HIV-1 infection of macrophages is dependent on evasion of innate immune cellular activation.

Objective: The cellular innate immune response to HIV-1 is poorly characterized. In view of HIV-1 tropism for macrophages, which can be activated via pattern recognition receptors to trigger antimicrobial defences, we investigated innate immune responses to HIV-1 by monocyte-derived macrophages.

Design: In a model of productive HIV-1 infection, cellular innate immune responses to HIV-1 were investigated, at the level of transcription factor activation, specific gene expression and genome-wide transcriptional profiling.

Porcine endogenous retroviruses PERV A and A/C recombinant are insensitive to a range of divergent mammalian TRIM5alpha proteins including human TRIM5alpha.

The potential risk of cross-species transmission of porcine endogenous retroviruses (PERV) to humans has slowed the development of xenotransplantation, using pigs as organ donors. Here, we show that PERVs are insensitive to restriction by divergent TRIM5alpha molecules despite the fact that they strongly restrict a variety of divergent lentiviruses. We also show that the human PERV A/C recombinant clone 14/220 reverse transcribes with increased efficiency in human cells, leading to significantly higher infectivity.

Rhesus macaque TRIM5 alleles have divergent antiretroviral specificities.

TRIM5alpha is a potent barrier to cross-species retroviral transmission, and TRIM5alphas from different species have divergent antiretroviral specificities. Multiple TRIM5 alleles circulate within rhesus macaque populations. Here we show that they too have different antiretroviral specificities, highlighting how TRIM5 genotypes contribute to protection in an individual or a population.

Independent evolution of an antiviral TRIMCyp in rhesus macaques.

The antiretroviral restriction factor TRIM5 has recently emerged as an important mediator of innate immunity and species-specific inhibition of retroviral replication in mammals. Selection pressure from pathogenic infection has driven rapid evolution of TRIM5 genes, leading to the antiviral specificities we see today. Remarkably, the New World owl monkey (Aotus trivirgatus) encodes a TRIM5 protein in which the antiviral determinants in the B30.

X box binding protein XBP-1s transactivates the Kaposi's sarcoma-associated herpesvirus (KSHV) ORF50 promoter, linking plasma cell differentiation to KSHV reactivation from latency.

Reactivation of lytic replication from viral latency is a defining property of all herpesviruses. Despite this, the authentic physiological cues for the latent-lytic switch are unclear. Such cues should ensure that viral lytic replication occurs under physiological conditions, predominantly in sites which facilitate transmission to permissive uninfected cells and new susceptible hosts.

Fusion of cyclophilin A to Fv1 enables cyclosporine-sensitive restriction of human and feline immunodeficiency viruses.

TRIM5alpha is a potent intracellular antiviral restriction factor governing species-specific retroviral replication. In the New World species owl monkey the coding region for the viral binding B30.2 domain of TRIM5alpha has been replaced by a cyclophilin A (CypA) pseudogene by retrotransposition.

Isolation of an active Lv1 gene from cattle indicates that tripartite motif protein-mediated innate immunity to retroviral infection is widespread among mammals.

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. Old World monkey TRIM5alpha blocks human immunodeficiency virus type 1 (HIV-1) infectivity, and the human and New World monkey TRIM5alpha proteins are inactive against HIV-1 but active against divergent murine (N-tropic murine leukemia virus [MLV-N]) and simian (simian immunodeficiency virus from rhesus macaque [SIVmac]) retroviruses, respectively. Here we demonstrate antiviral activity of the first nonprimate TRIM protein, from cattle, active against divergent retroviruses, including HIV-1.