Figure 1.
Implant viral loads in untreated- and 3TC-treated SCID-hu Thy/Liv mice are highly reproducible, and 3TC treatment after HIV-1 inoculation is nearly as effective as prophylactic treatment.
A, HIV-1 RNA in Thy/Liv implants of untreated mice and mice treated by twice-daily oral gavage with 3TC at 30 mg/kg per day beginning 1 day before inoculation with NL4-3 (means±SEM) Each experiment was performed in a mouse cohort made with tissues from a single donor. B, Implant p24 for the same groups as in panel A. C, Implant HIV-1 RNA in mice treated with 3TC beginning on day −1, day +1, day +3, and day +7 with respect to inoculation with the indicated HIV-1 strains. D, Implant p24 for the same groups as in panel C. Implants were collected 21 days after inoculation for NL4-3, 14 days for JD, and 42 days for Ba-L. *p≤0.05, compared with untreated mice for 5–7 mice per group.
Figure 2.
3TC treatment of HIV-1 JD-infected SCID-hu Thy/Liv mice inhibits viral replication and protects implants from virus-mediated thymocyte depletion.
Mice were treated by twice-daily oral gavage with 3TC at 300 mg/kg per day beginning on day +1 after inoculation, and Thy/Liv implants were collected 14, 21, and 28 days after inoculation. Antiviral efficacy was assessed by determining HIV-1 RNA (A), p24 (B), Gag-p24+ thymocytes (C), and MHC-I expression on DP thymocytes (D). Thymocyte protection was assessed by total implant cellularity (E), thymocyte viability (F), percentage of DP thymocytes (G), and CD4/CD8 ratio (H) for 3TC-treated mice versus untreated mice (means±SEM). *p≤0.05, compared with untreated mice for 5–7 mice per group.
Figure 3.
3TC treatment protects HIV-1 JD-infected Thy/Liv implants from thymocyte depletion.
Flow cytometric analysis of representative implants stained for CD4 and CD8 obtained 28 days after inoculation with HIV-1 JD shows severe depletion of DP and CD4+ thymocytes in an untreated mouse and nearly complete protection from thymocyte depletion by 3TC treatment (300 mg/kg per day beginning on day +1 after inoculation).
Figure 4.
(–)-FTC is more potent than 3TC against HIV-1 NL4-3 in SCID-hu Thy/Liv mice.
Mice were treated by twice-daily oral gavage with 3TC or (–)-FTC at 10, 30, and 100 mg/kg per day beginning on day –1. Antiviral efficacy was assessed by determining HIV-1 RNA (A) and p24 (B), and thymocyte protection was assessed by percentage of DP thymocytes (C) (means±SEM). *p≤0.05, compared with untreated mice for the number of mice indicated under each bar.
Figure 5.
Efavirenz is more potent than nevirapine against HIV-1 NL4-3 in SCID-hu Thy/Liv mice.
Mice were treated by twice-daily oral gavage with nevirapine or efavirenz at the indicated dosage levels beginning on day −1. Antiviral efficacy was assessed by determining HIV-1 RNA (A) and p24 (B), and thymocyte protection was assessed by percentage of DP thymocytes (C) (means±SEM). *p≤0.05, compared with untreated mice for the number of mice indicated under each bar.
Figure 6.
Atazanavir is more potent than indinavir against HIV-1 NL4-3 in SCID-hu Thy/Liv mice.
Mice were treated by twice-daily oral gavage with indinavir or atazanavir at 100, 300, and 1000 mg/kg per day beginning on day −1. Antiviral efficacy was assessed by determining HIV-1 RNA (A) and p24 (B), and thymocyte protection was assessed by percentage of DP thymocytes (C) (means±SEM). *p≤0.05, compared with untreated mice for the number of mice indicated under each bar.
Figure 7.
T-20 causes dose-dependent reductions in viral load in HIV-1 NL4-3 D36G-infected SCID-hu Thy/Liv mice.
Mice were treated by twice-daily subcutaneous injection with T-20 at 10, 30, and 100 mg/kg per day beginning on day −1. Antiviral efficacy was assessed by determining cell-associated HIV-1 RNA and p24. Data are expressed as means±SEM; *p≤0.05 for treated mice versus untreated mice by the Mann-Whitney U test for the number of mice indicated under each bar.
Table 1.
Antiretroviral drug dosage levels adjusted for difference in surface area-to-body weight ratio between mice and humans
Figure 8.
Multidrug-resistant (MDR) NY index case HIV-1 replicates and depletes thymocytes with kinetics comparable to HIV-1 NL4-3 in SCID-hu Thy/Liv mice.
Viral replication assessed by determining HIV-1 RNA (A), p24 (B), Gag-p24+ thymocytes (C), and MHC-I expression on DP thymocytes (D). Thymocyte protection was assessed by total implant cellularity (E), thymocyte viability (F), percentage of DP thymocytes (G), and CD4/CD8 ratio (H) for NL4-3 versus MDR NY index case HIV-1-infected mice (means±SEM). *p≤0.05, compared with untreated mice for 7 mice per group.