OA14.06
Background: A small percentage of HIV-infected people and SIV-infected macaques spontaneously control chronic-phase viral replication. This control is associated with certain major histocompatibility complex (MHC) class I alleles. However, only a minority of individuals with these protective MHC class I alleles suppress viral replication, suggesting additional loci act in concert with MHC genetics to mediate viral control.
Methods: We sequenced whole genomes of 12 SIV-infected Mauritian cynomolgus macaques (6 controllers and 6 progressors), all of whom share the control-associated MHC haplotype termed M1, and identified genetic variation that differentiated controllers from progressors. We assembled a second cohort to prospectively test the role of one such region on SIV control.
Results: We found the highest densities of control-associated variation on chromosomes 2, 3, 7, and 9. One of these regions is near (within ∼400 kilobases) a cluster of genes involved in antigen presentation and CD8(+) effector cell function, including the gene encoding the cytotoxic granule protein granzyme B (GzmB). The inheritance of a single granzyme B allele was associated with chronic-phase control of SIVmac239 (P=0.0001) and higher expression of GzmB by CD3(-)CD8(+) NK cells during early infection. We then assembled a cohort of MHC-identical M1(+) animals to prospectively test whether M1(+) animals with this “protective” GzmB allele control SIV infection; however, only 1 of 4 animals in this cohort controlled SIV.
Conclusions: Although we did not confirm a causal relationship between GzmB genetics and MHC-associated control of SIV, we established a framework for identifying candidate control-associated loci and prospectively testing causality. We are currently assessing whether any of these regions differentiate a larger cohort of Indian-origin rhesus macaque controllers (n=20) from the Indian-origin rhesus population in general (n=144).
