Gene neighbors may have taken turns battling retroviruses

December 20, 2007

SEATTLE - A cluster of antiviral genes in humans has likely battled retroviral invasions for millions of years. New research by Sara Sawyer, Ph.D., a postdoctoral research fellow in the Basic Sciences Division at Fred Hutchinson Cancer Center, now finds that in addition to the previously identified TRIM5 gene that can defend against retroviruses like HIV, a related gene right next door, called TRIM22, may have participated in antiviral defense.

These findings, published Dec. 21 in the open-access journal PLoS Pathogens, show that both TRIM5 and TRIM22 exhibit the hallmarks of rapid evolutionary adaptation (positive selection) required to defeat new retroviral invasions. However, their genetic proximity has resulted in positive selection in either TRIM5 or TRIM22, but not both. This suggests that at various times over the past millions of years, both genes alternately have defended against retroviruses.

"The identification of novel antiviral genes is important to understanding the genetic basis of differential human susceptibility to viral diseases," said Sawyer, the paper's lead author. She conducted the research in collaboration with senior author Harmit Singh Malik, Ph.D., of the Center's Basic Sciences Division and co-author Michael Emerman, Ph.D., of the Center's Human Biology Division.

The recent identification of TRIM5 as one of the genetic means that protect rhesus monkeys against HIV infection has opened up a new area of research in HIV biology. Previous work had shown that TRIM5 has been locked in genetic conflict with retroviruses throughout most of primate evolution, characterized by a higher than expected rate of amino acid change, referred to as positive selection.

The new Hutchinson Center study now suggests that one of the closest genes in evolutionary age and genetic proximity, TRIM22, also has the same hallmarks. However, unlike TRIM5, TRIM22 did not have antiviral activity against any modern viruses tested. "We are at an interesting point in this kind of research," Emerman said. "Instead of looking at which unknown antiviral gene protected against a given virus, we now need to ask which unknown virus may have been defeated by a given candidate antiviral gene. It is possible that this virus no longer exists today, but may have only existed in our evolutionary past."

TRIM5 and TRIM22 also appear to have discordant evolution in other mammals. Whereas the cow genome contains an expansion of TRIM5 genes and no TRIM22 gene, the dog genome encodes TRIM22 but has lost TRIM5. In spite of this evolutionary discordance, amino acid residues in TRIM22 found to be under positive selection are in remarkable proximity to those found previously to be critically important for TRIM5's antiviral activity. Thus, despite an ancient separation of the TRIM5 and TRIM22 genes, the "rules" by which they might combat viruses appear to be constant.

"This research was conducted via computer analysis and in tissue-culture cells and has not yet been tested in model organisms. Nonetheless, the evolutionary means to identify other potential antiviral TRIM genes in the human genome may identify novel candidates for therapeutic intervention," Malik said.
-end-
Grants from amfAR (The Foundation for AIDS Research), the National Institutes of Health, the Searle Scholars Program and the Burroughs Wellcome Fund supported this research.

At Fred Hutchinson Cancer Research Center, our interdisciplinary teams of world-renowned scientists and humanitarians work together to prevent, diagnose and treat cancer, HIV/AIDS and other diseases. Our researchers, including three Nobel laureates, bring a relentless pursuit and passion for health, knowledge and hope to their work and to the world. For more information, please visit fhcrc.org.

Fred Hutchinson Cancer Research Center

Related HIV Articles from Brightsurf:

BEAT-HIV Delaney collaboratory issues recommendations measuring persistent HIV reservoirs
Spearheaded by Wistar scientists, top worldwide HIV researchers from the BEAT-HIV Martin Delaney Collaboratory to Cure HIV-1 Infection by Combination Immunotherapy (BEAT-HIV Collaboratory) compiled the first comprehensive set of recommendations on how to best measure the size of persistent HIV reservoirs during cure-directed clinical studies.

The Lancet HIV: Study suggests a second patient has been cured of HIV
A study of the second HIV patient to undergo successful stem cell transplantation from donors with a HIV-resistant gene, finds that there was no active viral infection in the patient's blood 30 months after they stopped anti-retroviral therapy, according to a case report published in The Lancet HIV journal and presented at CROI (Conference on Retroviruses and Opportunistic Infections).

Children with HIV score below HIV-negative peers in cognitive, motor function tests
Children who acquired HIV in utero or during birth or breastfeeding did not perform as well as their peers who do not have HIV on tests measuring cognitive ability, motor function and attention, according to a report published online today in Clinical Infectious Diseases.

Efforts to end the HIV epidemic must not ignore people already living with HIV
Efforts to prevent new HIV transmissions in the US must be accompanied by addressing HIV-associated comorbidities to improve the health of people already living with HIV, NIH experts assert in the third of a series of JAMA commentaries.

The Lancet HIV: Severe anti-LGBT legislations associated with lower testing and awareness of HIV in African countries
This first systematic review to investigate HIV testing, treatment and viral suppression in men who have sex with men in Africa finds that among the most recent studies (conducted after 2011) only half of men have been tested for HIV in the past 12 months.

The Lancet HIV: Tenfold increase in number of adolescents on HIV treatment in South Africa since 2010, but many still untreated
A new study of more than 700,000 one to 19-year olds being treated for HIV infection suggests a ten-fold increase in the number of adolescents aged 15 to 19 receiving HIV treatment in South Africa, according to results published in The Lancet HIV journal.

Starting HIV treatment in ERs may be key to ending HIV spread worldwide
In a follow-up study conducted in South Africa, Johns Hopkins Medicine researchers say they have evidence that hospital emergency departments (EDs) worldwide may be key strategic settings for curbing the spread of HIV infections in hard-to-reach populations if the EDs jump-start treatment and case management as well as diagnosis of the disease.

NIH HIV experts prioritize research to achieve sustained ART-free HIV remission
Achieving sustained remission of HIV without life-long antiretroviral therapy (ART) is a top HIV research priority, according to a new commentary in JAMA by experts at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health.

The Lancet HIV: PrEP implementation is associated with a rapid decline in new HIV infections
Study from Australia is the first to evaluate a population-level roll-out of pre-exposure prophylaxis (PrEP) in men who have sex with men.

Researchers date 'hibernating' HIV strains, advancing BC's leadership in HIV cure research
Researchers have developed a novel way for dating 'hibernating' HIV strains, in an advancement for HIV cure research.

Read More: HIV News and HIV Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.