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Sooty Mangabey Genome Insights May Inform AIDS Research

NEW YORK (GenomeWeb) – A team led by researchers at Emory University have sequenced the genome of the sooty mangabey, comparing the DNA to other primates including humans to further research in AIDS resistance.

In contrast to infections with human immunodeficiency virus (HIV) in humans and simian immunodeficiency virus (SIV) in macaques, SIV infection of a natural host, sooty mangabeys (Cercocebus atys), is non-pathogenic despite high viremia. Previous genetic analysis has demonstrated HIV infection of humans appeared through cross-species transmissions of SIV from nonhuman primates, including chimpanzees and sooty mangabeys.

In a study published in Nature this week, the researchers conducted genome-wide comparative analyses of transcript assemblies from mangabeys and AIDS-susceptible species, to identify candidates for host genetic factors that influence susceptibility.

Led by Guido Silvestri, chief of microbiology and immunology at the Yerkes research center at Emory, the team identified several immune-related genes in the mangabey that highlight sequence divergence from macaques (Macaca mulatta) or humans. The most marked variations in the amino acid sequence of mangabeys compared to macaques included immune-regulatory protein intercellular adhesion molecule 2 (ICAM-2) and toll-like receptor-4 (TLR-4).

According to the study, ICAM-2 is a transmembrane glycoprotein expressed on various immune cells and "implicated in lymphocyte homing and recirculation." The team found a misalignment of the ICAM-2 proteins between the two species of primates, and further confirmed the expression of the protein's truncated form in additional mangabey genome sequences.

To test whether the observed genetic difference in ICAM-2 has functional consequences, the team measured ICAM-2 surface expression on immune cells from humans, macaques, and sooty mangabeys, with an antibody that recognizes a conserved epitope between the species. The study noted that the deletion in the ICAM-2 gene is unique to sooty mangabeys, and is not present in other SIV natural hosts or other primates, including baboons and macaques.

Afterward, the team examined alterations of the TLR-4 protein in the sooty mangabey genome. The gene usually triggers activation of pro-inflammatory cytokine induction, maturation, and activation in macrophages, dendritic cells, and other immune cells in response to lipopolysaccharides (LPS) on gram-negative bacteria.

According to the study, "during pathogenic HIV or SIV infections, exacerbated TLR-4 stimulation and concomitant pro-inflammatory signaling elicited by microbial translocation is considered a primary mechanism that underlies HIV-induced chronic immune activation." In the sooty mangabey gene, however, the team found that the variation reduced mRNA expression and secretion of LPS tumor necrosis factor gene in the cells.  

The study's results suggest that an inhibited form of TLR-4 might reduce immune activation in the sooty mangabeys as a response to SIV infection. The sooty mangabeys shared the genetic TLR-4 alteration with other SIV natural hosts, including vervets, drills, and colobus monkeys.

The researchers believe that the data provides a resource for comparative genomic studies of HIV and SIV pathogenesis, and may help clarify mechanisms and identify pathways that SIV-infected mangabeys use to avoid AIDS. The team is planning future sequencing projects that look at additional natural host species.

Silvestri's team believes studying SIV and how its natural hosts coexist could potentially lead to improvements in long-term care of patients infected with HIV, reduce mother-to-infant transmission, and guide the development of an HIV vaccine.