Modular Approaches to Understand the Immunobiology of Human Immunodeficiency Virus Latency

Despite advances in slowing the progression of acquired immunodeficiency syndrome (AIDS), there is no viable cure for human immunodeficiency virus (HIV). The challenge toward a cure is mainly the formation and maintenance of a latent reservoir of cells that harbor the virus in both replication-competent and replication-defective states. This small niche of quiescent cells has been identified to reside primarily in quiescent and memory CD4⁺ T cells, but parameters that could reliably distinguish an infected T cell from an uninfected one, if any, are not clear. In addition, the migratory properties and specific anatomical reservoirs of latent T cells are difficult to measure at a high resolution in humans. A functional cure of HIV would require targeting this population using innovative new clinical strategies. One constraint toward the empirical development of such approaches is the absence of a native small animal model for AIDS. Since HIV does not efficiently infect murine cells, probing molecular-genetic questions involving latently infected T cells homing to deep tissue sites, interacting with stroma and persisting through different treatment regimens, is challenging. The goal of this article is to discuss how examining the dynamics of T cells in mouse models can provide a framework for effectively studying these questions, even without infecting mice with HIV. The inflammatory and cytokine milieu found in early human HIV infections are being increasingly understood as a result of clinical measurements. Mouse studies that recreate this milieu can potentially be used to subsequently map the fate of T cells activated in this context as well as their migratory routes. In essence, such a framework could allow complementary studies in mice to enhance our understanding of aspects of the biology of HIV latency. This can be the basis of a modular approach to small animal HIV modeling, amenable to preclinical curative strategy development.