Humanized Mouse Models of HIV-1 Latency research

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A major obstacle in the pursuit of a cure for HIV infection is the existence of long-lived cells containing viral DNA integrated into the cellular genome. These latently infected cells spark renewed rounds of viral replication when suppressive antiretroviral therapy (ART) is interrupted. Researchers are now aiming to develop strategies to purge latently infected cells, and these efforts would be greatly aided by animal models that recapitulate—at least to some extent—what occurs in humans.

Two new papers in the Journal of Virology describe the creation of mice with human immune systems that support HIV infection and develop a reservoir of latently infected, resting CD4 T cells similar to those observed in HIV-positive people. The researchers express hope that these models will facilitate the preclinical evaluation of approaches to depleting the latent reservoir, thereby reducing the need to conduct potentially risky human trials.

There are some potential limitations, however. The small size of mice limits the blood volume that can be sampled, so the degree of HIV viral load suppression by ART can only be assessed down to around 500-800 copies/mL. The extent of engraftment of the human immune system is also not complete, so for example some tissues in the Rag2-/-{gamma}c-/- mice such as the gut and female reproductive tract show a minimal presence of human cells whereas these locations may represent important HIV reservoirs in humans. The short lifespan of the mice also constrains the ability of the model to fully mirror ART treatment of HIV in people. Despite these caveats, humanized mice add to the range of options available to researchers pursuing a cure, and will likely be complimented by the further development of non-human primate models.
J Virol. 2011 Oct 19. [Epub ahead of print]

Latent HIV-1 Infection of Resting CD4+ T Cells in the Humanized Rag2-/-{gamma}c-/- Mouse.

Choudhary S, Archin N, Cheema M, Dahl N, Garcia JV, Margolis D.

Abstract

Persistent 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 non-human primate (NHP) or human studies. We report that in humanized Rag2(-/-)γ(c)(-/-) mice, as in humans, following HIV-1 infection with CCR5 tropic JR-CSF and suppression of viremia by ART, 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). Replication competent virus was recovered from pooled resting CD4(+) T cells in seven of sixteen mice with a median frequency of 8 (range 2-12) infected cells per million, 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 assessment 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.
http://jvi.asm.org/content/early/2011/10/14/JVI.05590-11.abstract


J Virol. 2011 Oct 19. [Epub ahead of print]

Generation of HIV Latency in BLT Humanized Mice.

Denton PW, Olesen R, Choudhary SK, Archin NM, Wahl A, Swanson MD, Chateau M, Nochi T, Krisko JF, Spagnuola RA, Margolis DM, Garcia JV.

Source

Division of Infectious Diseases, Department of Internal Medicine, Center for AIDS Research.

Abstract

Here we demonstrate that a combination of tenofovir, emtricitabine and raltegravir effectively suppresses peripheral and systemic HIV replication in BLT humanized mice. We also demonstrate that antiretroviral therapy (ART) treated BLT humanized mice harbor latently infected resting human CD4(+) T cells that can be induced ex vivo to produce HIV. We observed that the levels of infected resting human CD4(+) T cells present in BLT mice are within the range of those observed circulating in patients undergoing suppressive ART. These results demonstrate the potential of BLT humanized mice as an attractive model for testing the in vivo efficacy of novel HIV eradication strategies.
http://jvi.asm.org/content/early/2011/10/14/JVI.06120-11.abstract