One example is the tripartite motif-containing protein 5 alpha (TRIM5α), a cytoplasmic factor that restricts retroviral infection in a species-specific fashion.
To address whether TRIM5alpha contributes to the outcome of retroviral infection in a susceptible host species, we investigated the impact of TRIM5 polymorphisms in rhesus monkeys on the course of a simian immunodeficiency virus (SIV) infection.
It is hoped that research on TRIM5alpha will contribute to the establishment of new and improved models for HIV replication and AIDS pathogenesis, point the way towards novel therapeutic targets to stem the tide of the human AIDS epidemic, provide an experimental window onto the early, post-entry stages of the retroviral replication cycle, and even inspire the search for other cellular factors that modulate retroviral infection.
Lv1/TRIM5alpha (tripartite motif 5alpha) has recently emerged as an important factor influencing species-specific permissivity to retroviral infection in a range of primates, including humans.
TRIM5alpha severely restricts productive retroviral infections at the postentry and preintegration steps by destabilizing the incoming viral capsid via ubiquitination.
The SPRY domain of TRIM5alpha, which may be responsible for recognition of incoming viral capsids showed higher nonsynonymous/synonymous substitution ratios than the non-SPRY domain, indicating that the adaptive evolution of TRIM5alpha in primates might be an innate strategy developed in defending retrovirus infection during primate evolution.
These results lead us to define that the transcription and protein synthesis of TRIM5alpha could be modulated by IFN, suggesting that TRIM5alpha may play a role in an IFN-induced antiviral state against retrovirus infection.
These data indicate that TRIM5alpha can confer broad innate immunity to retrovirus infection in primate cells and is likely to be an important natural barrier to cross-species retrovirus transmission.
Transcription and translation of cyclin-dependent kinase inhibitor 1 (p21<sup>Cip1</sup>) and SAM domain and HD domain-containing protein 1 (SAMHD1) were analyzed by TaqMan PCR and Western blot experiments. siRNA experiment was applied to study the role of p53 downstream gene p21<sup>Cip1</sup> in the restriction of retrovirus infection.
SAMHD1 blocks retroviral infection at the level of reverse transcription in myeloid cells and resting CD4+ T cells and is counteracted by the accessory protein Vpx, which is encoded by human immunodeficiency virus 2 (HIV-2) and several simian immunodeficiency virus (SIV) strains.
Our findings show that SAMHD1 in the mouse blocks retroviral infection at the level of reverse transcription and is regulated through cell cycle-dependent phosphorylation.
Host restriction factors such as SAMHD1 and Trex1 play important roles in regulating innate immune sensing, and have led to the idea that innate immune defense and host restriction actually converge at different levels to determine the outcome of retroviral infection.
Collectively, these findings indicate that phosphorylation modulates the ability of SAMHD1 to block retroviral infection without affecting its ability to decrease cellular dNTP levels.
Both studies suggest that SAMHD1 is important for regulating the intracellular dNTP pool and the intrinsic immunity against retroviral infection, despite different outcomes of HIV-1 vector transduction in these mouse models.
Recent studies addressed the important question if other IFNα subtypes would be more potent against retroviral infections in in vitro and in vivo experiments.
Unexpectedly, knockout of PQBP1 in THP-1 cells causes significantly increased type I IFN production in response to transfected cytosolic nucleic acids or DNA damage, unlike what is seen in response to retroviral infection.