HIV-1 capsids from B27/B57+ elite controllers escape Mx2 but are targeted by TRIM5α, leading to the induction of an antiviral state

Mérindol, Natacha; El-Far, Mohamed; Sylla, Mohamed; Masroori, Nasser; Dufour, Caroline; Li, Jiaxin; Cherry, Pearl; Plourde, Mélodie B.; Tremblay, Cécile; Berthoux, Lionel

doi:10.1371/journal.ppat.1007398

Cited by 29 publications

(36 citation statements)

References 68 publications

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“…Furthermore, the HIV-restrictive effect of priming was substantially reduced (albeit not eliminated) in TRIM5 knockout THP-1 cells ( Fig 6F ) and was restored following TRIM5 add-back (Figs 6G and S4D ), thus establishing that the effect is at least partially TRIM5-dependent. These results mirror those reported by Merindol et al [ 14 ], who found that prior exposure of macrophages to TRIM5-restricted HIV-1 isolates from an elite controller population conferred protection against infection by wild type HIV-1 in a manner requiring TRIM5, UBC13, and TAK1. Since the ability of human TRIM5 to restrict HIV-1 in THP-1 cells is only effective secondarily to priming with a restricted virus, we refer to this effect as s econdary T RIM5 r estriction (STR).…”

Section: Resultssupporting

confidence: 90%

“…TRIM5 can stimulate innate immune signaling in response to its recognition of restriction-sensitive retroviral cores [ 12 – 14 ]. Our results showing a requirement for autophagy factors in activation of these same immune pathways in response to TRIM5 over-expression suggested that autophagy factors may also contribute to TRIM5-dependent signaling in response to retroviral capsid.…”

Section: Resultsmentioning

confidence: 99%

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A non-canonical role for the autophagy machinery in anti-retroviral signaling mediated by TRIM5α

et al. 2020

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TRIM5α is a key cross-species barrier to retroviral infection, with certain TRIM5 alleles conferring increased risk of HIV-1 infection in humans. TRIM5α is best known as a species-specific restriction factor that directly inhibits the viral life cycle. Additionally, it is also a pattern-recognition receptor (PRR) that activates inflammatory signaling. How TRIM5α carries out its multi-faceted actions in antiviral defense remains incompletely understood. Here, we show that proteins required for autophagy, a cellular self-digestion pathway, play an important role in TRIM5α’s function as a PRR. Genetic depletion of proteins involved in all stages of the autophagy pathway prevented TRIM5α-driven expression of NF-κB and AP1 responsive genes. One of these genes is the preeminent antiviral cytokine interferon β (IFN-β), whose TRIM5-dependent expression was lost in cells lacking the autophagy proteins ATG7, BECN1, and ULK1. Moreover, we found that the ability of TRIM5α to stimulate IFN-β expression in response to recognition of a TRIM5α-restricted HIV-1 capsid mutant (P90A) was abrogated in cells lacking autophagy factors. Stimulation of human macrophage-like cells with the P90A virus protected them against subsequent infection with an otherwise resistant wild type HIV-1 in a manner requiring TRIM5α, BECN1, and ULK1. Mechanistically, TRIM5α was attenuated in its ability to activate the kinase TAK1 in autophagy deficient cells, and both BECN1 and ATG7 contributed to the assembly of TRIM5α-TAK1 complexes. These data demonstrate a non-canonical role for the autophagy machinery in assembling antiviral signaling complexes and in establishing a TRIM5α-dependent antiviral state.

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Section: Resultssupporting

confidence: 90%

Section: Resultsmentioning

confidence: 99%

A non-canonical role for the autophagy machinery in anti-retroviral signaling mediated by TRIM5α

et al. 2020

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“…The role of human TRIM5α in suppression of HIV-1 has been controversial, in part because early studies suggested no restriction of laboratory strains of HIV-1. However, recent studies suggest that cytotoxic T lymphocyte (CTL)-selected HIV-1 isolates from so-called ‘elite controllers’ are susceptible to restriction by human TRIM5α 38 , and genetic studies suggest that human polymorphisms in TRIM5 impact disease progression 13 . To further examine whether TRIM5α in human cells restricts flavivirus replication, we first immunoprecipitated LGTV NS2B/3 following ectopic expression in unmodified HEK293 cells which revealed an interaction with endogenous TRIM5α (Fig.…”

Section: Resultsmentioning

confidence: 99%

TRIM5α restricts flavivirus replication by targeting the viral protease for proteasomal degradation

