Replication trimmed back

A long-standing point of intrigue has been how certain non-human primates are resistant to HIV-1. The discovery in macaque monkeys of a protein that resides in mysterious cytoplasmic bodies holds the key.

Mammals have lived with retroviruses throughout their history. To avoid the detrimental effects of these RNA viruses, mammals have evolved a large number of genes to inhibit their replication. Certain non-human primates strongly ‘restrict’ HIV-1, blocking infection soon after this retrovirus enters the cell and before it starts making DNA from its RNA template during reverse transcription. Sodroski and colleagues (page 848 of this issue1) have now isolated a gene, known as TRIM5α, that is responsible for this restriction in rhesus macaques. The work uncovers key players in the early steps of virus replication, and may lead to new approaches towards inhibiting HIV-1.

The prototypical gene blocking early events in the retroviral life cycle, the Fv1 locus, was first characterized in the 1970s. Fv1 blocks particular mouse leukaemia viruses (MuLVs) soon after reverse transcription. Whether or not a virus falls victim to Fv1 depends on its coat protein; in particular, a single residue at position 110 of the MuLV capsid coat determines this sensitivity. An important feature of the block is that it can be overcome if the virus is present in extremely high numbers. Fv1 was found to correspond to the capsid gene of a virus resident in the mouse genome, suggesting that it might compete with the incoming virus for critical host targets2. How Fv1 acts remains unclear, but there must be a specific interaction with the capsid protein of the incoming virus. Subsequently, many human cell lines have also been found to be resistant to particular MuLVs, an activity conferred by a gene named Ref1 (refs 3, 4). Remarkably, the capsid is also targeted, and virus sensitivity is again controlled by residue 110. The Ref1 gene of humans has not yet been isolated.

Excitement in the field increased with the realization that restriction was not limited to mouse viruses, but that many primates, including rhesus macaques and owl monkeys, restrict HIV-1 (refs 3, 59). The gene responsible, dubbed Lv1 (ref. 7), in some species restricted HIV-1 but not the related monkey virus SIVMAC. From a comparison of viruses containing portions of both HIV-1 and SIV genomes, the target of Lv1 was pinpointed to be the HIV-1 capsid protein10,11. Sodroski and colleagues1 have now isolated the gene responsible from a rhesus monkey complementary DNA library by selecting for cells that manifest resistance to HIV-based vectors. The success of this approach is testimony to the power of direct genetic selections. The active cDNA encodes TRIM5α.

TRIM5α, a protein resulting from differential processing of TRIM5 transcripts, passes all the tests as the main HIV-1 resistance factor present in primates1. First, expression of the cDNA in human cells renders them resistant to HIV-1 infection, and the induced block occurs at the right stage of the viral life cycle. The rhesus TRIM5α cDNA has potent antiviral activity, but its human counterpart does not, despite both proteins being expressed well. And whereas the rhesus gene product is active against HIV-1, it is only very weakly active against SIVMAC, and not at all active against MuLVs. Furthermore, TRIM5α blocks versions of the viruses that contain both macaque and human sequences — but only if the HIV-1 capsid region is present. Thus TRIM5α targets the HIV-1 capsid protein, as expected. Finally, ‘knock-down’ of TRIM5α, using small interfering RNA molecules that specifically target TRIM5α transcripts for destruction, relieved the block against HIV-1 in rhesus cells, but had no effect on MuLV infection.

What is known about TRIM proteins? Not much. They are defined by a cluster of three different protein motifs: a RING motif, which is rich in cysteines and binds zinc; one or two so-called B boxes, which also bind zinc; and a coiled-coil domain that is probably involved in the formation of protein complexes. All individual TRIM proteins can probably aggregate with their peers. Some might also form alliances with other TRIM proteins.

A look through the human genome reveals at least 37 TRIM family members12. The most famous member is PML, which can fuse with the retinoic acid receptor to cause some forms of leukaemia. PML also shows antiviral activity against many viruses. It resides in mysterious nuclear bodies of uncertain function, to which it may localize other proteins and selected messenger RNAs13. Each of the various TRIM proteins seems to localize to particular compartments within cells, forming discrete structures to which they entice other proteins. TRIM5 forms cytoplasmic speckles12, consistent with the fact that it blocks HIV-1 infection before reverse transcription.

How might TRIM5α block an incoming virus in the rhesus macaques? The work by Sodroski and colleagues1 offers a few possible explanations. Infection of human cells by HIV-1 induces PML to move into the cytoplasm and bind the virus14; the ability of TRIM proteins to aggregate into large structures and to attract other proteins into them suggests that TRIM5α might be binding and trapping the incoming virus in the rhesus macaques. Another possibility is that TRIM5α could influence whether, and how, the capsid is modified, and thus its localization. One such modification, reported for PML, is the addition of a ‘SUMO’ group. There are hints that the capsid proteins of MuLV and HIV-1 are indeed SUMOylated, and that this may be required for infection. Alternatively, TRIM5α might interfere with the normal uncoating of the viral RNA core that precedes reverse transcription. This could involve interactions with cyclophilin A, a protein thought to affect the stability of the HIV-1 core. Indeed, there are strong hints that HIV-1 restriction is modulated by cyclophilin A (refs 10, 15).

A final possibility is that TRIM5α initiates the degradation of the incoming HIV-1 particle. Other TRIM5 isoforms, including TRIM5δ, behave as ubiquitin ligases16 — they add ubiquitin to other proteins, which labels them for destruction by the proteasome, the cell's disposal system. Perhaps TRIM5α could transfer ubiquitin directly to the capsid. In support of this idea, treating human cells with proteasome inhibitors increased their susceptibility to HIV-1 infection17. Time will tell which of these ideas, if any, pan out.

Several straightforward questions arise. Does TRIM5α bind directly to the HIV-1 capsid protein? Does it cause its relocalization, modification or degradation? Does TRIM5α comprise a subunit of a ubiquitin ligase — or of a similarly acting SUMO transferase? Is reverse transcription itself blocked by TRIM5α, or is the resultant DNA degraded after synthesis? To what else might TRIM5α bind? Are TRIM proteins somehow involved in the mechanism of action of the Fv1, or the human Ref1, resistance genes?

All we can say for certain is that right now many laboratories are working furiously to be the first to find the answers to these questions. When the mechanism of action of TRIM5α is uncovered, the next goal will be to recreate its effects in a therapeutic treatment.


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Goff, S. Replication trimmed back. Nature 427, 791–793 (2004).

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