title: Efficient Inhibition of HIV Replication in the Gastrointestinal and Female Reproductive Tracts of Humanized BLT Mice by EFdA.
abstract: BACKGROUND
  The nucleoside reverse transcriptase inhibitor (NRTI) 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA) in preclinical development exhibits improved safety and antiviral activity profiles with minimal drug resistance compared to approved NRTIs. However, the systemic antiviral efficacy of EFdA has not been fully evaluated. In this study, we utilized bone marrow/liver/thymus (BLT) humanized mice to investigate the systemic effect of EFdA treatment on HIV replication and CD4+ T cell depletion in the peripheral blood (PB) and tissues. In particular, we performed a comprehensive analysis of the female reproductive tract (FRT) and gastrointestinal (GI) tract, major sites of transmission, viral replication, and CD4+ T cell depletion and where some current antiretroviral drugs have a sub-optimal effect.
  
  
  RESULTS
  EFdA treatment resulted in reduction of HIV-RNA in PB to undetectable levels in the majority of treated mice by 3 weeks post-treatment. HIV-RNA levels in cervicovaginal lavage of EFdA-treated BLT mice also declined to undetectable levels demonstrating strong penetration of EFdA into the FRT. Our results also demonstrate a strong systemic suppression of HIV replication in all tissues analyzed. In particular, we observed more than a 2-log difference in HIV-RNA levels in the GI tract and FRT of EFdA-treated BLT mice compared to untreated HIV-infected control mice. In addition, HIV-RNA was also significantly lower in the lymph nodes, liver, lung, spleen of EFdA-treated BLT mice compared to untreated HIV-infected control mice. Furthermore, EFdA treatment prevented the depletion of CD4+ T cells in the PB, mucosal tissues and lymphoid tissues.
  
  
  CONCLUSIONS
  Our findings indicate that EFdA is highly effective in controlling viral replication and preserving CD4+ T cells in particular with high efficiency in the GI and FRT tract. Thus, EFdA represents a strong potential candidate for further development as a part of antiretroviral therapy regimens.
authors.affiliation: Division of Infectious Diseases, Center for AIDS Research, University of North Carolina at Chapel Hill, School of Medicine, Chapel Hill, North Carolina, United States of America.
authors.forename: Uma
authors.initials: U
authors.lastname: Shanmugasundaram
authors.affiliation: Division of Infectious Diseases, Center for AIDS Research, University of North Carolina at Chapel Hill, School of Medicine, Chapel Hill, North Carolina, United States of America.
authors.forename: Martina
authors.initials: M
authors.lastname: Kovarova
authors.affiliation: Division of Infectious Diseases, Center for AIDS Research, University of North Carolina at Chapel Hill, School of Medicine, Chapel Hill, North Carolina, United States of America.
authors.forename: Phong T
authors.initials: PT
authors.lastname: Ho
authors.affiliation: Division of Infectious Diseases, Center for AIDS Research, University of North Carolina at Chapel Hill, School of Medicine, Chapel Hill, North Carolina, United States of America.
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Schramm
authors.affiliation: Division of Infectious Diseases, Center for AIDS Research, University of North Carolina at Chapel Hill, School of Medicine, Chapel Hill, North Carolina, United States of America.
authors.forename: Angela
authors.initials: A
authors.lastname: Wahl
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Parniak
authors.affiliation: Division of Infectious Diseases, Center for AIDS Research, University of North Carolina at Chapel Hill, School of Medicine, Chapel Hill, North Carolina, United States of America.
authors.forename: J Victor
authors.initials: JV
authors.lastname: Garcia
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage*; D001853:Bone Marrow / Q000187:drug effects / Q000473:pathology / Q000821:virology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects; D003839:Deoxyadenosines / Q000008:administration & dosage*; D004195:Disease Models, Animal; D005260:Female; D041981:Gastrointestinal Tract / Q000187:drug effects / Q000821:virology; D041722:Genes, Transgenic, Suicide; D015658:HIV Infections / Q000188:drug therapy* / Q000473:pathology / Q000821:virology; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors; D015497:HIV-1 / Q000187:drug effects* / Q000472:pathogenicity; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000473:pathology / Q000821:virology; D008297:Male; D051379:Mice; D060737:Reproductive Tract Infections / Q000188:drug therapy* / Q000473:pathology / Q000821:virology; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage; D013950:Thymus Gland / Q000187:drug effects / Q000821:virology; D014779:Virus Replication / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; D003839:Deoxyadenosines; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase; C558823:islatravir