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

• 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
• ISSN: 1999-4915; 1999-4915
• DOI: 10.3390/v11030256

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.