Simian immunodeficiency viruses (SIV) naturally infect a variety of nonhuman primates of African origin. SIV seroprevalence is particulariy high in some troops of sooty mangabeys (Cercocebus atys atys). While SIV share many structural and biological properties with human immunodeficiency viruses (HIV), they rarely induce AIDS in their natural hosts. The causative factors that underlie the ability of the same SIV isolate to induce disease in one species and a chronic but benign infection in another species are host genetic factors that have to a large extent been little characterized. A central component of these genetic factors is the Major Histocompatibiltiy Complex (MHC), within which the MHC class I and II antigen-presenting genes reside, alongside a large number of other genes, including some that control MHC-I and -II expression and genes that are in other ways involved in the host immune response. As the human genome project has shown many times over, the establishment of framework genomic DNA sequences can provide fundamental support for, and extension of, a plethora of basic and clinical research studies that are now advancing human health. However, as the human genome project has also shown, establishing framework DNA sequences for regions of the genome harboring immune response genes, including notably the MHC region, is difficult and has largely been ignored by those efforts. We propose to combine commercially available advancements in sequencing technology with methods proven to produce high quality genomic sequence to yield a completed phased genomic DNA sequence of the sooty mangabey MHC as a resource for future studies, including comparative analysis with the rhesus macaque MHC sequence, which we previously completed. Such a resource will provide a direction for functional testing of genetic factors that relate to long- term nonprogression of SIV infection in rhesus macaques, and then to the same phenotype for HIV-1 infection in humans. The identification of causative host genetic factors that control HIV-1 infection in humans would have important implications for disease treatment as well as for vaccine design. To accomplish these objectives we propose to carry out the following specific aims: (1) To derive complete and high quality genomic sequences of the major histocompatibility complex (MHC) and killer Ig-like receptor (KIR) regions from the sooty mangabey. (2) To annotate and make available the derived sequences with an emphasis towards relevance to the SIV research community.
(provided by applicant): Simian immunodeficiency viruses (SIV) naturally infect a variety of nonhuman primates and share many structural and biological properties with human immunodeficiency viruses (HIV), but rarely induce AIDS in their natural hosts. We propose to produce a completed phased genomic DNA sequence of the sooty mangabey major histocompatibility complex (MHC) as a resource for future studies using animal models of human HIV-1 infection. This resource will contribute to identifying causative host genetic factors controlling HIV-1 infection in humans, providing direction for disease treatment as well as for vaccine design.
|Goodridge, Jodie P; Burian, Aura; Lee, Ni et al. (2013) HLA-F and MHC class I open conformers are ligands for NK cell Ig-like receptors. J Immunol 191:3553-62|