Adult neurogenic deficits in HIV-1 Tg26 transgenic mice

BACKGROUND: Even in the antiretroviral treatment (ART) era, HIV-1-infected patients suffer from milder forms of HIV-1-associated neurocognitive disorders (HAND). While the viral proteins Tat and gp120 have been shown to individually inhibit the proliferation and neural differentiation of neural stem cells (NSCs), no studies have characterized the effects of all the combined viral proteins on adult neurogenesis. METHODS: The HIV-1 Tg26 transgenic mouse model was used due to its clinical relevance to ART-controlled HIV-1-infected patients who lack active viral replication but suffer from continuous stress from the viral proteins. Quantitative RT-PCR analysis was performed to validate the expression of viral genes in the neurogenic zones. In vitro stemness and lineage differentiation assays were performed in cultured NSCs from HIV-1 Tg26 transgenic mice and their wild-type littermates. Hippocampal neurogenic lineage analysis was performed to determine potential changes in initial and late differentiation of NSCs in the subgranular zone (SGZ). Finally, fluorescent retroviral labeling of mature dentate granule neurons was performed to assess dendritic complexity and dendritic spine densities. RESULTS: Varying copy numbers of partial gag (p17), tat (unspliced and spliced variants), env (gp120), vpu, and nef transcripts were detected in the neurogenic zones of Tg26 mice. Significantly fewer primary neurospheres and a higher percentage of larger sized primary neurospheres were generated from Tg26 NSCs than from littermated wild-type mouse NSCs, implying that Tg26 mouse NSCs exhibit deficits in initial differentiation. In vitro differentiation assays revealed that Tg26 mouse NSCs have reduced neuronal differentiation and increased astrocytic differentiation. In the SGZs of Tg26 mice, significantly higher amounts of quiescent NSCs, as well as significantly lower levels of active NSCs, proliferating neural progenitor cells, and neuroblasts, were observed. Finally, newborn mature granule neurons in the dentate gyri of Tg26 mice had deficiencies in dendritic arborization, dendritic length, and dendritic spine density. CONCLUSIONS: Both in vitro and in vivo studies demonstrate that HIV-1 Tg26 mice have early- and late-stage neurogenesis deficits, which could possibly contribute to the progression of HAND. Future therapies should be targeting this process to ameliorate, if not eliminate HAND-like symptoms in HIV-1-infected patients.