Chiramel

Meyerson

McNally

et al. 2019

Preprint

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33Tripartite motif-containing protein 5a (TRIM5a) functions as a cellular antiviral restriction 34 factor with exquisite specificity towards the capsid lattices of retroviruses. The relative avidity 35 of TRIM5a binding to retrovirus capsids directly impacts primate species susceptibility to 36 infection, but the antiviral role of TRIM5a is thought limited to retroviruses. In contrast to this 37 current understanding, here we show that both human and rhesus TRIM5a possess potent 38 antiviral function against specific flaviviruses through interaction with the viral protease 39 (NS2B/3) to inhibit virus replication. Importantly, TRIM5a was essential for the antiviral 40 function of IFN-I against sensitive flaviviruses in human cells. However, TRIM5a was ineffective 41 against mosquito-borne flaviviruses (yellow fever, dengue, and Zika viruses) that establish 42 transmission cycles in humans following emergence from non-human primates. Thus, TRIM5a 43 is revealed to possess remarkable plasticity in recognition of diverse virus families, with 44 potential to influence human susceptibility to emerging flaviviruses of global concern. 45 46 47 Main 48Flaviviruses (family Flaviviridae) include 53 recognized virus species of which 40 are known to 49 cause disease in humans, with over 40% of the world's population at risk of flavivirus infection 50 annually 1 . These viruses have high potential for emergence into human populations as 51 witnessed historically through global emergence of dengue virus (DENV), West Nile virus 52 (WNV), and Zika virus (ZIKV). Additional (re)emerging viruses of considerable medical 53 importance include yellow fever virus (YFV), Japanese encephalitis virus (JEV) and members of 54 the tick-borne encephalitis virus (TBEV) serogroup. Flaviviruses share in common a positive-55 sense single-stranded RNA (ssRNA) genome encoding a single polyprotein that is cleaved by 56 host cell signalases 2 and the viral protease to generate three structural (capsid [C], pre-57 membrane [M] and envelope [E]) and seven nonstructural (NS) proteins (NS1, NS2A, NS2B, NS3, 58NS4A, NS4B and NS5) 3 . Two of the nonstructural proteins have enzymatic activity; the NS3 59 protein encodes the viral RNA helicase and together with its co-factor NS2B (NS2B/3) functions 60

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“…TRIM5α restriction acts at the pre-integration phase of the life-cycle, displays cross-talk with the adaptive immune response and may negatively affect viral RC. There is evidence to support this proposition, as HIV-1 CTL escape variants display increased sensitivity to restriction by TRIM5α [107]. The RC of these escape variants may be further reduced, given the functional constraints on capsid structure [108].…”

Section: Conclusion: Possible Causal Factors Which Promote Hiv-2 Disementioning

confidence: 97%

“…There is evidence to support this proposition, as HIV-1 CTL escape variants display increased sensitivity to restriction by TRIM5α [107]. TRIM5α restriction acts at the pre-integration phase of the life-cycle, displays cross-talk with the adaptive immune response and may negatively affect viral RC.…”

Section: Conclusion: Possible Causal Factors Which Promote Hiv-2 Disementioning

confidence: 99%

Delayed disease progression in HIV-2: the importance of TRIM5α and the retroviral capsid

Boswell

Rowland‐Jones

2019

Clinical and Experimental Immunology

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HIV-2 is thought to have entered the human population in the 1930s through cross-species transmission of SIV from sooty mangabeys in West Africa. Unlike HIV-1, HIV-2 has not led to a global pandemic, and recent data suggest that HIV-2 prevalence is declining in some West African states where it was formerly endemic. Although many early isolates of HIV-2 were derived from patients presenting with AIDS-defining illnesses, it was noted that a much larger proportion of HIV-2-infected subjects behaved as long-term non-progressors (LTNP) than their HIV-1-infected counterparts. Many HIV-2-infected adults are asymptomatic, maintaining an undetectable viral load for over a decade. However, despite lower viral loads, HIV-2 progresses to clinical AIDS without therapeutic intervention in most patients. In addition, successful treatment with anti-retroviral therapy (ART) is more challenging than for HIV-1. HIV-2 is significantly more sensitive to restriction by host restriction factor tripartite motif TRIM5α than HIV-1, and this difference in sensitivity is linked to differences in capsid structure. In this review we discuss the determinants of HIV-2 disease progression and focus on the important interactions between TRIM5α and HIV-2 capsid in long-term viral control.

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HIV-1 capsids from B27/B57+ elite controllers escape Mx2 but are targeted by TRIM5α, leading to the induction of an antiviral state

Cited by 29 publications

References 68 publications

A non-canonical role for the autophagy machinery in anti-retroviral signaling mediated by TRIM5α

A non-canonical role for the autophagy machinery in anti-retroviral signaling mediated by TRIM5α

TRIM5α restricts flavivirus replication by targeting the viral protease for proteasomal degradation

Delayed disease progression in HIV-2: the importance of TRIM5α and the retroviral capsid

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