Restriction of HIV-1 by TRIM5α

Type 1 interferon suppresses viral replication by upregulating the expression of interferon-stimulated genes with diverse antiviral properties. The replication of human immunodeficiency virus type 1 (HIV-1) is naturally inhibited by interferon, with the steps between viral entry and chromosomal integration of viral DNA being notably susceptible. The interferonstimulated gene myxovirus resistance 2 has been defined as an effective postentry inhibitor of HIV-1, but is only partially responsible for interferon's suppressive effect. Human TRIM5α, in contrast with many nonhuman orthologues, has not generally been ascribed substantial HIV-1 inhibitory function, a finding attributed to ineffective recognition of cytoplasmic viral capsids by TRIM5α. Here, researchers demonstrate that interferon-α-mediated stimulation of the immunoproteasome, a proteasome isoform mainly present in immune cells and distinguished from the constitutive proteasome by virtue of its different catalytic β-subunits, as well as the proteasome activator 28 regulatory complex, and the associated accelerated turnover of TRIM5α underpin the reprogramming of human TRIM5α for effective capsid-dependent inhibition of HIV-1 DNA synthesis and infection. These observations identify a mechanism for regulating human TRIM5α antiviral function in human cells and rationalize how TRIM5α participates in the immune control of HIV-1 infection.

HIV-1 cA determines IFN-α-induced restriction by human TRIM5α

TRIM5α-mediated inhibition is initiated through the recognition of viral capsids in the cytoplasm, leading to their fragmentation and the suppression of reverse transcription (viral DNA synthesis). The suppression of HIV-1 by human TRIM5α is not, therefore, the result of a generalized induction of TRIM5α antilentiviral activity by IFN-α. Consistent with our findings with the endogenous gene, ectopically expressed human TRIM5α inhibited HIV-1 infection very effectively when IFN-α was added. Removing the SPRY domain abolished this effect, whereas including mutations (R332G and R335G) that have previously been shown to confer anti-HIV-1 activity still did so to a minor extent and without compromising activation by IFN-α.

HIV-1 restriction by human TRIM5α is regulated by the immunoproteasome

The immunoproteasome is predominantly expressed in cells of haematopoietic origin in response to inflammatory cytokines such as IFN, and differs from the constitutive proteasome with respect to the identity of its three proteolytic β-subunits and dependence on the PA28 regulatory complex. With some variation, all five proteins accumulated to higher levels in the presence of IFN-α. All knockdowns conferred a degree of relief from inhibition by IFN-α, with PA28A silencing being the most effective to the extent that the magnitude of rescue matched that observed with silencing of TRIM5α itself. The functional interdependence of the IFN-α-activated anti-HIV-1 phenotypes of human TRIM5α and the immunoproteasome was established by the substantial diminution in the level of rescue from IFN-α inhibition that was observed after PA28A silencing in cells that lacked TRIM5α.

TRIM5α restriction has been widely perceived to be important for preventing zoonotic retroviral infections, whereas being ineffective in controlling viruses in their natural hosts. Although there have been sporadic reports of human TRIM5α affecting HIV-1 infection either by suppression of certain HLA-associated CTL escape mutant viruses or by inducing autophagy in Langerhans cells, our findings demonstrate broad, nonstrain-specific inhibition of HIV-1 infection by human TRIM5α.

TRIM5 Antibodies