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ROUTE-‐SPECIFIC
SELECTION
DURING
MOTHER-‐TO-‐CHILD
TRANSMISSION
OF
HIV-‐1
by
Kyle
J
Nakamura
A
Dissertation
Presented
to
the
FACULTY
OF
THE
USC
GRADUATE
SCHOOL
UNIVERSITY
OF
SOUTHERN
CALIFORNIA
In
Partial
Fulfillment
of
the
Requirements
for
the
Degree
DOCTOR
OF
PHILOSOPHY
(SYSTEMS
BIOLOGY
AND
DISEASE)
August
2011
Copyright
2011
Kyle
J
Nakamura
Object Description
| Title | Route-specific selection during mother-to-child transmission of HIV-1 |
| Author | Nakamura, Kyle J. |
| Author email | kjnakamu@usc.edu;knakamura98@gmail.com |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Systems Biology and Disease |
| School | Keck School of Medicine |
| Date defended/completed | 2011-05-02 |
| Date submitted | 2011-07-06 |
| Date approved | 2011-07-06 |
| Restricted until | 2011-07-06 |
| Date published | 2011-07-06 |
| Advisor (committee chair) | Aldrovandi, Grace M. |
| Advisor (committee member) |
Nash, Kevin Cannon, Paula Watanabe, Richard |
| Abstract | The struggle to contain and extinguish the worldwide HIV/AIDS pandemic, now in its 30th year, may represent the single greatest challenge faced by modern medical science. Despite billions of dollars in research funding and the dedicated work of thousands of scientists and clinicians HIV/AIDS has already claimed over 25 million lives. There are ~33 million people currently living with HIV and ~2.7 million new infections occurred last year. Approximately 2.1 million children are currently HIV+, the vast majority of who acquired the virus from their mothers. While great strides have been made in the development of drugs to treat HIV infection, such medications are expensive and the majority of people who need them currently lack access. Efforts at developing an HIV vaccine have met with almost relentless failure, and only one human trial has thus far produced modest positive results. One of the greatest challenges facing HIV vaccine development is the incredible genetic heterogeneity of circulating viral strains, and HIVs ability to rapidly mutate in order to escape immune pressure. ❧ There is some hope. HIV transmission is extremely inefficient, often resulting from the outgrowth of a single genetic variant. This extreme genetic bottleneck implies the action of powerful selective forces, yet there is precious little data available on the genetic and functional properties of variants that successfully establish infection in a new host, and almost no data on how these selective criteria may vary by route of transmission. An improved understanding of the selective forces acting on viral variants during transmission could open up new strategies to interfere with the process. By answering the question “what defines a winner?” we can refine our approaches to specifically target the viral variants most capable of establishing chronic infection in a susceptible host. ❧ In this context, mother-to-child transmission (MTCT) represents both an important medical and humanitarian concern, as well as a powerful system in which to study transmission dynamics. Unlike other forms of transmission, MTCT allows unambiguous identification of the source donor. Furthermore, MTCT involves three distinct, mutually exclusive, and serial exposures (in utero, during labor and delivery, and postnatally by breastfeeding). By studying the early-transmitted virus from the infected infants, and comparing those variants to the virus circulating in the chronically infected mothers, we can identify the specific features selected for during transmission and how that selection may vary by exposure. This knowledge will, in turn, help us unravel the molecular mechanisms underlying HIV transmission, and ultimately provide new targets for intervention. ❧ In our study we explore the genotypic and phenotypic selection that occurs during transmission of HIV from mother to child. We define a unique ‘molecular signature’ for virus transmitted in utero and by breastfeeding. This study represents, to our knowledge, the first description of transmission-route-specific selection in HIV; and as such permanently alters the way in which MTCT should be approached. We also describe a series of HIV infected subjects harboring antibody resistant variants previously thought to be extremely rare, but which appear to occur with greater frequency in pregnant women and their infected offspring. The identification and characterization of these variants has implications for both vaccine development and our understanding of the structure/function of HIV’s envelope protein. |
| Keyword | HIV; AIDS; mother-to-child transmission |
| Language | English |
| Part of collection | University of Southern California dissertations and theses |
| Publisher (of the original version) | University of Southern California |
| Place of publication (of the original version) | Los Angeles, California |
| Publisher (of the digital version) | University of Southern California. Libraries |
| Provenance | Electronically uploaded by the author |
| Type | texts |
| Legacy record ID | usctheses-m |
| Rights | Nakamura, Kyle J. |
| Access conditions | The author retains rights to his/her dissertation, thesis or other graduate work according to U.S. copyright law. Electronic access is being provided by the USC Libraries in agreement with the author, as the original true and official version of the work, but does not grant the reader permission to use the work if the desired use is covered by copyright. It is the author, as rights holder, who must provide use permission if such use is covered by copyright. The original signature page accompanying the original submission of the work to the USC Libraries is retained by the USC Libraries and a copy of it may be obtained by authorized requesters contacting the repository e-mail address given. |
| Repository name | University of Southern California Digital Library |
| Repository address | USC Digital Library, University of Southern California, University Park Campus MC 7002, 106 University Village, Los Angeles, California 90089-7002, USA |
| Repository email | cisadmin@usc.edu |
| Archival file | uscthesesreloadpub_Volume71/etd-NakamuraKy-44.pdf |
Description
| Title | Page 1 |
| Full text | ROUTE-‐SPECIFIC SELECTION DURING MOTHER-‐TO-‐CHILD TRANSMISSION OF HIV-‐1 by Kyle J Nakamura A Dissertation Presented to the FACULTY OF THE USC GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (SYSTEMS BIOLOGY AND DISEASE) August 2011 Copyright 2011 Kyle J Nakamura |
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