The interplay between host and virus that controls disease progression in HIV- and SIV-infected individuals is undoubtedly complex. Host factor(s) play a major role in this process, however, because in the SIV-infected macaque, differences in disease progression and survival persist even though identical virus stocks, doses, and routes of inoculation are used for infection. We have developed a simplified in vitro assay that significantly correlated with disease progression after infection in vivo. The amount of virus produced from primary CD4+ T cells obtained from uninfected monkeys and infected in vitro correlated significantly with the rate of disease progression and survival after inoculation of the animal. The goal of this dissertation was to conduct a detailed molecular and immunological analysis of why differential in vivo virus production occurs and how it relates to disease progression and survival.
Analyses of the events occurring during virus infection in vivo revealed two findings: 1) low virus production was caused by a decreased efficiency of the early steps of reverse transcription, which affected virus dissemination in the culture, and 2) low virus production was associated with a decreased susceptibility to mitogen-induced apoptosis both the presence and absence of virus infection. Together, these data suggest that multiple, cooperative factors mediated by the host cell have a profound impact on virus production and the rate of virus spread in vivo.
Subsequently, the impact of these events on infection and disease progression in vivo in these same animals was examined in detail. After infection, the four high producer animals exhibited characteristics of rapid progressors (higher viral loads during the set-point, faster decline in memory CD4+ T cells, weaker virus-specific immune responses), while the low producers, in contrast, appeared to be slow progressors. Interestingly, the number of infected cells in the peripheral blood and the timing of their emergence, rather than the peak viral load, was an accurate indicator of the eventual set point.
We believe the results from acute infection in vivo are a direct result of slower viral replication during the very first few rounds of infection, as suggested by our in vitro data. The finding that incredibly early events during in vivo infection appeared to play a dominant role in the disease outcome underscores the studies of others who have shown that a better clinical prognosis can be achieved the earlier that antiretroviral treatment is initiated after infection. The studies presented here will hopefully enable not only the identification of novel host factors that influence disease outcome, but will also provide a framework for the design of new therapeutic agents that target specific host factors exerting their influence very early after infection.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-07242003-115541 |
| Date | 12 September 2003 |
| Creators | Hartman, Amy L. |
| Contributors | Simon Barratt-Boyes, D.V.M., Ph.D., Albert Donnenberg, Ph.D., Todd Reinhart, Sc.D., JoAnne Flynn, Ph.D., Michael Murphey-Corb, Ph.D. |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu:80/ETD/available/etd-07242003-115541/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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