The influence of HIV-1 proviral burden on disease progression and response to antiretroviral therapy

Russell, Rodney S. (2000) The influence of HIV-1 proviral burden on disease progression and response to antiretroviral therapy. Masters thesis, Memorial University of Newfoundland.

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    Available under License - The author retains copyright ownership and moral rights in this thesis. Neither the thesis nor substantial extracts from it may be printed or otherwise reproduced without the author's permission.
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Abstract

When HIV-1 infects CD4⁻ T cells, its RNA genome is reverse transcribed into double stranded proviral DNA which translocates to the nucleus and integrates into the host cell genome. This integrated proviral DNA can remain silent, but ultimately is the source of all HIV-1 replication. Therefore, we hypothesize that the size of the HIV-1 proviral pool determines the rate of disease progression and is a useful prognostic indicator of the durability of responsiveness to antiretroviral therapy. To test this hypothesis, we developed a nonradioactive quantitative PCR-based proviral load assay and measured the frequency of CD4⁻ T cells containing HIV-1 proviral DNA in 78 HIV-1-infected individuals. Our results show that HIV-1 proviral load is a stable pool of virus that is unaffected by current antiretroviral therapies. We found that HIV-1-infected individuals with higher proviral loads displayed a lower mean CD4⁻ T cell count and significantly higher mean peak plasma virus load. When we separated HIV-1-infected individuals into groups based on whether or not they responded to therapy, we found that non-responders had higher proviral loads than did responders. Taken together, these results indicate that the HIV-1 proviral DNA pool has a strong influence on the potential for immune reconstitution and viral suppression in response to antiretroviral therapy, suggesting that HIV-1 proviral load is much more important than originally believed. Current regimens of antiretroviral therapy are not going to be sufficient to eradicate HIV, and new therapies that target this pool of HIV-1 proviral load are needed. -- The second aim of my study was to evaluate the effects of the CCR5∆32 HIV-1 coreceptor mutation on the rate of HIV-1 disease progression, and to determine whether the slower rate of disease progression reported in CCR5∆32 heterozygotes could be due to lower levels of HIV-1 proviral DNA. We found that the heterozygous individuals in our group displayed slower rates of disease progression than individuals homozygous for wild type CCR5. However when we compared HIV-1 proviral load between groups of CCR5∆32 heterozygous and CCR5wt homozygous individuals, we saw only a slight difference in mean proviral load. This result indicates that the slower rates of disease progression observed in the CCR5∆32 heterozygotes is not due to a decreased HIV-1 proviral load.

Item Type: Thesis (Masters)
URI: http://research.library.mun.ca/id/eprint/1455
Item ID: 1455
Additional Information: Bibliography: leaves 102-123
Department(s): Medicine, Faculty of
Date: 2000
Date Type: Submission
Library of Congress Subject Heading: HIV infections--Research; HIV infections--Treatment
Medical Subject Heading: HIV Infections; HIV-1; Proviruses; Disease Progression; Antiretroviral Therapy, Highly Active

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