Date Published: July 11, 2016
Publisher: Public Library of Science
Author(s): David F. Boyd, Amit Sharma, Daryl Humes, Cecilia Cheng-Mayer, Julie Overbaugh, Guido Silvestri.
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.
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]. Infection with HIV-1 in people and SIV in non-human primates induces a robust IFN-I response within days of infection [3–7]. 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 . 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 .
We took advantage of the SHIV macaque model to define the role of IFNα in infection and found that infection selects for viruses that are resistant to the inhibitory effects of IFNα in macaques. Pathogenic SHIVs, which have been developed to model HIV-1 transmission and pathogenesis in macaques, are resistant to IFNα, whereas the SHIVs based on HIV-1 variants circulating in humans, including transmitted viruses, are inhibited by IFNα. Differences in sensitivity to IFNα were determined by the HIV-1 Envelope protein, which is considered a key feature of the SHIV models. Our findings underscore critical differences between SHIVs adapted for replication in macaques and HIV-1 variants isolated directly from infected individuals, including those that were recently transmitted, which represent the most biologically relevant targets of HIV-1 vaccine and prevention efforts.