Essays on Science and SocietyGE PRIZE-WINNING ESSAY

Why Old World Monkeys Are Resistant to HIV-1

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Science  07 Dec 2007:
Vol. 318, Issue 5856, pp. 1565-1566
DOI: 10.1126/science.1152905

Humans have been exposed to retroviruses for millions of years. Indeed, a significant portion of our genome consists of endogenous retroviruses—reminders of our vulnerability to past infections. The HIV/AIDS epidemic, which began nearly a century ago when simian immunodeficiency virus (SIV) passed from chimpanzees into a human host, is the latest episode in the longstanding coevolutionary struggle between retroviruses and their hosts.

GE Healthcare and Science are pleased to present the prize-winning essay by Matt Stremlau, a regional winner for North America who is the Grand Prize winner of the GE & Science Prize for Young Life Scientists.

Human immunodeficiency virus type 1 (HIV-1) causes AIDS in humans, and to a lesser extent, in chimpanzees (1, 2). However, not long after the discovery of HIV-1, scientists realized that certain primate species were resistant to HIV-1 infection. In particular, monkeys from Africa and Asia, referred to as Old World monkeys, could not be infected with HIV-1 and did not develop AIDS (3). This discovery brought both excitement and frustration. The block to HIV-1 replication in Old World monkey cells hindered efforts to develop an animal model for testing drugs and vaccines. On the other hand, Old World monkeys had evolved for millions of years in Africa—the epicenter of the current HIV-1 epidemic. Perhaps exposure to past HIV-1-like epidemics led to the emergence of an antiviral defense that protected them against HIV-1.

Determining the cause of HIV-1 resistance in Old World monkey cells stymied HIV researchers for nearly two decades. An early view was that the block resulted from expression of an incompatible receptor on the surface of Old World monkey cells. However, identification of the HIV-1 co-receptor in the mid-1990s disproved this hypothesis. Subsequent studies demonstrated that HIV-1 could enter Old World monkey cells, but a block that targeted the viral capsid prevented the establishment of a permanent infection (4).

Using a genetic screen, we identified TRIM5α as the primary block to HIV-1 replication in Old World monkey cells (5). The expression of rhesus monkey TRIM5α in human cells potently inhibited HIV-1 infection and prevented the accumulation of reverse transcripts. Importantly, reducing the expression of TRIM5α in rhesus monkey cells with small interfering RNA relieved the block to HIV-1.

We initially hypothesized that TRIM5α functioned as a cofactor necessary for capsid uncoating. However, subsequent findings argued against this hypothesis. First, knocking down human TRIM5α showed no effects on HIV-1 replication in human cells. Second, rodent cells, which do not express TRIM5α, supported HIV-1 infection if engineered to express an appropriate receptor. Finally, human TRIM5α does not associate with the HIV-1 capsid in biochemical assays. Thus, TRIM5α appeared to have evolved primarily as an inhibitory factor aimed at thwarting viral replication, rather than a host factor co-opted by HIV-1 to promote infection.

Further evidence that TRIM5α functions primarily as a modulator of innate immunity against retroviruses emerged from comparing the sequences of TRIM5 α orthologs from different primate species. We found dramatic length variation, and an unusually high ratio of nonsynonymous to synonymous changes in the C-terminal domain of TRIM5α orthologs (6) suggesting that TRIM5α has been subjected to strong positive selective pressure during primate evolution. Furthermore, episodic changes in the TRIM5α C-terminal domain coincide with periods of retroviral epidemics (6). Indeed, a recent report suggests that selective changes occurred in the TRIM5α lineage during acquisition of resistance to an ancient retrovirus. These changes may have had the unfortunate consequence of attenuating TRIM5α potency against HIV-1 (7).

Does TRIM5α have the ability to block infection by other retroviruses? We found that TRIM5α from various Old World monkey species conferred potent resistance to HIV-1, but not SIV (5). New World monkey TRIM5α proteins, in contrast, blocked SIV but not HIV-1 infection. Human TRIM5α inhibited N-MLV and EIAV replication (8, 9). Thus, the variation among TRIM5 orthologs accounts for the observed patterns of post-entry blocks to retroviral replication among primate species.

To determine why Old World monkey TRIM5α but not human TRIM5 α, potently blocks HIV-1, we systematically altered the human sequence to more closely resemble the monkey sequence. Remarkably, we found that a single amino acid determines the antiviral potency of human TRIM5α (10). If a positively charged arginine residue in the C-terminal domain of human TRIM5α is either deleted or replaced with an uncharged amino acid, human cells gain the ability to inhibit HIV-1 infection (11). Perhaps some humans have already acquired this change and are naturally resistant to HIV-1 infection.

Blocking HIV

Rhesus Monkey TRIM5α targets the viral capsid to block HIV-1 replication.

How does TRIM5α inhibit infection? Following viral entry into the host cell, the capsid core, which encases the viral RNA, must disassemble to allowreverse transcription of the viral RNA into DNA (see the figure). Host factors that mediate capsid uncoating are presumed to exist, but have not been identified.

Because early studies demonstrated that sequences within the capsid determined susceptibility to the block, we asked if TRIM5α associated with the capsid. The association of TRIM5α with the capsid was dependent on the C-terminal domain and the association was necessary for restriction (12). TRIM5α proteins from various Old World monkey species bound the HIV-1 capsid; however, TRIM5α variants that did not restrict HIV, such as New World monkey TRIM5α, did not associate with the capsid cores. Human TRIM5α exhibited a very weak association with the HIV-1capsid cores, explaining the lower potency of human TRIM5α in blocking HIV-1 infection (12).

Why does association of TRIM5α with the viral capsid inhibit infection? Previous studies of HIV-1 capsid mutants suggest that capsid disassembly may be a temporally regulated process with either too rapid or too slow disassembly compromising viral infectivity (13). By following the fate of viral cores in the cytosol just after viral entry, we found that TRIM5α caused capsid cores to undergo rapid, and premature, disassembly (12, 14). Accelerated uncoating of the capsid correlated with the ability of TRIM5α variants from different species to restrict HIV-1, SIV, and N-MLV infections. Future studies are needed to determine how TRIM5α promotes rapid disassembly of capsid and why accelerated disassembly is detrimental to infection. Perhaps accelerated disassembly of the retroviral capsid prematurely exposes the viral RNA or viral enzymes to degradation.

The discovery of TRIM5α not only answered a long-standing question in the HIV field, it also revealed a new pathway that protects cells from retroviral infection. The human genome encodes more than 50 members of the TRIM family. Recently, TRIM25 was shown to be essential for RIG-I-mediated antiviral activity (15) and TRIM family members such as TRIM1, TRIM19 (PML), and TRIM22, may block other viruses (16).

At a time when policy-makers and the public express frustration over our inability to produce an HIV vaccine, it is hoped that the discovery of TRIM5α will precipitate new ideas for how to protect human hosts from retroviral infection. Perhaps in the case of retroviruses, innate intracellular immunity mediated by factors like TRIM5α and APOBEC play a particularly crucial role. Efforts aimed at enhancing these innate immune defenses may ultimately prove to be more effective at protecting humans from HIV than vaccine strategies aimed primarily at stimulating humoral or cellular immune responses.


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