Key Point:

Researchers have discovered a protein in monkeys—TRIM5alpha—that stops replication of HIV-1 within four hours of infection.

BOSTON—Human immunodeficiency virus (HIV) permanently joins its genetic material with the DNA of infected cells. Thus, once established, retroviruses like HIV cannot be eliminated. In an attempt to discover why some monkeys are resistant to HIV, researchers at Harvard University’s Dana-Farber Cancer Institute in Boston have identified a protein in Old World monkeys (TRIM5alpha) that restricts the early steps of HIV infection in cells.[1]

Two sets of human HeLa cells—ones that stably expressed rhesus monkey TRIM5alpha (TRIM5alpha[rh]) and control cells containing empty vector—were incubated with varying amounts of HIV-1, simian immunodeficiency virus (SIV), or murine leukemia virus (MLV).[1] TRIM5alpha[rh] efficiently blocked HIV-1 but had only a slight effect on SIV and no effect on MLV.

The investigators then used a polymerase chain reaction (PCR) assay to pinpoint when HIV-1 infection is blocked by TRIM5alpha[rh]. They incubated HIV-1 with either HeLa cells expressing TRIM5alpha[rh] or control HeLa cells. After two hours, the levels of early reverse transcripts were comparable in both cell groups. Later, however, reverse transcripts were barely detectable in the TRIM5alpha[rh]-expressing cells. “TRIM5alpha inhibited HIV-1 within the first four hours of infection,” said Joseph G. Sodroski, MD, one of the study’s principal authors and a Professor of Pathology at Harvard.

Interestingly, reverse transcripts were still present in abundance in the control cells. Thus, HIV-1 was impaired soon after the virus entered cells expressing TRIM5alpha[rh]: The protein either disrupts the synthesis of viral DNA or accelerates its decay.

SPECIES-SPECIFIC VIRUSES

TRIM5alpha[rh] and its human counterpart, TRIM5alphahu, have a number of differences in their genetic sequences; the investigators hypothesized that these differences account for why humans, but not Old World monkeys, can be infected by HIV-1. To test this, the two proteins were expressed in HeLa cells. The human TRIM5alpha protein inhibited HIV-1 infection much less efficiently than did TRIM5alpha[rh]. The investigators noted that this probably contributes to the differences in HIV susceptibility between species.

When variants of the TRIM5alpha[rh] protein were compared with wild-type TRIM5alpha[rh] to test their ability to stop HIV replication, only the wild-type protein effectively inhibited HIV-1. When the expression of TRIM5alpha[rh] was down-regulated, the efficiency with which HIV-1 could infect cells was increased, leading the investigators to conclude that TRIM5alpha[rh] is essential for the early block to HIV-1 in Old World monkeys. The fact that TRIM5alpha[rh] is more efficient at blocking replication of HIV-1 than of SIV illustrates how each virus evolved in its respective host species to interact as little as possible with endogenous TRIM5alpha.

Although TRIM5alpha[rh] has the potential for use in an HIV vaccine, Dr. Sodroski emphasized that “it would have to be used in a different way than classical viral vaccines are used.” He added that whether TRIM5alpha[rh] may be able to inhibit other human viruses is currently under investigation; it is too early to predict all of the therapeutic implications of his team’s findings.

Meanwhile, said Dr. Sodroski, “There are many avenues opened up by our discovery. These are limited only by the imagination of the researchers.”

—Gale Jurasek

Reference
1. Stremlau M, Owens CM, Perron MJ, et al. The cytoplasmic body component TRIM5alpha restricts HIV-1 infection in Old World monkeys. Nature. 2004;427:848-853.

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