TRIM5 alpha Drives SIVsmm Evolution in Rhesus Macaques

Wu, Fan; Kirmaier, Andrea; Goeken, Robert M.; Ourmanov, Ilnour; Hall, Laurie R.; Morgan, Jennifer; Matsuda, Kenta; Buckler-White, Alicia; Tomioka, Keiko; Plishka, Ronald J.; Whitted, Sonya; Johnson, Welkin E.; Hirsch, Vanessa M.

doi:10.1371/journal.ppat.1003577

Cited by 41 publications

(57 citation statements)

References 79 publications

(109 reference statements)

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“…When Gag capsid sequences from SIVsm804E were compared with the parental SIVsmE543-3, we observed two amino acid substitutions in the cyclophilin A binding loop (L89I and A91P). These two substitutions are at the tip of the loop, which is known to be important for resistance to the host TRIM Cyp allele (30). Analysis of gag sequences of historical viral stocks revealed that these two amino acid substitutions were already present in SIVsmH631Br, and they were conserved in following passages (data not shown).…”

Section: Resultsmentioning

confidence: 96%

“…We have previously reported that certain host TRIM5␣ genotypes restrict replication of SIVsmE543-3 replication in vivo (29,30). Rhesus TRIM5 genotypes can be characterized based on polymorphisms at position 339 to 341 as permissive (TRIM Q/Q ), moderately susceptible (TRIM TFP/Q and TRIM Q/CypA ), or restrictive (TRIM TFP/TFP , TRIM TFP/CypA , and TRIM CypA/CypA ) for SIVsmE543-3.…”

Section: Resultsmentioning

confidence: 99%

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Characterization of Simian Immunodeficiency Virus (SIV) That Induces SIV Encephalitis in Rhesus Macaques with High Frequency: Role of TRIM5 and Major Histocompatibility Complex Genotypes and Early Entry to the Brain

Matsuda

Dang

Brown³

et al. 2014

J Virol

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Although nonhuman primate models of neuro-AIDS have made tremendous contributions to our understanding of disease progression in the central nervous system (CNS) of human immunodeficiency virus type 1 (HIV-1)-infected individuals, each model holds advantages and limitations. In this study, in vivo passage of SIVsmE543 was conducted to obtain a viral isolate that can induce neuropathology in rhesus macaques. After a series of four in vivo passages in rhesus macaques, we have successfully isolated SIVsm804E. SIVsm804E shows efficient replication in peripheral blood mononuclear cells (PBMCs) and monocyte-derived macrophages (MDMs) in vitro and induces neuro-AIDS in high frequencies in vivo. Analysis of the acute phase of infection revealed that SIVsm804E establishes infection in the CNS during the early phase of the infection, which was not observed in the animals infected with the parental SIVsmE543-3. Comprehensive analysis of disease progression in the animals used in the study suggested that host major histocompatibility complex class I (MHC-I) and TRIM5␣ genotypes influence the disease progression in the CNS. Taken together, our findings show that we have successfully isolated a new strain of simian immunodeficiency virus (SIV) that is capable of establishing infection in the CNS at early stage of infection and causes neuropathology in infected rhesus macaques at a high frequency (83%) using a single inoculum, when animals with restrictive MHC-I or TRIM5␣ genotypes are excluded. SIVsm804E has the potential to augment some of the limitations of existing nonhuman primate neuro-AIDS models. IMPORTANCE Human immunodeficiency virus (HIV) is associated with a high frequency of neurologic complications due to infection of the central nervous system (CNS). Although the use of antiviral treatment has reduced the incidence of severe complications, milder disease of the CNS continues to be a significant problem. Animal models to study development of neurologic disease are needed. This article describes the development of a novel virus isolate that induces neurologic disease in a high proportion of rhesus macaques infected without the need for prior immunomodulation as is required for some other models.

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Section: Resultsmentioning

confidence: 96%

Section: Resultsmentioning

confidence: 99%

Characterization of Simian Immunodeficiency Virus (SIV) That Induces SIV Encephalitis in Rhesus Macaques with High Frequency: Role of TRIM5 and Major Histocompatibility Complex Genotypes and Early Entry to the Brain

Matsuda

Dang

Brown³

et al. 2014

J Virol

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“…It is noteworthy that the CA proteins of both SIVmac and SIVmne have the glutamine-glutamine pair at positions 89 and 90. Thus, after cross-species transmission of the group GP SIVsmm, TRIMCyp in the new hosts likely drove the evolution of the group Q SIVmac and SIVmne viruses (56). Restriction factors like TRIMCyp or TRIM5␣ may likewise have provided selection pressure for the evolution of group Q SIVs in other monkey species.…”

