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. 2009 Aug;83(16):8254-8.
doi: 10.1128/JVI.00580-09. Epub 2009 Jun 3.

Suppression of human immunodeficiency virus type 1 (HIV-1) viremia with reverse transcriptase and integrase inhibitors, CD4+ T-cell recovery, and viral rebound upon interruption of therapy in a new model for HIV treatment in the humanized Rag2-/-{gamma}c-/- mouse

Shailesh K Choudhary  1 , Naser L Rezk, William L Ince, Manzoor Cheema, Liguo Zhang, Lishan Su, Ronald Swanstrom, Angela D M Kashuba, David M Margolis
Affiliations

Suppression of human immunodeficiency virus type 1 (HIV-1) viremia with reverse transcriptase and integrase inhibitors, CD4+ T-cell recovery, and viral rebound upon interruption of therapy in a new model for HIV treatment in the humanized Rag2-/-{gamma}c-/- mouse

Shailesh K Choudhary et al. J Virol. 2009 Aug.

Abstract

A small animal model that reproduces human immunodeficiency virus type 1 (HIV-1) pathogenesis may allow modeling of new therapeutic strategies in ways not approachable in mononuclear cell culture. We find that, as in humans, combination antiretroviral therapy (ART) in humanized (hu-) Rag2(-/-)gamma(c)(-/-) mice allows suppression of viremia below the limits of detection and recovery of CD4(+) cells, while interruption of ART results in viral rebound and renewed loss of CD4(+) T cells. Failure of ART in infected mice is associated with the appearance of drug resistance mutations. The hu-Rag2(-/-)gamma(c)(-/-) mouse may therefore facilitate testing of novel approaches to HIV replication and persistence.

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Figures

FIG. 1.
FIG. 1.
Pharmacokinetics of ART in Rag2−/−γc−/− mice. Mice were dosed with FTC, TFV, and L-870812 (L-812) at 60, 50 and 20 mg/kg body weight by single intraperitoneal injection. Serum and gastrointestinal tissue samples from ileum and rectum were collected and frozen at −80°C until analysis. As the PK profiles were similar for ileum and rectal regions of IT, data were combined. The data shown are the mean concentration ± standard error of the single-dose PK profile of FTC, TFV, and L-870812 over a 24-h period in serum (A) and IT (B) of mice after combined intraperitoneal injection. n = 3 for serum, and n = 6 for tissue.
FIG. 2.
FIG. 2.
hu-CD4+ T-cell reconstitution, infection, and novel antiretroviral therapy in hu-Rag2−/−γc−/− mice. (A) T-cell reconstitution at 20 weeks postengraftment. Live cells were defined based on their forward and side scatter and single cells based on forward scatter height and area. Single, live cells were subsequently gated on the hu-CD45+/mouse CD45 and hu-CD3+ population. (B) Memory hu-CD4+ T cells reconstitute in blood and tissue. Human T cells gated on the CD4+ population (circled) were analyzed for memory marker CD45RO and activation marker CD25. PBMC, peripheral blood mononuclear cells. (C) hu-CD4+ T-cell expression of CCR5 and CXCR4. (D) hu-CD11b+ cells are detected in several lymphoid tissues. (E) Suppression of plasma viremia and recovery of hu-CD4+ T cells in individual hu-Rag2−/−γc−/− mice. Animals were infected with JRCSF (25 ng p24/mouse) and treated with L-870812, TFV, and FTC at 20, 50, and 60 mg/kg/daily, respectively. Blue lines and squares show plasma viremia, while green lines and triangles show CD4+ percentages, both drawn on a logarithmic scale. The percentage of hu-CD4+ T cells represents the percentage of this cell population in total peripheral blood mononuclear cells obtained from mouse blood. The percentage of hu-CD4+ T cells = % hu-CD45+/mouse CD45− cells × (% CD3+ cells gated on hu-CD45+ cells/100) × (% CD4+ cells gated on hu-CD45+ CD3+/100). Due to the small available volume of mouse plasma, dilution is required, and so the limit of assay detection of viral RNA is <500 copies (Cps)/ml. Shading indicates time prior to infection (green), following infection (purple), after initiation of ART (yellow), and following discontinuation of ART (gray). TFV- and L-870812-related mutations were detected in plasma of M4 and M5 upon failure of therapy or rebound. Experiments terminated by death of the mouse are indicated by asterisks.
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