Latent HIV-1 infection of resting CD4⁺ T cells in the humanized Rag2⁻/⁻ γc⁻/⁻ mouse.
Persistent human immunodeficiency virus type 1 (HIV-1) infection of resting CD4⁺ T cells, unaffected by antiretroviral therapy (ART), provides a long-lived reservoir of HIV infection. Therapies that target this viral reservoir are needed to eradicate HIV-1 infection. A small-animal model that recapitulates HIV-1 latency in resting CD4⁺ T cells may accelerate drug discovery and allow the rational design of nonhuman primate (NHP) or human studies. We report that in humanized Rag2⁻/⁻ γ(c)⁻/⁻ (hu-Rag2⁻/⁻ γ(c)⁻/⁻) mice, as in humans, resting CD4⁺ T cell infection (RCI) can be quantitated in pooled samples of circulating cells and tissue reservoirs (e.g., lymph node, spleen, bone marrow) following HIV-1 infection with the CCR5-tropic JR-CSF strain and suppression of viremia by ART. Replication-competent virus was recovered from pooled resting CD4⁺ T cells in 7 of 16 mice, with a median frequency of 8 (range, 2 to 12) infected cells per million T cells, demonstrating that HIV-1 infection can persist despite ART in the resting CD4⁺ T cell reservoir of hu-Rag2⁻/⁻ γ(c)⁻/⁻ mice. This model will allow rapid preliminary assessments of novel eradication approaches and combinatorial strategies that may be challenging to perform in the NHP model or in humans, as well as a rigorous analysis of the effect of these interventions in specific anatomical compartments.
Department of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA. schoudha@med.unc.edu
Shailesh K
SK
Choudhary
Nancie M
NM
Archin
Manzoor
M
Cheema
Noelle P
NP
Dahl
J Victor
JV
Garcia
David M
DM
Margolis
D000818:Animals; D019380:Anti-HIV Agents / Q000627:therapeutic use; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000821:virology*; D059447:Cell Cycle Checkpoints; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D017735:Virus Latency
D019380:Anti-HIV Agents; D004268:DNA-Binding Proteins; C499308:Rag2 protein, mouse