Krümmung ist ein Maß dafür, inwieweit zwei symmetrische Bilinearformen lokal verschieden sind. Im Gegensatz dazu ist symplektische Geometrie die einer antisymmetrischen, vom Punkt einer Mannigfaltigkeit abhängenden Bilinearform — also die Geometrie einer 2-Form ω. Dabei zeigt sich, dass lokal alle symplektischen Mannigfaltigkeiten äquivalent sind, ein Krümmungsbegriff im Sinne der Riemannschen Geometrie tritt nicht in Erscheinung. Symplektische Strukturen unterscheiden sich gegebenenfalls nur global. Historisch führte die Formulierung der Mechanik im Sinne von Hamilton auf die symplektische Geometrie, daraus resultiert ihre wesentliche Rolle.
Simian immunodeficiency virus (SIV) infection of nonhuman primates is the predominant model for preclinical evaluation of human immunodeficiency virus (HIV) vaccines. These studies frequently utilize high-doses of SIV that ensure infection after a single challenge but do not recapitulate critical facets of sexual HIV transmission. Investigators are increasingly using low-dose challenges in which animals are challenged once every week or every two weeks in order to better replicate sexual HIV transmission. Using this protocol, some animals require over ten challenges before SIV infection is detectable, potentially inducing localized immunity. Moreover, the lack of certainty over which challenge will lead to productive infection prevents tissue sampling immediately surrounding the time of infection. Here we challenged Mauritian cynomolgus macaques with 100 50% tissue culture infectious doses (TCID50) of SIVmac239 intrarectally three times a day for three consecutive days. Ten of twelve animals had positive plasma viral loads after this challenge regimen. This approach represents a straightforward advance in SIV challenge protocols that may avoid induction of local immunity, avoid inconsistent timing between last immunization and infection, and allow sampling immediately after infection using low-dose challenge protocols.
BackgroundIt is generally accepted that CD8+ T cell responses play an important role in control of immunodeficiency virus replication. The association of HLA-B27 and -B57 with control of viremia supports this conclusion. However, specific correlates of viral control in individuals expressing these alleles have been difficult to define. We recently reported that transient in vivo CD8+ cell depletion in simian immunodeficiency virus (SIV)-infected elite controller (EC) macaques resulted in a brief period of viral recrudescence. SIV replication was rapidly controlled with the reappearance of CD8+ cells, implicating that these cells actively suppress viral replication in ECs.Methods and FindingsHere we show that three ECs in that study made at least seven robust CD8+ T cell responses directed against novel epitopes in Vif, Rev, and Nef restricted by the MHC class I molecule Mamu-B*08. Two of these Mamu-B*08-positive animals subsequently lost control of SIV replication. Their breakthrough virus harbored substitutions in multiple Mamu-B*08-restricted epitopes. Indeed, we found evidence for selection pressure mediated by Mamu-B*08-restricted CD8+ T cells in all of the newly identified epitopes in a cohort of chronically infected macaques.ConclusionsTogether, our data suggest that Mamu-B*08-restricted CD8+ T cell responses effectively control replication of pathogenic SIVmac239. All seven regions encoding Mamu-B*08-restricted CD8+ T cell epitopes also exhibit amino acid replacements typically seen only in the presence of Mamu-B*08, suggesting that the variation we observe is indeed selected by CD8+ T cell responses. SIVmac239 infection of Indian rhesus macaques expressing Mamu-B*08 may therefore provide an animal model for understanding CD8+ T cell-mediated control of HIV replication in humans.
Assume that the compact Riemannian spin manifold $(M^n,g)$ admits a $G$-structure with characteristic connection $\nabla$ and parallel characteristic torsion ($\nabla T=0$), and consider the Dirac operator $D^{1/3}$ corresponding to the torsion $T/3$. This operator plays an eminent role in the investigation of such manifolds and includes as special cases Kostant's ``cubic Dirac operator'' and the Dolbeault operator. In this article, we describe a general method of computation for lower bounds of the eigenvalues of $D^{1/3}$ by a clever deformation of the spinorial connection. In order to get explicit bounds, each geometric structure needs to be investigated separately; we do this in full generality in dimension 4 and for Sasaki manifolds in dimension 5.
Replicate similarity was assessed using the Morisita-Horn similarity index, with a value of 0 indicating the lowest possible similarity between the samples and a value of 1 indicating the highest possible similarity between them. Replicates with a Morisita-Horn value of <0.75 were both excluded to decrease confounding variables and inconsistent sampling. *Data not available or insufficient reads (<20,000), ***Sufficient reads to keep in analysis (>20,000), ##Viral load data not available.
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