Developing improved challenge viruses for macaque models of HIV-1 infection
Boyd, David Fielding
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Infection of macaques with SIV/HIV chimeric viruses (SHIVs) is often used as a model of HIV-1 infection for pre-clinical vaccine studies. Although SHIV infection of macaques serves as the gatekeeper of promising vaccine candidates, it is limited by the fact there are a very small number of SHIVs available, and they do not represent the large genetic diversity of globally circulating HIV-1 variants. In addition, SHIVs that are able to establish persistent infection in macaques are a highly selected subset of viruses that require multiple rounds of adaption in lab culture or by serial animal-animal passage. This thesis describes the changes that occur in SHIVs as they are adapted for replication in macaques as well as the selective pressures in macaques that drive these changes. First, we investigated the antigenic changes that occur in the envelope protein (Env) as HIV-1 is adapted for replication in macaques. Mutations that permit HIV-1 Env to use the macaque CD4 receptor for entry disrupted quaternary epitopes in the Env trimer that are key targets of current vaccine strategies. SHIVs that were adapted by serial passage in macaques and are currently used in pre-clinical vaccine trials exhibited antigenic properties similar to HIV-1 Envs adapted to macaque CD4. These results indicate that there are antigenic consequences of adapting HIV-1 for replication in macaques and that adaptation to the macaque CD4 receptor compromises the ability to test vaccines that target key quaternary epitopes on HIV-1 Env. Next, we investigated the viral determinants that contribute to the ability of SHIVs to replicate in macaques and establish persistent infection. We compared the replication capacity in macaque cells of nine SHIVs encoding HIV-1 sequences that represent circulating HIV-1 variants, lab-cultured variants and macaque-passaged variants. By generating chimeras between a macaque-passaged SHIV with high replication capacity and a circulating SHIV with low replication capacity, we determined that HIV-1 Env is a critical determinant of the ability to replicate to high levels in macaque cells. In addition, the amount of Env present in virions and expressed in infected macaque cells predicts the ability to replicate to high levels. Finally, we studied the ability of SHIVs to resist the type-I interferon (IFN-I) response, an important component of innate immunity to viruses. Pathogenic SHIVs that have been adapted by macaque-passage were highly resistant to treatment with IFN-I compared to SHIVs encoding circulating HIV-1 Envs. Both replication capacity in macaque cells and virion-associated Env content predicted the ability of SHIVS to overcome the macaque IFN-I response. These results suggested that the process of adaptation for replication in macaques selects for variants that are resistant to the IFN-I response. Overall, these studies describe the changes that occur in SHIVs as they are adapted for replication in macaques and the host pressures that contribute to these changes. Improved understanding of this process of adaption may allow for rational design of pathogenic SHIVs that are more representative of HIV-1 variants circulating in people.
- Pathobiology