<p>Standardsystem idag är, även när det gäller de mindre systemen, så omfattande att det är svårt att välja det bästa systemet för en verksamhet om man inte vet vad man egentligen behöver. Risken är då stor att företaget får betala för onödiga funktioner eller inte får den funktionalitet i systemet som de anser vara viktig. </p><p>När man blickar bakåt i tiden kan man konstatera att eftersom det framförallt varit större verksamheter som intresserat sig för standardsystem har även större delen av forskningen som gjorts inom området bedrivits med större anskaffningsprojekt som bas. Exempel på en stor metod för anskaffning av standardsystem är SIV-metoden. Valet av ett affärssystem på ett litet företag skulle bli enklare och ge ett bättre resultat med en anskaffningsmetod som är mer anpassad till de mindre företagens behov. Eftersom vi antar att verksamhetsanalysen ska genomföras av utomstående krävs dessutom att analysmetoden lämpar sig för detta. Vår problemanalys har mynnat ut i en fråga om hur lämplig är metoden mini-SIV (som en krympt variant av SIV) för val av standardsystem i små företag utifrån ett externt perspektiv? </p><p>Vår forskningsfråga omfattar tre begrepp: anskaffning av standardsystem med hjälp av mini-SIV, små företag och dess exklusivitet i sammanhanget och ett externt perspektiv det vill säga konsultens roll i valprocessen. </p><p>Den empiriska delen av vår forskning genomfördes på företaget Keeplastics i Norrköping. Diskussion av studiens resultat i relation till den teoretiska referensramen har lett till en ny konsultmetod för val av standardsystem på småföretag.</p>

Standardsystem idag är, även när det gäller de mindre systemen, så omfattande att det är svårt att välja det bästa systemet för en verksamhet om man inte vet vad man egentligen behöver. Risken är då stor att företaget får betala för onödiga funktioner eller inte får den funktionalitet i systemet som de anser vara viktig. När man blickar bakåt i tiden kan man konstatera att eftersom det framförallt varit större verksamheter som intresserat sig för standardsystem har även större delen av forskningen som gjorts inom området bedrivits med större anskaffningsprojekt som bas. Exempel på en stor metod för anskaffning av standardsystem är SIV-metoden. Valet av ett affärssystem på ett litet företag skulle bli enklare och ge ett bättre resultat med en anskaffningsmetod som är mer anpassad till de mindre företagens behov. Eftersom vi antar att verksamhetsanalysen ska genomföras av utomstående krävs dessutom att analysmetoden lämpar sig för detta. Vår problemanalys har mynnat ut i en fråga om hur lämplig är metoden mini-SIV (som en krympt variant av SIV) för val av standardsystem i små företag utifrån ett externt perspektiv? Vår forskningsfråga omfattar tre begrepp: anskaffning av standardsystem med hjälp av mini-SIV, små företag och dess exklusivitet i sammanhanget och ett externt perspektiv det vill säga konsultens roll i valprocessen. Den empiriska delen av vår forskning genomfördes på företaget Keeplastics i Norrköping. Diskussion av studiens resultat i relation till den teoretiska referensramen har lett till en ny konsultmetod för val av standardsystem på småföretag.

\(CD8^+\) cytotoxic T lymphocytes (CTLs) play a critical role in controlling human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) replication. The CTL responses that are thought to be the most protective against HIV and SIV are those that are of high frequency, recognize multiple epitopes, and perform multiple antiviral functions. Therefore, current vaccines aim to elicit CTLs possessing these characteristics. However, the phenomenon of immunodominance likely limits the potential of vaccines from generating such CTL responses by restricting the breadth of epitopes recognized by CTLs and the frequency and functionality of these CTL responses. In this dissertation, we explored the relationship between SIV epitope dominance and the functionality of the epitope-specific CTL populations. We also examined factors that contribute to the development of SIV epitope immunodominance hierarchies. We initially investigated the relationship between SIV epitope dominance and the antiviral functionality of the epitope-specific CTL populations in rhesus monkeys. We performed a gene expression analysis in dominant and subdominant epitope-specific CTLs during the acute phase of SIV infection and observed differential expression of a number of genes during this time. Subsequent in vitro functional studies of these epitope-specific CTL populations during the chronic phase of infection confirmed the presence of differences in maturation phenotype and functional capacity of dominant and subdominant epitope-specific CTLs. These studies demonstrate a relationship between epitope dominance and antiviral functionality of epitopespecific CTLs and suggest that dominant and subdominant epitope-specific CTLs may differ in their protective role against HIV acquisition and replication. This has important implications for vaccine design. In subsequent studies, we investigated the contribution of the binding of the peptide:MHC (pMHC) complex to the T cell receptor (TCR) in the development of immunodominance hierarchies. Using surface plasmon resonance, we measured the kinetics and the affinity of the interactions between dominant and subdominant epitope pMHC complexes with their respective TCRs. We found that epitope dominance was associated with higher affinities of pMHC:TCR binding. These findings indicate a molecular interaction that may be manipulated in vaccine-induced CTL responses to enhance their frequency and functional capacity.

