A common animal model used in HIV-1 vaccine and prevention studies is infection of macaques with SHIV, a chimeric virus that combines parts of the monkey (SIV) and human (HIV) viral genomes. Most SHIV variants require adaptation in culture or in animal models to exhibit both high replication capacity and pathogenicity. HIV infection is known to robustly induce the type I interferon (IFN-I) response, a key arm of the innate immune system, which in turn up-regulates a suite of proteins with antiviral activity. However, to what extent if any, the IFN-I response affects SHIV adaptation remains unclear. A new Fred Hutch study from the Overbaugh Laboratory (Human Biology and Public Health Sciences Divisions), led by former graduate student Dr. David Boyd and published in PLoS Pathogens, tested the hypothesis that adaptation of SHIVs results in IFN-I resistance.
"A major challenge in the field of HIV vaccine research has been the lack of an animal model that predicts vaccine efficacy in people. Viruses used to challenge macaques in vaccine studies have undergone extensive adaption both in cell culture and by animal-animal passage, and these adapted viruses don’t necessarily reflect the biological properties of those circulating in people", said Dr. Boyd. The study began by testing a panel of nine SHIV variants that represented four viruses encoding HIV-1 sequences from infected individuals (MG505, Q23, QF495 and BG505), two viruses derived from variants derived from cell culture adaptation (AD8, SF162), and three viruses adapted by animal-animal passage in macaques (AD8-EO, SF162P3 and 1157ipd3N4), for their ability to replicate in immortalized macaque lymphocytes in the presence or absence of IFNα. Strikingly, the authors found that animal-adapted and cell culture-adapted SHIV variants, but not their circulating counterparts, exhibited higher replication kinetics and IFNα resistance.
Next, the investigators sought to map the viral determinants of IFNα resistance by generating a chimera between an animal-adapted SHIV (AD8-EO) and a circulating SHIV (Q23AE). Because only chimeras that contained the env gene, but not other sequences, from AD8-EO rescued replication capacity and IFNα resistance, the researchers concluded that the env gene, which encodes the Envelope surface glycoprotein (Env), is the major determinant of SHIV adaptation. A combination of western blotting and RT-qPCR revealed the Env protein content, but not env mRNA, correlated with IFNα resistance, suggesting post-transcriptional control. Finally, the authors corroborated their results by comparing the IFNα sensitivity of a parental SHIV obtained from a non-cultured variant (SHIVC109mc) with variants isolated from either the third (SHIVC109P3, SHIVC109P3N) or fourth animal passage (SHIVC109P4). As before, the animal-adapted variants exhibited increased replication and IFNα resistance during the first few months of infection, coinciding with the peak IFNα response. In summary, this study showed that differences in IFNα sensitivity distinguishes SHIVs used to model HIV-1 infection from those based on circulating HIV-1 variants and uncovers a key role for the Envelope protein in mediating the process of adaptation to the IFNα response. Said Dr. Boyd,"Our results suggest that the type-I interferon response is a strong selective pressure in the host that drives changes in HIV-1 as it is adapted to a new species. Increased resistance to the macaque interferon response was associated with increased levels of the Envelope protein. Engineering HIV-1 for increased envelope expression may be a strategy to develop novel challenge viruses that are able to establish persistent infection in the macaque host."
Boyd DF, Sharma A, Humes D, Cheng-Mayer C, Overbaugh J. 2016. Adapting SHIVs in vivo selects for envelope-mediated interferon-alpha resistance. PLoS Pathog, 12(7), e1005727.
Funding for this work was provided by the National Institutes of Health and an amfAR Mathilde Krim Fellowship in Basic Biomedical Research.