Abstract
The human immunodeficiency virus type-1 (HIV-1) Rev protein regulates the nuclear export of intron-containing viral RNAs by recruiting the CRM1 nuclear export receptor. Here, we employed a combination of functional and phylogenetic analyses to identify and characterize a species-specific determinant within human CRM1 (hCRM1) that largely overcomes established defects in murine cells to the post-transcriptional stages of the HIV-1 life cycle. hCRM1 expression in murine cells promotes the cytoplasmic accumulation of intron-containing viral RNAs, resulting in a substantial stimulation of the net production of infectious HIV-1 particles. These stimulatory effects require a novel surface-exposed element within HEAT repeats 9A and 10A, discrete from the binding cleft previously shown to engage Rev's leucine-rich nuclear export signal. Moreover, we show that this element is a unique feature of higher primate CRM1 proteins, and discuss how this sequence has evolved from a non-functional, ancestral sequence.
Highlights
human immunodeficiency virus type-1 (HIV-1) is unable to replicate in most non-human species due to species-specific differences in cellular factors that either inhibit or promote viral replication
We show that differences between the mouse and human forms of the essential host protein CRM1, a protein required for the transport of macromolecules from the nucleus to the cytoplasm, underlie this problem
Key amino acid differences between the mouse/human CRM1 proteins are identified and computational analyses of divergent animal CRM1 proteins reveal a unique motif in higher primates likely acquired in response to ancient evolutionary pressures
Summary
HIV-1 is unable to replicate in most non-human species due to species-specific differences in cellular factors that either inhibit or promote viral replication. Mice and other rodents represent notable examples and exhibit multiple cellular deficiencies in pathways required for efficient HIV-1 replication [2]. While these deficiencies have impeded the development of a small animal model with which to study HIV-1, murine cell lines have served as powerful tools for delineating important molecular attributes of species-specific HIV-1 co-factors, including the CD4 entry receptor [3,4] and CCR5 co-receptor [5], as well as the cyclin T1 (CycT1/CCNT1) transcription co-factor [6,7]. The combined provision of human versions of CD4, co-receptor (CCR5 or CXCR4) and CycT1 to murine cell lines does not restore HIV-1 replication, largely reflecting additional deficiencies that affect post-transcriptional steps of the virus life cycle [8,9,10]
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