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Longitudinal Imaging of HIV-1 Infect...

Ventura, John D.

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Longitudinal Imaging of HIV-1 Infection and Recrudescence in Humanized Mice.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Longitudinal Imaging of HIV-1 Infection and Recrudescence in Humanized Mice./
作者:	Ventura, John D.
出版者:	Ann Arbor : ProQuest Dissertations & Theses, : 2019,
面頁冊數:	174 p.
附註:	Source: Dissertations Abstracts International, Volume: 81-03, Section: B.
Contained By:	Dissertations Abstracts International81-03B.
標題:	Microbiology. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=13809192
ISBN:	9781088309070

Longitudinal Imaging of HIV-1 Infection and Recrudescence in Humanized Mice.
Ventura, John D.

Longitudinal Imaging of HIV-1 Infection and Recrudescence in Humanized Mice. - Ann Arbor : ProQuest Dissertations & Theses, 2019 - 174 p.

Source: Dissertations Abstracts International, Volume: 81-03, Section: B.

Thesis (Ph.D.)--Yale University, 2019.

This item must not be sold to any third party vendors.

An estimated 37 million people globally suffer from Human Immunodeficiency Virus-1 (HIV-1) infection with 1.7 million newly acquired infections occurring on average each year. About 40 million people have died. Although crucial advances in combined antiretroviral therapy (cART) over the last two decades have transformed an HIV-1 diagnosis into a tolerable and controlled condition, enabling over 20 million people living with HIV-1 to enjoy healthy and productive lives, no cure or vaccine yet exists. Developing a successful cure strategies will require a firm understanding of a critical feature of HIV-1 immunopathogenesis: the generation of a persistent and long-lived latent reservoir that will initiate a recrudescent infection upon the removal of antiretroviral suppression. The latent reservoir remains the primary obstacle for cure development and most putative cure strategies proposed fundamentally address its eradication or permanent suppression. In vivo monitoring of longitudinal HIV-1 infection in small animal models would benefit ongoing HIV-1 research and cure efforts. Towards this end, we developed and characterized replication-competent GFP and Nanoluciferase (Nluc) expressing HIV-1 reporter viruses from two clinical transmitted / founder (T/F) stains, TRJO.c and Q23.BG505. Our design introduces a reporter gene with Nef under the translational regulation of the native encephalomyocarditis virus (ECMV) internal ribosome entry site (IRES) sequence without additional modification to the genome. Near-native Nef expression and Nef function was preserved in all reporter viruses tested and viral particle infectivity was not compromised by the introduction of the reporter gene. Reporter expression is maintained for at least two weeks in infected primary CD4 T cell and 15 days in humanized mice, a marked improvement over previous reporter virus design. Nluc expressing T/F reporter viruses permitted unbiased visualization and quantification of HIV-1 infected cells and longitudinal HIV-1 spread in multiple humanized mice models permissive to HIV-1 infection at a sensitivity of as few as 20-40 infected cells. Nluc signal was strongly correlated with both the increase of reverse transcriptase activity and the number of infected cells in blood plasma before Nluc reporter expression became unstable after 15 days post-infection. Using this system, we were able to follow the spread of the infected cell population in vivo from initial inoculation and observe early cellular infection foci in secondary lymphoid tissues and subsequent systemic spread via the detection of infected cells in blood-filtering tissues, such as the spleen. In order to directly observe sites of viral rebound, infected humanized mice were placed on a daily regimen of cART for a period of 4-5 weeks after which the regimen was lifted and the mice were imaged longitudinally until rebound was observed. Interestingly, we observed recrudescent infection in the same lymphoid tissues where infection was first observed prior to ART treatment. This finding is consistent with the model that latency is established early may consist of memory cell subsets that have tissue-resident properties. In addition, these findings demonstrate the utility of our system for localizing and subsequently studying latent cellular and tissue reservoirs involved in HIV-1 recrudescent infection. Lastly, with the capacity to longitudinally record the kinetics of latent HIV-1 reactivation, we envision using our system as a platform to preclinically test novel drug candidates targeting long-lived HIV-1 reservoirs.

ISBN: 9781088309070Subjects--Topical Terms:

536250
Microbiology.
Subjects--Index Terms:

Human Immunodeficiency Virus

Longitudinal Imaging of HIV-1 Infection and Recrudescence in Humanized Mice.
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