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Updated: Jul 18, 2026
Humanized NOG Mice for Intravaginal HIV Exposure and Treatment of HIV Infection
Published on: January 31, 2020
Post-exposure prophylaxis for SIV revisited: animal model for HIV prevention
Peter Emau1, Yonghou Jiang, Michael B Agy
1Washington National Primate Research Center, University of Washington, Box 357330 Health Sciences Building, Seattle, Washington 98195, USA. pemau@bart.rprc.washington.edu
Background:
A 4-week, uninterrupted treatment with 9-(2-phosphonyl-methoxypropyly)adenine (PMPA, commonly called tenofovir) completely prevents simian immunodeficiency virus (SIVmne) infection in cynomolgus macaques if treatment begins within 24 hours after SIVmne inoculation, but is less effective if treatment is delayed or duration of treatment is shortened. Critical factors for efficacy include timing and duration of treatment, potency of antiretroviral drug and a contribution from antiviral immune responses. Therefore, we evaluated the impact of one or more treatment interruptions plus SIVmne re-exposures on efficacy of PMPA treatment to prevent SIVmne infection in cynomolgus macaques. We also evaluated whether macaques with pre-existing SIV immune responses show increased efficacy of treatment. Eight PMPA-treated, virus-negative and seronegative macaques, and five PMPA-treated, virus-negative but weakly or strongly seropositive macaques were re-inoculated with SIVmne and treated with PMPA starting 24 hr post inoculation. Thereafter, they received either a 5-week treatment involving one interruption plus one SIVmne challenge or a 10-week treatment involving six interruptions plus six SIVmne challenges early during treatment. Parameters measured were plasma SIV RNA, SIV-antibody response, CD4+ T lymphocyte subsets and in vivo CD8+ cell-suppression of virus infection.
Results:
All seronegative macaques developed persistent antibody response beginning 4 to 8 weeks after stopping PMPA-treatment in absence of viremia in a majority of macaques and coinciding with onset of intermittent viremia in other macaques. In contrast, all weakly or strongly seropositive macaques showed immediate increase in titers (> 1600) of SIV antibodies, even before the end of PMPA-treatment, and in absence of detectable viremia. However, in vivo CD8+-cell depletion revealed CD8 cell-suppression of viremia and persistence of virus in the macaques as long as 2 years after PMPA-treatment, even in aviremic macaques. Unlike untreated macaques, a treated macaque controlled viral replication and blocked CD4+ T cell depletion when challenged with a heterologous chimeric SIV/HIV-1 virus called SHIV89.6P.
Conclusion:
A single interruption plus one SIVmne challenge was as sufficient as six interruptions plus six SIVmne challenges in reducing efficacy of PMPA, but results in long-term persistence of virus infection suppressed by CD8+ cells. Efficacy of PMPA treatment was highest in macaques with pre-existing SIV immune responses.
Insights
Tenofovir (PMPA) treatment efficacy against simian immunodeficiency virus (SIVmne) in macaques is reduced by treatment interruptions and re-challenges. Pre-existing immune responses enhance tenofovir
Area of Science:
- Virology
- Immunology
- Pharmacology
Background:
- Uninterrupted 9-(2-phosphonyl-methoxypropyly)adenine (PMPA, tenofovir) treatment prevents simian immunodeficiency virus (SIVmne) infection in macaques if initiated within 24 hours post-inoculation.
- Treatment efficacy is sensitive to timing, duration, drug potency, and host antiviral immune responses.
- This study investigates the impact of treatment interruptions and re-exposures on PMPA efficacy and the role of pre-existing immunity.
Purpose of the Study:
- To evaluate the impact of treatment interruptions and SIVmne re-exposures on the efficacy of PMPA in preventing SIVmne infection in cynomolgus macaques.
- To determine if macaques with pre-existing SIV immune responses exhibit enhanced efficacy of PMPA treatment.
Main Methods:
- Eight PMPA-treated, virus-negative, seronegative macaques and five PMPA-treated, virus-negative, seropositive macaques were re-inoculated with SIVmne.
- Treatment involved PMPA initiated 24 hours post-inoculation, followed by either a 5-week regimen with one interruption/challenge or a 10-week regimen with six interruptions/challenges.
- Measured parameters included plasma SIV RNA, SIV-antibody response, CD4+ T lymphocyte subsets, and in vivo CD8+ cell-mediated suppression of infection.
Main Results:
- All seronegative macaques developed persistent antibody responses post-treatment, with a majority remaining aviremic.
- Seropositive macaques showed rapid increases in SIV antibody titers, even during PMPA treatment, and remained aviremic.
- CD8+ cell depletion revealed persistent, suppressed viremia for up to 2 years post-treatment, even in aviremic macaques. Treated macaques controlled viral replication against a heterologous SIV/HIV-1 challenge.
Conclusions:
- Treatment interruptions and re-challenges significantly reduced PMPA efficacy, with single and multiple interruptions yielding similar reductions.
- PMPA treatment resulted in long-term, CD8+ cell-suppressed viral persistence.
- The efficacy of PMPA treatment was notably higher in macaques possessing pre-existing SIV immune responses.
