Conditional Immune Escape During Chronic Simian Immunodeficiency Virus Infection
Check out our new paper in the Journal of Virology detailing the evolution of within-host simian immunodeficiency virus, or SIV, the monkey version of HIV. We observed that SIV has a harder time escaping the immune systems of hosts having extra variation in the genes encoding their immune system receptors; thus escape from the immune system is somewhat “conditional” upon the genetic makeup of the infected individual. To read more and learn about the potential applications of this work, read the details below.
ABSTRACT:
Anti-HIV CD8 T cells included in therapeutic treatments will need to target epitopes that do not accumulate escape mutations. Identifying which epitopes do not accumulate variants, but retain immunogenicity, depends on both host MHC genetics and the likelihood for an epitope to tolerate variation. We previously found that immune escape during acute SIV infection is conditional; the accumulation of mutations in T cell epitopes is limited and the rate of accumulation depends on the number of epitopes being targeted. We now test the hypothesis that conditional immune escape extends into chronic SIV infection and that epitopes with preserved wild-type sequence have the potential to elicit epitope-specific CD8 T cells. We deep sequenced SIV from Mauritian cynomolgus macaques (MCMs) that were homozygous and heterozygous for the M3 MHC haplotype and had been infected with SIV for about one year. When interrogating variation within individual epitopes restricted by M3 MHC alleles, we found three categories of epitopes, that we called Categories A, B, and C. Category B epitopes readily accumulated variants in M3 homozygous MCMs, but this was less common in M3 heterozygous MCMs. We then determined that chronic CD8 T cells specific for these epitopes were more likely preserved in the M3 heterozygous MCMs, when compared to M3 homozygous MCMs. We provide evidence that epitopes known to escape from chronic CD8 T cell responses in animals that are homozygous for a set of MHC alleles are preserved and retain immunogenicity in a host that is heterozygous for the same MHC alleles.
IMPORTANCE. Anti-HIV CD8 T cells that are part of therapeutic treatments will need to target epitopes that do not accumulate escape mutations. Defining these epitope sequences is a necessary precursor to designing approaches that enhance the functionality of CD8 T cells with the potential to control virus replication during chronic infection or after reactivation of latent virus. Using MHC homozygous and heterozygous Mauritian cynomolgus macaques, we now provide evidence that epitopes known to escape from chronic CD8 T cell responses in animals that are MHC homozygous are preserved and retain immunogenicity in a host that is heterozygous for the same MHC alleles. Importantly, our findings support the conditional immune escape hypothesis, such that the potential to present a greater number of CD8 T cell epitopes within a single animal can delay immune escape in targeted epitopes. As a result, certain epitope sequences can retain immunogenicity into chronic infection.
FULL STUDY:
Gellerup D, Balgeman A, Nelson CW, Ericsen A, Scarlotta M, Hughes AL, O’Connor S (2015) Conditional immune escape during chronic SIV infection. Journal of Virology 90(1):545-52.