Cell-to-cell contact facilitates HIV transmission from lymphocytes to astrocytes via CXCR4

Li, Guan Han; Anderson, C E; Jaeger, Laura; Do, Thao; Major, Eugene O.; Nath, Avindra

doi:10.1097/qad.0000000000000605

Cited by 48 publications

(54 citation statements)

References 76 publications

(73 reference statements)

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“…Recent data from in vitro studies have suggested that astrocytes could be infected following cell‐to‐cell contacts with HIV‐1‐infected cells (Li et al, ; Luo and He, ). It has been proposed that the mechanism by which astrocytes get infected in vivo is most likely through physical contacts with virus‐infected lymphocytes and/or microglia/macrophages.…”

Section: Resultsmentioning

confidence: 99%

“…First, endocytosis leads to a very inefficient infection mode due to degradation of most HIV‐1 particles in the endosomal apparatus (Chauhan et al, ; Hao and Lyman, ). Second, a more efficient mode of entry relies on cell‐to‐cell contacts through cocultivation with virus‐infected lymphocytes, which involves a CD4‐independent fusion of immature/budding virions via gp120‐CXCR4 interactions (Li et al, ; Luo and He, ).…”

Section: Introductionmentioning

confidence: 99%

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Astrocytes sustain long‐term productive HIV‐1 infection without establishment of reactivable viral latency

Barat

Proust

Deshière

et al. 2018

Glia

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The "shock and kill" HIV-1 cure strategy proposes eradication of stable cellular reservoirs by clinical treatment with latency-reversing agents (LRAs). Although resting CD4 T cells latently infected with HIV-1 constitute the main reservoir that is targeted by these approaches, their consequences on other reservoirs such as the central nervous system are still unknown and should be taken into consideration. We performed experiments aimed at defining the possible role of astrocytes in HIV-1 persistence in the brain and the effect of LRA treatments on this viral sanctuary. We first demonstrate that the diminished HIV-1 production in a proliferating astrocyte culture is due to a reduced proliferative capacity of virus-infected cells compared with uninfected astrocytes. In contrast, infection of non-proliferating astrocytes led to a robust HIV-1 infection that was sustained for over 60 days. To identify astrocytes latently infected with HIV-1, we designed a new dual-color reporter virus called NL4.3 eGFP-IRES-Crimson that is fully infectious and encodes for all viral proteins. Although we detected a small fraction of astrocytes carrying silent HIV-1 proviruses, we did not observe any reactivation using various LRAs and even strong inducers such as tumor necrosis factor, thus suggesting that these proviruses were either not transcriptionally competent or in a state of deep latency. Our findings imply that astrocytes might not constitute a latent reservoir per se but that relentless virus production by this brain cell population could contribute to the neurological disorders seen in HIV-1-infected persons subjected to combination antiretroviral therapy.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Astrocytes sustain long‐term productive HIV‐1 infection without establishment of reactivable viral latency

Barat

Proust

Deshière

et al. 2018

Glia

View full text Add to dashboard Cite

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“…Among the deleterious nonstructural HIV‐1 proteins expressed by infected astrocytes is Tat, which can be secreted (Fan & He, ), damages the BBB, promotes glutamate excitotoxicity and exacerbates neuroinflammation (reviewed in [Cisneros & Ghorpade, ]). Finally, astrocytes were shown to be capable of transmitting HIV to immune cells by cell‐to‐cell contact in co‐culture experiments (Li et al, ), suggesting that they also contribute to virus spread. For a more in‐depth discussion of the potential of astrocytes to form virus reservoirs and promote neurological damage to the brain and HAND, the reader is referred to selected reviews (Carroll & Brew, ; Gray, Brew, & Churchill, ; Li, Henderson, & Nath, ; Saylor et al, ).…”

Section: Introductionmentioning

confidence: 99%

Synthetic AAV/CRISPR vectors for blocking HIV‐1 expression in persistently infected astrocytes

Kunze

Börner

Kienle

et al. 2017

Glia

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Astrocytes, the most abundant cells in the mammalian brain, perform key functions and are involved in several neurodegenerative diseases. The human immunodeficiency virus (HIV) can persist in astrocytes, contributing to the HIV burden and neurological dysfunctions in infected individuals. While a comprehensive approach to HIV cure must include the targeting of HIV-1 in astrocytes, dedicated tools for this purpose are still lacking. Here we report a novel Adeno-associated virus-based vector (AAV9P1) with a synthetic surface peptide for transduction of astrocytes. Analysis of AAV9P1 transduction efficiencies with single brain cell populations, including primary human brain cells, as well as human brain organoids demonstrated that AAV9P1 targeted terminally differentiated human astrocytes much more efficiently than neurons. We then investigated whether AAV9P1 can be used to deliver HIV-inhibitory genes to astrocytes. To this end we generated AAV9P1 vectors containing genes for HIV-1 proviral editing by CRISPR/Cas9. Latently HIV-1 infected astrocytes transduced with these vectors showed significantly diminished reactivation of proviruses, compared with untransduced cultures. Sequence analysis identified mutations/deletions in key HIV-1 transcriptional control regions. We conclude that AAV9P1 is a promising tool for gene delivery to astrocytes and may facilitate inactivation/destruction of persisting HIV-1 proviruses in astrocyte reservoirs.