Section: Discussionmentioning

confidence: 99%

Contribution of Glutamine Residues in the Helix 4-5 Loop to Capsid-Capsid Interactions in Simian Immunodeficiency Virus of Macaques

Tipper¹,

Sodroski²

2014

J Virol

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Following retrovirus entry, the viral capsid (CA) disassembles into its component capsid proteins. The rate of this uncoating process, which is regulated by CA-CA interactions and by the association of the capsid with host cell factors like cyclophilin A (CypA), can influence the efficiency of reverse transcription. Inspection of the CA sequences of lentiviruses reveals that several species of simian immunodeficiency viruses (SIVs) have lost the glycine-proline motif in the helix 4-5 loop important for CypA binding; instead, the helix 4-5 loop in these SIVs exhibits an increase in the number of glutamine residues. In this study, we investigated the role of these glutamine residues in SIVmac239 replication. Changes in these residues, particularly glutamine 89 and glutamine 92, resulted in a decreased efficiency of core condensation, decreased stability of the capsids in infected cells, and blocks to reverse transcription. In some cases, coexpression of two different CA mutants produced chimeric virions that exhibited higher infectivity than either parental mutant virus. For this complementation of infectivity, glutamine 89 was apparently required on one of the complementing pair of mutants and glutamine 92 on the other. Modeling suggests that glutamines 89 and 92 are located on the distal face of hexameric capsid spokes and thus are well positioned to contribute to interhexamer interactions. Requirements to evade host restriction factors like TRIMCyp may drive some SIV lineages to evolve means other than CypA binding to stabilize the capsid. One solution used by several SIV strains consists of glutamine-based bonding. IMPORTANCEThe retroviral capsid is an assembly of individual capsid proteins that surrounds the viral RNA. After a retrovirus enters a cell, the capsid must disassemble, or uncoat, at a proper rate. The interactions among capsid proteins contribute to this rate of uncoating. We found that some simian immunodeficiency viruses use arrays of glutamine residues, which can form hydrogen bonds efficiently, to keep their capsids stable. This strategy may allow these viruses to forego the use of capsid-stabilizing factors from the host cell, some of which have antiviral activity.

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“…Spontaneous control of viral replication has been observed in at least two macaque species (rhesus and cynomolgus) with specific MHC or TRIM5a alleles [35][36][37]. Some SIVagm strains (SIVagm.ver90 and SIVagm.…”

Section: Animal Models Of Spontaneous Protectionmentioning

confidence: 99%

Immune responses during spontaneous control of HIV and AIDS: what is the hope for a cure?

Sáez‐Cirión

Jacquelin

Barré‐Sinoussi

et al. 2014

Phil. Trans. R. Soc. B

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International audienceHIV research has made rapid progress and led to remarkable achievements in recent decades, the most important of which are combination antiretroviral therapies (cART). However, in the absence of a vaccine, the pandemic continues, and additional strategies are needed. The 'towards an HIV cure' initiative aims to eradicate HIV or at least bring about a lasting remission of infection during which the host can control viral replication in the absence of cART. Cases of spontaneous and treatment-induced control of infection offer substantial hope. Here, we describe the scientific knowledge that is lacking, and the priorities that have been established for research into a cure. We discuss in detail the immunological lessons that can be learned by studying natural human and animal models of protection and spontaneous control of viraemia or of disease progression. In particular, we describe the insights we have gained into the immune mechanisms of virus control, the impact of early virus-host interactions and why chronic inflammation, a hallmark of HIV infection, is an obstacle to a cure. Finally, we enumerate current interventions aimed towards improving the host immune response

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TRIM5 alpha Drives SIVsmm Evolution in Rhesus Macaques

Cited by 41 publications

References 79 publications

Characterization of Simian Immunodeficiency Virus (SIV) That Induces SIV Encephalitis in Rhesus Macaques with High Frequency: Role of TRIM5 and Major Histocompatibility Complex Genotypes and Early Entry to the Brain

Characterization of Simian Immunodeficiency Virus (SIV) That Induces SIV Encephalitis in Rhesus Macaques with High Frequency: Role of TRIM5 and Major Histocompatibility Complex Genotypes and Early Entry to the Brain

Contribution of Glutamine Residues in the Helix 4-5 Loop to Capsid-Capsid Interactions in Simian Immunodeficiency Virus of Macaques

Immune responses during spontaneous control of HIV and AIDS: what is the hope for a cure?

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