Treating and preventing infectious disease requires not just an understanding of the infectious agent, but also of the underlying genetics governing susceptibility of the host. Traditionally, this amounted to a focus on genes of the adaptive immune system. However, equally important are those cellular factors that interact directly with viral macromolecules, either as positive cofactors for virus replication, or as intrinsic host mechanisms for suppressing viral infection. The latter includes the restriction factors - with TRIM5, APOBEC3, BST2/tetherin, SAMHD1, Schlafen-11 and Mx2 being well-studied examples. While individual restriction factors have been extensively studied in isolation (typicall by overexpression in heterologous cell lines), their combined impact at the level of the host organism and the host-population has not been carefully examined. While the antiviral activity of these restriction factors in cell culture is consistent with a role in preventing cross-species transmission of primate lentiviruses in nature, there are little-to-no data that directly support tis hypothesis. In this proposal, we will track the evolution of primate lentiviruses during the earliet stages of adapting to a non-native host (SIVsmm in rhesus macaques) using a combination of next- generation sequencing and bioinformatics tools customized for studying RNA virus populations (AIMS 1 & 3); and establish the biological significance of individual restrictions in terms of the evolutionary consequences of resistance for relative viral fitness (AIM 2).
This study will determine the extent to which host genes act as genetic barriers to cross-species transmission of primate lentiviruses, and how these AIDS-causing viruses evolve to overcome such barriers when they spillover from their natural reservoirs into non-native hosts.
|Diehl, William E; Patel, Nirali; Halm, Kate et al. (2016) Tracking interspecies transmission and long-term evolution of an ancient retrovirus using the genomes of modern mammals. Elife 5:e12704|
|Wu, Fan; Kirmaier, Andrea; White, Ellen et al. (2016) TRIM5? Resistance Escape Mutations in the Capsid Are Transferable between Simian Immunodeficiency Virus Strains. J Virol 90:11087-11095|
|McCarthy, Kevin R; Kirmaier, Andrea; Autissier, Patrick et al. (2015) Evolutionary and Functional Analysis of Old World Primate TRIM5 Reveals the Ancient Emergence of Primate Lentiviruses and Convergent Evolution Targeting a Conserved Capsid Interface. PLoS Pathog 11:e1005085|
|Johnson, Welkin E (2015) Endogenous Retroviruses in the Genomics Era. Annu Rev Virol 2:135-59|
|Land, Allison M; Wang, Jiayi; Law, Emily K et al. (2015) Degradation of the cancer genomic DNA deaminase APOBEC3B by SIV Vif. Oncotarget 6:39969-79|
|McCarthy, Kevin R; Johnson, Welkin E (2014) Plastic proteins and monkey blocks: how lentiviruses evolved to replicate in the presence of primate restriction factors. PLoS Pathog 10:e1004017|
|Kirmaier, Andrea; Krupp, Annabel; Johnson, Welkin E (2014) Understanding restriction factors and intrinsic immunity: insights and lessons from the primate lentiviruses. Future Virol 9:483-497|
|Sholukh, Anton M; Byrareddy, Siddappa N; Shanmuganathan, Vivekanandan et al. (2014) Passive immunization of macaques with polyclonal anti-SHIV IgG against a heterologous tier 2 SHIV: outcome depends on IgG dose. Retrovirology 11:8|
|Butler, Katherine; Morgan, Jennifer S; Hanson, Debra L et al. (2013) Susceptibility to repeated, low-dose, rectal SHIVSF162P3 challenge is independent of TRIM5 genotype in rhesus macaques. AIDS Res Hum Retroviruses 29:1091-4|
|Byrareddy, Siddappa N; Ayash-Rashkovsky, Mila; Kramer, Victor G et al. (2013) Live attenuated Rev-independent Nef¯SIV enhances acquisition of heterologous SIVsmE660 in acutely vaccinated rhesus macaques. PLoS One 8:e75556|
Showing the most recent 10 out of 20 publications