Abstract
Lentiviruses are able to establish persistent infection in their respective hosts despite a potent type-I interferon (IFN-I) response following transmission. A number of IFN-I-induced host factors that are able to inhibit lentiviral replication in vitro have been identified, and these studies suggest a role for IFN-induced factors as barriers to cross-species transmission. However, the ability of these factors to inhibit viral replication in vivo has not been well characterized, nor have the viral determinants that contribute to evasion or antagonism of the host IFN-I response. In this study, we hypothesized that the host IFN-I response serves as a strong selective pressure in the context of SIV/HIV chimeric virus (SHIV) infection of macaques and sought to identify the viral determinants that contribute to IFN-I resistance. We assessed the ability of SHIVs encoding HIV-1 sequences adapted by serial passage in macaques versus SHIVs encoding HIV sequences isolated directly from infected individuals to replicate in the presence of IFNα in macaque lymphocytes. We demonstrate that passage in macaques selects for IFNα resistant viruses that have higher replication kinetics and increased envelope content. SHIVs that encode HIV-1 sequences derived directly from infected humans were sensitive to IFNα –induced inhibition whereas SHIVs obtained after passage in macaques were not. This evolutionary process was directly observed in viruses that were serially passaged during the first few months of infection–a time when the IFNα response is high. Differences in IFNα sensitivity mapped to HIV-1 envelope and were associated with increased envelope levels despite similar mRNA expression, suggesting a post-transcriptional mechanism. These studies highlight critical differences in IFNα sensitivity between HIV-1 sequences in infected people and those used in SHIV models.
Highlights
The innate immune system presents the first host defense against viral infection
We demonstrate that the process of adapting SIV/HIV chimeric virus (SHIV) for replication in macaques selects for viruses that are resistant to the IFNα response, and we identity important viral determinants that contribute to this resistance
We demonstrate that envelope differences selected in vivo allow SHIVs to adapt to the IFNα response; adapted HIV-1 variants encode IFNα resistant Envelope surface glycoprotein (Env), whereas Envs obtained directly from infected individuals early in their infection are sensitive, suggesting that IFNα may have an inhibitory effect on viruses spreading in humans that has not been observed through the study of adapted viruses
Summary
The innate immune system presents the first host defense against viral infection. Host cells are able to sense the presence of viral infection and respond by producing type-I interferon (IFN-I), which, in turn, leads to the up-regulation of hundreds of host genes that are potentially antiviral [1,2]. IFN-I production, including IFNα, is part of a larger systemic cytokine storm that precedes the establishment of set-point viral load suggesting that the IFN-I response may play a role in limiting viral replication during acute infection and influence disease progression [8]. In support of this hypothesis, a recent study of SIV infection in rhesus macaques demonstrated that blocking the IFN-I response resulted in higher plasma viral loads during acute infection, increased reservoir size and faster progression to AIDS [9]. The biological properties that contribute to the ability of some HIV-1 variants to resist the IFN-I response remain unclear
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