Rabbits as a model to study HIV-1 infection and the search for new innate immunity players in resting CD4 T cells

Hanna-Mari Baldauf
2018
Once infected with human immunodeficiency virus (HIV), currently available pharmacotherapies can only partly control, but not cure infection. Thus, there remains an urgent need for more potent and conceptually novel antiviral therapeutics, including the development of prophylactic and therapeutic HIV vaccines. To develop such novel treatment strategies, the use of animal models is critical to study virus replication and disease progression in vivo. On the other side, understanding how innate
more » ... nding how innate immunity works in primary human HIV target cells is important to find novel measures to inhibit or even eradicate HIV. Furthermore, knowledge gained from innate immunity studies in human cells can be transferred to animal model development. Here, we focus on both establishing rabbits as a suitable candidate to study HIV pathogenesis and identifying SAM domain and HD domain-containing protein 1 (SAMHD1) and a currently unknown protein as important cellular factors inhibiting HIV replication in primary resting T cells. Cells from New Zealand white rabbits display a remarkable HIV susceptibility ex vivo as they express only three blocks to full-length HIV replication. Deficits at the level of entry and reverse transcription could be overcome by transient expression of human CD4/CCR5 on primary rabbit macrophages and by using a HIV/ simian immunodeficiency virus (SIV) capsid chimera to avoid recognition by rabbit tripartite motif-containing protein 5 (TRIM5). The nature of the third barrier, causing a HIV infectivity defect in primary rabbit macrophages, remains elusive. As the phenotype resembles the antiviral activity of serine incorporator proteins 3/5 (SERINC3/5), we analyzed SERINC3/5 orthologs from mouse, rat and rabbit, and compared them to the human counterparts. We found that all orthologs are highly conserved at amino acid level. In the absence of viral antagonists, all rodent and lagomorph SERINC3 and SERINC5 orthologs displayed anti-HIV activity comparable to the human orthologs, generally with lower restriction activ [...]
doi:10.5282/edoc.24163 fatcat:vkvjewptvbdodcvfpmenpb6xnu