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“…Thus, CD4-independent viruses likely are strongly selected against in vivo (32,48,49). Nonetheless, although not strictly CD4 independent, HIVs and SIVs with the ability to utilize low levels of CD4 for entry are well described, and this phenotype has been proposed to contribute to the infection of macrophages and microglial cells, which exhibit a lower density of CD4 than T cells (32,(43)(44)(45)(50)(51)(52)(53)(54)(55)(56)(57). For one neuropathic SIV isolate, its ability to cause AIDS encephalopathy in macaques correlated with the infection of brain-derived endothelial cells that expressed CCR5 but not CD4 (58).…”

mentioning

confidence: 99%

Derivation and Characterization of a CD4-Independent, Non-CD4-Tropic Simian Immunodeficiency Virus

Swanstrom

Haggarty

Jordan

et al. 2016

J Virol

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CD4 tropism is conserved among all primate lentiviruses and likely contributes to viral pathogenesis by targeting cells that are critical for adaptive antiviral immune responses. Although CD4-independent variants of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) have been described that can utilize the coreceptor CCR5 or CXCR4 in the absence of CD4, these viruses typically retain their CD4 binding sites and still can interact with CD4. We describe the derivation of a novel CD4-independent variant of pathogenic SIVmac239, termed iMac239, that was used to derive an infectious R5-tropic SIV lacking a CD4 binding site. Of the seven mutations that differentiate iMac239 from wild-type SIVmac239, a single change (D178G) in the V1/V2 region was sufficient to confer CD4 independence in cell-cell fusion assays, although other mutations were required for replication competence. Like other CD4-independent viruses, iMac239 was highly neutralization sensitive, although mutations were identified that could confer CD4-independent infection without increasing its neutralization sensitivity. Strikingly, iMac239 retained the ability to replicate in cell lines and primary cells even when its CD4 binding site had been ablated by deletion of a highly conserved aspartic acid at position 385, which, for HIV-1, plays a critical role in CD4 binding. iMac239, with and without the D385 deletion, exhibited an expanded host range in primary rhesus peripheral blood mononuclear cells that included CCR5 ؉ CD8 ؉ T cells. As the first non-CD4-tropic SIV, iMac239-⌬D385 will afford the opportunity to directly assess the in vivo role of CD4 targeting on pathogenesis and host immune responses. IMPORTANCECD4 tropism is an invariant feature of primate lentiviruses and likely plays a key role in pathogenesis by focusing viral infection onto cells that mediate adaptive immune responses and in protecting virions attached to cells from neutralizing antibodies. Although CD4-independent viruses are well described for HIV and SIV, these viruses characteristically retain their CD4 binding site and can engage CD4 if available. We derived a novel CD4-independent, CCR5-tropic variant of the pathogenic molecular clone SIVmac239, termed iMac239. The genetic determinants of iMac239's CD4 independence provide new insights into mechanisms that underlie this phenotype. This virus remained replication competent even after its CD4 binding site had been ablated by mutagenesis. As the first truly non-CD4-tropic SIV, lacking the capacity to interact with CD4, iMac239 will provide the unique opportunity to evaluate SIV pathogenesis and host immune responses in the absence of the immunomodulatory effects of CD4 ؉ T cell targeting and infection.T he primate lentiviruses human immunodeficiency virus type 1 (HIV-1), HIV-2, and simian immunodeficiency virus (SIV) share a mechanism of target cell entry by interacting with CD4 and a member of the chemokine receptor family (1-3). CD4 binding to the envelope glycoprotein (Env) trimer initiates a ca...

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Cell-to-cell contact facilitates HIV transmission from lymphocytes to astrocytes via CXCR4

Cited by 48 publications

References 76 publications

Astrocytes sustain long‐term productive HIV‐1 infection without establishment of reactivable viral latency

Astrocytes sustain long‐term productive HIV‐1 infection without establishment of reactivable viral latency

Synthetic AAV/CRISPR vectors for blocking HIV‐1 expression in persistently infected astrocytes

Derivation and Characterization of a CD4-Independent, Non-CD4-Tropic Simian Immunodeficiency Virus

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