Over 35 million individuals worldwide suffer HIV-1 infection. Despite the advent of highly active antiretroviral therapy (HAART), which can suppress HIV-1 viremia indefinitely in infected persons, infection persists even after decades of continuous treatment. HIV-1 persistence is achieved through the establishment of a latent reservoir of long-lived, quiescent memory CD4+ T lymphocytes, which harbor functional integrated HIV-1 proviruses that can reinitiate viremia upon cessation of HAART. Attempts to eradicate this latent reservoir via the administration of putative `latency-reversing agents' (LRAs in humans have failed, suggesting that the molecular nature of latency in vivo is incompletely understood. Latently HIV-1-infected cells are notoriously difficult to study as they are extremely rare among circulating lymphocytes in treated humans, and they cannot be directly isolated by any known means. These roadblocks have complicated accurate assessments of latent reservoir size in HIV-1-infected humans, and have prohibited molecular characterization of latently infected cells ex vivo. The proposed work would utilize a novel, replication-competent HIV-1 reporter virus capable of labeling HIV-1-infected cells, including latently infected cells, t characterize HIV-1 latency in an established humanized mouse model. The use of such a virus will permit the identification and isolation of latently infected cells, enabling molecular profilig of purified latent populations for the first time.
Specific aims i nclude measuring the establishment of HIV-1 latent reservoirs in humanized mice, transcriptomic and integration profiling of latently infected cells ex vivo, and detecting the reactivation and/or depletion of latently infected cells during suppressive therapy.
HIV-1 infection, while treatable, cannot presently be cured because it establishes a durable latent reservoir of infection that persists despite decades of therapy. All attempts to eradicate latent HIV-1 infection in humans have failed to date, suggesting that HIV-1 latency is incompletely understood. The proposed work shall attempt dissection of HIV-1 latency in humanized mice to accelerate HIV-1 cure research.
|Horwitz, Joshua A; Bar-On, Yotam; Lu, Ching-Lan et al. (2017) Non-neutralizing Antibodies Alter the Course of HIV-1 Infection In Vivo. Cell 170:637-648.e10|
|Scheid, Johannes F; Horwitz, Joshua A; Bar-On, Yotam et al. (2016) HIV-1 antibody 3BNC117 suppresses viral rebound in humans during treatment interruption. Nature 535:556-60|
|Lu, Ching-Lan; Murakowski, Dariusz K; Bournazos, Stylianos et al. (2016) Enhanced clearance of HIV-1-infected cells by broadly neutralizing antibodies against HIV-1 in vivo. Science 352:1001-4|