CD8+ T cells responses are critical in the immune defense against human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infection. A major challenge for vaccine development is that HIV/SIV can rapidly mutate to escape containment by the CD8+ T cell response. Therefore, optimal virus control by a vaccine will likely require clonally diverse CD8+ T cells capable of recognizing mutant viruses. Mucosal tissues play a fundamental role in early HIV/SIV pathogenesis by serving as the site for viral entry, CD4+ T cell depletion, and a reservoir for viral replication. Vaccine strategies that induce effective mucosal immunity will likely be critical for protection against HIV/SIV. We examined the SIV Gag p11C-specific CD8+ T cell responses in peripheral blood, gastrointestinal (GI) mucosal and lung mucosal tissues of rhesus monkeys expressing the MHC class I molecule Mamu-A*01. We first investigated the clonal composition of this cell population during the acute and chronic phases of SIVmac infection. We showed that there is a narrowing of the clonal repertoire from acute to chronic infection and the same clonal populations of virus-specific CD8+ T cells are present in the systemic and mucosal compartments of chronically SIV-infected animals. These data indicated that virus-specific CD8+ T cells establish broadly distributed immune responses. Next, we examined the clonal diversity of systemic and mucosal p11C-specific CD8+ T cells induced by prime-boost vaccination. We found that systemic prime-boost vaccination induced clonally diverse p11C-specific populations in mucosal tissues. There were high levels of clonal sharing between systemic and mucosal compartments soon after vaccination. However, later following vaccination there was decreased clonal sharing between the GI mucosa and the systemic circulation. We showed that this was due to limited trafficking of p11C-specific CD8+ T cells to the GI mucosa following vaccination. Overall, these studies indicate that following SIV infection and systemic vaccination the same p11C-specific clones are present in mucosal and systemic compartments. Moreover, the apparent immune compartmentalization is a consequence of differences in cell trafficking between systemic and mucosal CD8+ T cells. These observations have important implications for the design of HIV vaccines that generate effective mucosal immunity.

Macrophages are target cells for human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infection that serve as viral reservoirs in brain, lung, gut, and other tissues, and play important roles in disease pathogenesis, particularly HIV/SIV-associated neurological disease. Macrophages express low levels of the HIV/SIV receptor CD4, but mechanisms by which macrophage-tropic viruses use low CD4 to mediate spreading infections are poorly understood. One mechanism involves enhanced envelope glycoprotein (Env) interaction with CD4 or CCR5, but this phenotype is frequently associated with increased neutralization sensitivity to antibodies targeting CD4/CCR5 binding sites. Moreover, this mechanism does not explain how these neutralization-sensitive viruses evade immune responses while establishing spreading infections. In this dissertation, we sought to identify SIV Env determinants for macrophage tropism and characterize mechanisms by which they enhance virus replication in macrophages. To identify viral variants capable of inducing macrophage-associated pathogenesis, we cloned Env sequences from SIV-infected macaques at early and late stage infection, and identified an early variant in blood that shares >98% sequence identity with the consensus sequence of late variants in brain from macaques with neurological disease. SIV clones encoding this Env variant mediated high levels of fusion, replicated efficiently in rhesus PBMC and macrophages, and induced multinucleated giant cell formation upon infection of macrophage cultures. We identified an N-linked glycosylation site, N173 in the V2 region, as a determinant of macrophage tropism. Loss of N173 enhanced SIVmac239 macrophage tropism, while restoration of N173 in SIVmac251 reduced macrophage tropism, but enhanced neutralization resistance to CD4/CCR5 binding site antibodies. SIVmac239 N173Q, which lacks the N173 glycosylation site, mediated CD4-independent fusion and cell-to-cell transmission with CCR5-expressing cells, but could not infect CD4-negative cells in single-round infections. Thus, CD4-independent phenotypes were detected only in the context of cell-cell contact. The N173Q mutation had no effect on SIVmac239 gp120 binding to CD4 in BIACORE and co-immunoprecipitation assays. These findings suggest that loss of the N173 glycosylation site increases SIVmac239 replication in macrophages by enhancing CD4-independent cell-to-cell transmission through CCR5-mediated fusion. This mechanism may facilitate escape of macrophage-tropic viruses from neutralizing antibodies, while promoting spreading infections by these viruses in vivo.

Natural killer (NK) cells can kill virus-infected cells without prior antigenic exposure, and are therefore important for controlling viral replication prior to the onset of adaptive immune responses. Primate NK cells express activating and inhibitory killer-cell immunoglobulin-like receptors (KIRs) that bind to specific major histocompatibility complex (MHC) class I molecules. The importance of KIR interactions with MHC class I in human immunodeficiency virus (HIV) pathogenesis is demonstrated by the association of select KIR and MHC class I genotypes with delayed progression to acquired immunodeficiency syndrome (AIDS).

Diss. (sammanfattning) Stockholm : Karol. inst., 2003. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2003. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2004. / Härtill 4 uppsatser.

Thesis (Ph.D.) -- University of Texas Southwestern Medical Center at Dallas, 2005. / On campus access only. Vita. Bibliography: 120-147.