Humanized mouse models of HIV infection

Because of the limited tropism of HIV, in vivo modeling of this virus has been almost exclusively limited to other lentiviruses, such as simian immunodeficiency virus, that reproduce many important characteristics of HIV infection. However, there are significant genetic and biological differences among lentiviruses and some HIV-specific interventions are not effective against other lentiviruses in nonhuman hosts. For these reasons, much emphasis has recently been placed on developing alternative animal models that support HIV replication and recapitulate key aspects of HIV infection and pathogenesis in humans. Humanized mice, CD34⁺ hematopoietic progenitor cell transplanted immunodeficient mice, and in particular mice also implanted with human thymus/liver tissue (bone marrow liver thymus mice) that develop a functional human immune system, have been the focus of a great deal of attention as possible models to study virtually all aspects of HIV biology and pathogenesis. Humanized mice are systemically reconstituted with human lymphoid cells, offering rapid, reliable, and reproducible experimental systems for HIV research. Peripheral blood of humanized mice can be readily sampled longitudinally to assess reconstitution with human cells and to monitor HIV replication, permitting the evaluation of multiple parameters of HIV infection such as viral load levels, CD4⁺ T-cell depletion, immune activation, as well as the effects of therapeutic interventions. Of high relevance to HIV transmission is the extensive characterization and validation of the reconstitution with human lymphoid cells of the female reproductive tract and of the gastrointestinal tract of humanized bone marrow liver thymus mice that renders them susceptible to both vaginal and rectal HIV infection. Other important attributes of all types of humanized mice include: (i) their small size and cost that make them widely accessible; (ii) multiple cohorts of humanized mice can be made from multiple human donors and each cohort has identical human cells, permitting control of intragenetic variables; (iii) continuous de novo production of human immune cells from the transplanted CD34⁺ cells within each humanized mouse facilitates long-term experiments; (iv) both primary and laboratory HIV isolates can be used for experiments; and (v) in addition to therapeutic interventions, rectal and vaginal HIV prevention approaches can be studied. In summary, humanized mice can have an important role in virtually all aspects of HIV research, including the analysis of HIV replication, the evaluation of HIV restriction factors, the characterization of successful biomedical HIV prevention strategies, the evaluation of new treatment regimens, and the evaluation of novel HIV eradication strategies.