Determinants of SIV/HIV-1 infection in the female reproductive tract in both the non-human primate model and humans / Shaheed A. Abdulhaqq.

Format:

Book

Manuscript

Thesis/Dissertation

Author/Creator:

Abdulhaqq, Shaheed A., author.

Contributor:

Montaner, Luis J., degree supervisor.

Ertl, Hildegund C. J., degree committee member.

Hoxie, James A., degree committee member.

Paterson, Yvonne J., degree committee member.

Weiner, David B., degree committee member.

University of Pennsylvania. Department of Cell and Molecular Biology.

Language:

English

Subjects (All):

Penn dissertations--Cell and molecular biology.

Cell and molecular biology--Penn dissertations.

Local Subjects:

Penn dissertations--Cell and molecular biology.

Cell and molecular biology--Penn dissertations.

Physical Description:

xvi, 271 leaves ; 29 cm

Production:

[Philadelphia, Pennsylvania] : [University of Pennsylvania], 2014.

Summary:

Women comprise approximately 50% of the 35 million global HIV-1 infections to date. Most HIV-1 infections occur through male-to-female sexual transmission. However, male-to-female viral transmission is inefficient with rates estimated to fall between 1:100 and 1:1000, depending on various factors, such as the viral transmitter's seminal viral load or concurrent sexually transmitted infections. This suggests that a series of sub-infectious HIV-1 exposures is likely to occur prior to an infectious exposure. Yet, it is unknown what impact either semen or sub-infectious virion exposure has on immune function or activation in the female reproductive tract or periphery, and if these exposures influence subsequent infectious HIV-1 exposure. To elucidate the mechanisms regulating viral transmission, we performed the following sets of experiments: (1) we tested the impact of cervico-vaginal acute exposure to non-replicating SIV virions on the female reproductive tract in non-human primates (NHP); (2) we assessed the status and function of both cervico-vaginal and peripheral immune effectors in a cohort of HIV-1 high-risk female sex workers; and (3) we tested the impact of repeated exposure to semen and/or non-infectious virus on the female reproductive tract in NHP. Our results indicate that intra-vaginal exposure to non-replicating SIV virions in rhesus macaques induces acute recruitment of CD4+ T-cells and CD123+ plasmacytoid dendritic cells. Infectious SIV challenge of this inflamed environment results in an enhanced SIV infection. We determined that HIV-1 high-risk female sex workers had reduced levels of T-cell activation, reduced cervico-vaginal immune activation despite higher immune cell infiltrates and high-levels of Interferon epsilon, a type I Interferon. Finally, we established that rhesus macaques intra-vaginally-exposed for a period of 20-weeks to semen had reduced T-cell activation and high levels of cervico-vaginal immune cell infiltrates and type I Interferon signaling as compared to controls resembling results found in high-risk female sex workers. These semen-exposed macaques also had fewer SIV infections as compared to macaques not receiving semen after low-dose intra-vaginal SIVmac251 challenge. Our work establishes a role for semen in modulation of the cervico-vaginal microenvironment and potentially lowering infection susceptibility.

Notes:

Ph. D. University of Pennsylvania 2014.

Department: Cell and Molecular Biology.

Supervisor: Luis J. Montaner.

Includes bibliographical references.

OCLC:

907969277