TY - JOUR
T1 - Recovery of Latent HIV-1 from Brain Tissue by Adoptive Cell Transfer in Virally Suppressed Humanized Mice
AU - Su, Hang
AU - Sravanam, Sruthi
AU - Sillman, Brady
AU - Waight, Emiko
AU - Makarov, Edward
AU - Mathews, Saumi
AU - Poluektova, Larisa Y.
AU - Gorantla, Santhi
AU - Gendelman, Howard E.
AU - Dash, Prasanta K.
N1 - Funding Information:
We acknowledge the technical support given in this project by Lili Guo for providing outstanding technical assistance for preparing the humanized mice. We would like to thank Dr. Benson Edagwa for helping in the generation and characterization of nanoformulations used for the mice study. This work was supported by the University of Nebraska Foundation and by the National Institute of Health grants awarded to University of Nebraska Medical Center including P01 DA028555, R01MH115860, R01MH121402 and R24OD018546. The funding agency have no role in the design of the experiments.
Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
PY - 2021/12
Y1 - 2021/12
N2 - Defining the latent human immunodeficiency virus type 1 (HIV-1) burden in the human brain during progressive infection is limited by sample access. Human hematopoietic stem cells (hu-HSCs)-reconstituted humanized mice provide an opportunity for this study. The model mimics, in measure, HIV-1 pathophysiology, transmission, treatment, and elimination in an infected human host. However, to date, brain HIV-1 latency in hu-HSC mice during suppressive antiretroviral therapy (ART) was not studied. To address this need, hu-HSC mice were administered long acting (LA) ART 14 days after HIV-1 infection was established. Animals were maintained under suppressive ART for 3 months, at which time HIV-1 infection was detected at low levels in brain tissue by droplet digital polymerase chain reaction (ddPCR) test on DNA. Notably, adoptive transfer of cells acquired from the hu-HSC mouse brains and placed into naive hu-HSC mice demonstrated viral recovery. These proof-of-concept results demonstrate replication-competent HIV-1 reservoir can be established in hu-HSC mouse brains that persists during long-term ART treatment. Hu-HSC mice-based mouse viral outgrowth assay (hu-MVOA) serves as a sensitive tool to interrogate latent HIV-1 brain reservoirs. Graphic Abstract: [Figure not available: see fulltext.].
AB - Defining the latent human immunodeficiency virus type 1 (HIV-1) burden in the human brain during progressive infection is limited by sample access. Human hematopoietic stem cells (hu-HSCs)-reconstituted humanized mice provide an opportunity for this study. The model mimics, in measure, HIV-1 pathophysiology, transmission, treatment, and elimination in an infected human host. However, to date, brain HIV-1 latency in hu-HSC mice during suppressive antiretroviral therapy (ART) was not studied. To address this need, hu-HSC mice were administered long acting (LA) ART 14 days after HIV-1 infection was established. Animals were maintained under suppressive ART for 3 months, at which time HIV-1 infection was detected at low levels in brain tissue by droplet digital polymerase chain reaction (ddPCR) test on DNA. Notably, adoptive transfer of cells acquired from the hu-HSC mouse brains and placed into naive hu-HSC mice demonstrated viral recovery. These proof-of-concept results demonstrate replication-competent HIV-1 reservoir can be established in hu-HSC mouse brains that persists during long-term ART treatment. Hu-HSC mice-based mouse viral outgrowth assay (hu-MVOA) serves as a sensitive tool to interrogate latent HIV-1 brain reservoirs. Graphic Abstract: [Figure not available: see fulltext.].
KW - Adoptive transfer
KW - Brain
KW - Human immunodeficiency virus type one (HIV-1)
KW - Humanized mice
KW - Latent virus recovery
KW - Mouse viral outgrowth assay
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U2 - 10.1007/s11481-021-10011-w
DO - 10.1007/s11481-021-10011-w
M3 - Article
C2 - 34528173
AN - SCOPUS:85114953733
SN - 1557-1890
VL - 16
SP - 796
EP - 805
JO - Journal of Neuroimmune Pharmacology
JF - Journal of Neuroimmune Pharmacology
IS - 4
ER -