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August 03, 2010

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Scientists learning how monkeys fend off “monkey AIDS”

March 10, 2010
Courtesy of Science 
Translational Medicine
and World Science staff

Bi­ol­o­gists say they have dis­cov­ered a key rea­son why mon­key im­mune sys­tems are usu­ally able to keep the mon­key ver­sion of the vi­rus be­hind AIDS in check.

The ex­plana­t­ion is a more di­verse im­mune re­sponse, ac­cord­ing to re­search­ers, who add that the find­ings may be use­ful for de­sign­ing an AIDS vac­cine for hu­mans.

The path­o­gen that causes AIDS—in hu­mans known as HIV, or hu­man im­mun­od­e­fi­cien­cy vi­rus—has a close rel­a­tive that in­fects mon­keys. This is called SIV, or sim­i­an im­mun­od­e­fi­cien­cy vi­rus. 

Di­a­gram of how a typ­i­cal retro­vi­rus, a vi­rus of the fam­i­ly to which HIV be­longs, in­vades cells. At left, the vi­rus pen­e­trates the out­er de­fenses to en­ter the cell. It then con­verts its ge­net­ic ma­te­ri­al in­to DNA, the main form of ge­net­ic in­for­ma­tion stor­age used by an­i­mals. The vi­ral DNA then makes its way in­to the nu­cle­us, where it in­te­grates it­self with the an­i­mal's own DNA. Next the vi­ral DNA starts pro­duc­ing cop­ies of a new vi­rus, shown emerg­ing from the cell at right.

Both vi­ruses are nearly iden­ti­cal in their ge­net­ic struc­ture. Like oth­er vi­ruses, they are par­t­i­cles con­tain­ing genes that al­low them to in­vade the body by hi­jack­ing its cel­lu­lar ma­chin­ery and us­ing it to rep­li­cate them­selves. 

But de­spite the si­m­i­lar­ity in the two vi­ruses, mon­keys sel­dom suf­fer se­vere con­se­quenc­es from their own form of it, though hu­man HIV leads to the deadly scourge of AIDS.

Some stud­ies of HIV-infected peo­ple have in­di­cat­ed that the dis­ease is bet­ter con­trolled when the pa­tient’s im­mune re­sponse is broader. This means in par­tic­u­lar that more parts of the vi­rus are rec­og­nized by the body’s T cells, white blood cells that play a key role in or­ches­trat­ing a tai­lored im­mune re­sponse to a dis­ease threat.

In the new stu­dy, pub­lished in the March 10 is­sue of the re­search jour­nal Sci­ence Transla­t­ional Med­i­cine, re­search­ers used a mon­key spe­cies called Mau­ri­tian cy­no­mol­gus macaques to test wheth­er a more di­verse im­mune re­sponse leads to bet­ter dis­ease con­trol.

T cells are able to rec­og­nize in­vaders be­cause the body pro­duces spe­cial mo­le­cules that serve as mark­ers for the im­mune sys­tem to dis­tin­guish cells that be­long in the body from those that don’t. The genes that make these mo­le­cules are known as MHC, or ma­jor his­to­com­pat­ibil­ity com­plex, genes. More di­ver­sity in these genes leads to more di­ver­sity in their pro­ducts.

The an­a­lyzed mon­keys were un­usu­al in that they came from a popula­t­ion with lim­it­ed MHC ge­net­ic di­vers­ity, said the in­ves­ti­ga­tors, Shel­by O’­Con­nor of the Uni­vers­ity of Wis­con­sin, Mad­i­son and col­leagues. This al­lowed the team to iden­ti­fy an­i­mals that, for a giv­en set of MHC genes, had ei­ther two iden­ti­cal cop­ies of each gene or two dif­fer­ent forms.

They found that the pri­ma­tes with low­er MHC di­vers­ity had nearly 80 times more of the vi­rus in their blood than those with a great­er num­ber of dif­fer­ent MHC genes. These more for­tu­nate mon­keys had about 20 MHC genes pre­s­ent as sin­gle cop­ies, com­pared to only 12 un­ique genes for their more badly af­fect­ed peers.

By ex­am­in­ing the se­quences of the vi­ruses repli­cat­ing in these an­i­mals, the re­search­ers ob­tained a de­tailed snap­shot of the im­mune re­sponse to SIV. The da­ta sug­gest that an­i­mals with a more di­verse im­mune re­sponse gen­er­at­ed more T cells and so were more ef­fec­tive at curb­ing the vi­rus’s abil­ity to rep­li­cate, ac­cord­ing to O’­Con­nor and col­leagues. The study sup­ports the no­tion that vac­cines should be de­signed to elic­it the broad­est pos­si­ble cel­lu­lar im­mune re­sponse to HIV, the group added.

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Biologists say they have discovered a key reason why monkey immune systems are usually able to keep monkey version of the virus behind AIDS in check. The explanation is a more diverse immune response, according to researchers, who add that the findings may be useful for designing an AIDS vaccine for humans. Called HIV, or human immunodeficiency virus, in in humans, the pathogen that causes AIDS has a close relative that infects monkeys. This is called SIV, or simian immunodeficiency virus. Both viruses are nearly identical in their genetic structure. Like other viruses, they are particles containing genes that allow them to invade the body by hijacking its cellular machinery and using it to replicate themselves. But despite the similarity in the two viruses, monkeys seldom suffer severe consequences from their own form of it, though human HIV leads to the deadly scourge of AIDS. Some studies of HIV-infected people have indicated that the disease is better controlled when the individual’s immune response is broader. This means in particular that more parts of the virus are recognized by the immune system’s T cells, white blood cells that play a key role in orchestrating a tailored immune response to a disease threat. In the new study, to appear in the March 10 issue of the research journal Science Translational Medicine, researchers used a monkey species called Mauritian cynomolgus macaques to test whether a more diverse immune response leads to better disease control. T cells are able to recognize invaders because the body produces special molecules that serve as markers for the immune system to distinguish cells that belong in the body from those that don’t. The genes that make these molecules are known as MHC, or major histocompatibility complex, genes. The analyzed monkeys were unusual in that they came from a population with limited MHC genetic diversity, said the investigators, Shelby O’Connor of the University of Wisconsin, Madison and colleagues. This allowed the team to identify animals that, for a given set of MHC genes, had either two identical copies of each gene or two different forms. They found that the primates with lower MHC diversity had nearly 80 times more of the virus in their blood than those with a greater number of different MHC genes. These more fortunate monkeys had about 20 MHC genes present as single copies, compared to only 12 unique genes for their more badly affected peers. By examining the sequences of the viruses replicating in these animals, the researchers obtained a detailed snapshot of the immune response to SIV. The data suggest that animals with a more diverse immune response generated more T cells and so were more effective at curbing the virus’s ability to replicate, according to O’Connor and colleagues. The study supports the notion that vaccines should be designed to elicit the broadest possible cellular immune response to HIV, the group added.