Adapting SHIVs In Vivo Selects for Envelope-Mediated Interferon-α Resistance

Boyd, David F.; Sharma, Amit; Humes, Daryl; Cheng‐Mayer, Cecilia; Overbaugh, Julie

doi:10.1371/journal.ppat.1005727

Cited by 10 publications

(19 citation statements)

References 43 publications

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“…Recently, we examined the sensitivity of a panel of adapted and unadapted SHIVs to IFNα in macaque lymphocytes and found that the unadapted SHIVs were potently inhibited by IFNα despite encoding the SIV antagonists of known restriction factors [25]. In contrast, SHIVs encoding adapted HIV-1 variants were largely resistant to IFNα.…”

Section: Introductionmentioning

confidence: 99%

Macaque interferon-induced transmembrane proteins limit replication of SHIV strains in an Envelope-dependent manner

et al. 2019

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HIV-1 does not persistently infect macaques due in part to restriction by several macaque host factors. This has been partially circumvented by generating chimeric SIV/HIV-1 viruses (SHIVs) that encode SIV antagonist of known restriction factors. However, most SHIVs replicate poorly in macaques unless they are further adapted in culture and/or macaques (adapted SHIVs). Therefore, development of SHIVs encoding HIV-1 sequences derived directly from infected humans without adaptation (unadapted SHIVs) has been challenging. In contrast to the adapted SHIVs, the unadapted SHIVs have lower replication kinetics in macaque lymphocytes and are sensitive to type-1 interferon (IFN). The HIV-1 Envelope (Env) in the chimeric virus determines both the reduced replication and the IFN-sensitivity differences. There is limited information on macaque restriction factors that specifically limit replication of the more biologically relevant, unadapted SHIV variants. In order to identify the IFN-induced host factor(s) that could contribute to the inhibition of SHIVs in macaque lymphocytes, we measured IFN-induced gene expression in immortalized pig-tailed macaque (Ptm) lymphocytes using RNA-Seq. We found 147 genes that were significantly upregulated upon IFN treatment in Ptm lymphocytes and 31/147 were identified as genes that encode transmembrane helices and thus are likely present in membranes where interaction with viral Env is plausible. Within this group of upregulated genes with putative membrane-localized proteins, we identified several interferon-induced transmembrane protein (IFITM) genes, including several previously uncharacterized Ptm IFITM3 -related genes. An evolutionary genomic analysis of these genes suggests the genes are IFITM3 duplications not found in humans that are both within the IFITM locus and also dispersed elsewhere in the Ptm genome. We observed that Ptm IFITMs are generally packaged at higher levels in unadapted SHIVs when compared to adapted SHIVs. CRISPR/Cas9-mediated knockout of Ptm IFITMs showed that depletion of IFITMs partially rescues the IFN sensitivity of unadapted SHIV. Moreover, we found that the depletion of IFITMs also increased replication of unadapted SHIV in the absence of IFN treatment, suggesting that Ptm IFITMs are likely important host factors that limit replication of unadapted SHIVs. In conclusion, this study shows that Ptm IFITMs selectively restrict replication of unadapted SHIVs. These findings suggest that restriction factors including IFITMs vary in their potency against different SHIV variants and may play a role in selecting for viruses that adapt to species-specific restriction factors.

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Section: Introductionmentioning

confidence: 99%

Macaque interferon-induced transmembrane proteins limit replication of SHIV strains in an Envelope-dependent manner

et al. 2019

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“…Indeed, Transmitted/Founder (T/F) viruses have been shown to be IFN-resistant (Fenton-May et al, 2013;Iyer et al, 2017). Furthermore, adapting SHIVs to rhesus macaques (RMs) selects for Env-mediated IFNα-resistance (Boyd et al, 2016). Additionally, inhibition of the IFN-response by administration of a IFNα receptor antagonist has been shown to result in high viral loads during acute infection and faster progression to AIDS in a pathogenic SIV-RM model (Sandler et al, 2014).…”

