Poster abstracts
Poster number 90 submitted by Anna C Smith
Adaptive changes in viral envelope resulting from adaptation of simian-tropic HIV-1 to macaques confers resistance to interferon
A. C. Smith (Depts of Veterinary Biosciences and Microbial Infection & Immunity), H. Weight (Divison of Human Biology, Fred Hutchinson Cancer Research Center), J. Overbaugh (Divison of Human Biology, Fred Hutchinson Cancer Research Center), A. Sharma (Depts of Veterinary Biosciences and Microbial Infection & Immunity)
Abstract:
HIV-1 does not persistently infect macaques due to restriction by several type-I interferon (IFN)-induced host-factors. Therefore, chimeric SIV/HIV-1 viruses (SHIVs) encoding the SIV antagonists of restrictive host-factors and HIV-1 Envelope glycoprotein (Env), are used to infect macaques to model HIV-1 infection. A major limitation of the SHIV/macaque model is that SHIVs generated in vitro replicate poorly in macaques. A small subset of SHIVs has been successfully adapted for high-level replication through serial passage in macaques. We have previously identified that serial macaque-passage selects for IFN-resistant SHIV variants that have higher replication in macaque lymphocytes. The viral determinant(s) contributing to increased replication and IFN resistance in macaque-passaged SHIVs have not been examined.
In order to identify the viral determinant(s) of macaque-passaged SHIVs that confer resistance to IFN, we generated SHIV infectious molecular clones (IMCs) encoding the parental env and representative env clones from sequential macaque-passaged viruses. We found that the unpassaged, parental SHIV IMC is potently inhibited by IFN (mean IC50 28 U/ml), whereas the SHIV IMCs encoding macaque-passaged envs are resistant to IFN inhibition (mean IC50 >5000 U/ml). In addition, we found that SHIV IMCs encoding macaque-passaged envs have high replication capacity and most, but not all, have more virion Env content. Next, we took a gain-of-function approach and generated chimeras that introduce portions of env gene from IFN-resistant SHIV IMC into the parental IFN-sensitive SHIV IMC. Using this approach, we mapped the determinant of IFN resistance and high replication capacity to the C2 region of the gp120 subunit of HIV-1 Env.
In conclusion, the adaptive changes in HIV-1 env resulting from serial macaque-passage of SHIVs are sufficient to increase resistance to IFN, replication capacity, and virion Env content. Thus, the host IFN response serves as a strong selective pressure during the process of adaption of SHIV to macaques.
Keywords: Human immunodeficiency virus, Simian-human immunodeficiency virus, Type-I interferon