Cellular HIV Reservoirs and Viral Rebound from the Lymphoid Compartments of 4'-Ethynyl-2-Fluoro-2'-Deoxyadenosine (EFdA)-Suppressed Humanized Mice

Although antiretroviral therapy (ART) greatly suppresses HIV replication, lymphoid tissues remain a sanctuary site where the virus may replicate. Tracking the earliest steps of HIV spread from these cellular reservoirs after drug cessation is pivotal for elucidating how infection can be prevented. I...

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Bibliographic Details
Published in:Viruses 2019-03, Vol.11 (3), p.256
Main Authors: Maidji, Ekaterina, Moreno, Mary E, Rivera, Jose M, Joshi, Pheroze, Galkina, Sofiya A, Kosikova, Galina, Somsouk, Ma, Stoddart, Cheryl A
Format: Article
Language:English
Subjects:
Animals
Antibodies
Antiretroviral drugs
Antiretroviral therapy
cellular reservoir
Cloning
DC-SIGN
Dendritic cells
Deoxyadenosine
Deoxyadenosines - pharmacology
Disease Models, Animal
Disease Reservoirs - virology
Female
Flow cytometry
Gene expression
HIV
HIV Infections - drug therapy
HIV-1 - drug effects
HIV-1 - physiology
Human immunodeficiency virus
Humans
Hybridization
Immunohistochemistry
infection
Laboratory animals
Lymphocytes
Lymphoid tissue
Lymphoid Tissue - virology
macrophage
Mice
Mice, Transgenic
Pathogenesis
Replication
Reverse Transcriptase Inhibitors - pharmacology
RNA-directed DNA polymerase
RNAscope
Thymus gland
Transcription
Virus Replication - drug effects
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Summary:Although antiretroviral therapy (ART) greatly suppresses HIV replication, lymphoid tissues remain a sanctuary site where the virus may replicate. Tracking the earliest steps of HIV spread from these cellular reservoirs after drug cessation is pivotal for elucidating how infection can be prevented. In this study, we developed an in vivo model of HIV persistence in which viral replication in the lymphoid compartments of humanized mice was inhibited by the HIV reverse transcriptase inhibitor 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA) to very low levels, which recapitulated ART-suppression in HIV-infected individuals. Using a combination of RNAscope in situ hybridization (ISH) and immunohistochemistry (IHC), we quantitatively investigated the distribution of HIV in the lymphoid tissues of humanized mice during active infection, EFdA suppression, and after drug cessation. The lymphoid compartments of EFdA-suppressed humanized mice harbored very rare transcription/translation-competent HIV reservoirs that enable viral rebound. Our data provided the visualization and direct measurement of the early steps of HIV reservoir expansion within anatomically intact lymphoid tissues soon after EFdA cessation and suggest a strategy to enhance therapeutic approaches aimed at eliminating the HIV reservoir.
ISSN:1999-4915
1999-4915
DOI:10.3390/v11030256