Section: Possible Role Of Interferon Response In Control Of Macaque-tmentioning

confidence: 99%

Toward a Macaque Model of HIV-1 Infection: Roadblocks, Progress, and Future Strategies

2020

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The human-specific tropism of Human Immunodeficiency Virus Type 1 (HIV-1) has complicated the development of a macaque model of HIV-1 infection/AIDS that is suitable for preclinical evaluation of vaccines and novel treatment strategies. Several innate retroviral restriction factors, such as APOBEC3 family of proteins, TRIM5α, BST2, and SAMHD1, that prevent HIV-1 replication have been identified in macaque cells. Accessory proteins expressed by Simian Immunodeficiency virus (SIV) such as viral infectivity factor (Vif), viral protein X (Vpx), viral protein R (Vpr), and negative factor (Nef) have been shown to play key roles in overcoming these restriction factors in macaque cells. Thus, substituting HIV-1 accessory genes with those from SIV may enable HIV-1 replication in macaques. We and others have constructed macaquetropic HIV-1 derivatives [also called simian-tropic HIV-1 (stHIV-1) or Human-Simian Immunodeficiency Virus (HSIV)] carrying SIV vif to overcome APOBEC3 family proteins. Additional modifications to HIV-1 gag in some of the macaque-tropic HIV-1 have also been done to overcome TRIM5α restriction in rhesus and cynomolgus macaques. Although these viruses replicate persistently in macaque species, they do not result in CD4 depletion. Thus, these studies suggest that additional blocks to HIV-1 replication exist in macaques that prevent high-level viral replication. Furthermore, serial animalto-animal passaging of macaque-tropic HIV-1 in vivo has not resulted in pathogenic variants that cause AIDS in immunocompetent macaques. In this review, we discuss recent developments made toward developing macaque model of HIV-1 infection.

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“…Viral envelope has also demonstrated the capacity of overcoming host restrictions beyond virus entry. For example, passage of SIV/HIV chimeric virus (SHIV) in macaques in the presence of interferon-α led to the selection of interferon-α-resistant SHIV [98]. This resistance phenotype was mapped to viral Env protein that had a higher level of expression from the resistant virus.…”

Section: Env Protein Fights Back: Evasion Of Host Restriction On Vmentioning

confidence: 99%

HIV-1 Envelope Glycoprotein at the Interface of Host Restriction and Virus Evasion

Beitari

Wang

Liu

et al. 2019

Viruses

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Without viral envelope proteins, viruses cannot enter cells to start infection. As the major viral proteins present on the surface of virions, viral envelope proteins are a prominent target of the host immune system in preventing and ultimately eliminating viral infection. In addition to the well-appreciated adaptive immunity that produces envelope protein-specific antibodies and T cell responses, recent studies have begun to unveil a rich layer of host innate immune mechanisms restricting viral entry. This review focuses on the exciting progress that has been made in this new direction of research, by discussing various known examples of host restriction of viral entry, and diverse viral countering strategies, in particular, the emerging role of viral envelope proteins in evading host innate immune suppression. We will also highlight the effective cooperation between innate and adaptive immunity to achieve the synergistic control of viral infection by targeting viral envelope protein and checking viral escape. Given that many of the related findings were made with HIV-1, we will use HIV-1 as the model virus to illustrate the basic principles and molecular mechanisms on host restriction targeting HIV-1 envelope protein.

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Adapting SHIVs In Vivo Selects for Envelope-Mediated Interferon-α Resistance

Cited by 10 publications

References 43 publications

Macaque interferon-induced transmembrane proteins limit replication of SHIV strains in an Envelope-dependent manner

Macaque interferon-induced transmembrane proteins limit replication of SHIV strains in an Envelope-dependent manner

Toward a Macaque Model of HIV-1 Infection: Roadblocks, Progress, and Future Strategies

HIV-1 Envelope Glycoprotein at the Interface of Host Restriction and Virus Evasion

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