Restriction of HIV-1 replication in macrophages and CD4+ T cells from HIV controllers

Sáez‐Cirión, Asier; Hamimi, Chiraz; Bergamaschi, Anna; David, Annie; Versmisse, Pierre; Mélard, Adeline; Boufassa, Faroudy; Barré‐Sinoussi, Françoise; Lambotte, Olivier; Rouzioux, Christine; Pancino, Gianfranco

doi:10.1182/blood-2010-12-327106

Cited by 104 publications

(119 citation statements)

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“…It has been previously shown that infection conditions such as exogenous activation or high virus inoculum can influence viral replication (24,26). Although these cultures a Cytokine values significantly different from those of the NEG group are shown in bold (P Ͻ 0.05; FDR Ͻ 0.1).…”

Section: Resultsmentioning

confidence: 99%

“…Both CD4 ϩ and CD8 ϩ HIV-specific T cell responses are stronger in ECs than in subjects with progressive HIV infection (20)(21)(22). Some reports note that CD4 ϩ T cells from ECs are less susceptible to HIV infection (23,24), while others have found decreased virion production from HIV-infected cells in ECs (25) as well as decreased viral integration into the cellular genome (26). Moreover, the EC phenotype is associated with specific HLA-B and -C genotypes (27).…”

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confidence: 99%

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Cytokines Elevated in HIV Elite Controllers Reduce HIV ReplicationIn Vitroand Modulate HIV Restriction Factor Expression

Jacobs

Keating

Abdel‐Mohsen

et al. 2017

J Virol

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A subset of HIV-infected individuals termed elite controllers (ECs) maintain CD4 ϩ T cell counts and control viral replication in the absence of antiretroviral therapy (ART). Systemic cytokine responses may differentiate ECs from subjects with uncontrolled viral replication or from those who require ART to suppress viral replication. We measured 87 cytokines in four groups of women: 73 ECs, 42 with pharmacologically suppressed viremia (ART), 42 with uncontrolled viral replication (noncontrollers [NCs]), and 48 HIV-uninfected (NEG) subjects. Four cytokines were elevated in ECs but not NCs or ART subjects: CCL14, CCL21, CCL27, and XCL1. In addition, median stromal cell-derived factor-1 (SDF-1) levels were 43% higher in ECs than in NCs. The combination of the five cytokines suppressed R5 and X4 virus replication in resting CD4 ϩ T cells, and individually SDF-1␤, CCL14, and CCL27 suppressed R5 virus replication, while SDF-1␤, CCL21, and CCL14 suppressed X4 virus replication. Functional studies revealed that the combination of the five cytokines upregulated CD69 and CCR5 and downregulated CXCR4 and CCR7 on CD4 ϩ T cells. The CD69 and CXCR4 effects were driven by SDF-1, while CCL21 downregulated CCR7. The combination of the EC-associated cytokines induced expression of the anti-HIV host restriction factors IFITM1 and IFITM2 and suppressed expression of RNase L and SAMHD1. These results identify a set of cytokines that are elevated in ECs and define their effects on cellular activation, HIV coreceptor expression, and innate restriction factor expression. This cytokine pattern may be a signature characteristic of HIV-1 elite control, potentially important for HIV therapeutic and curative strategies.IMPORTANCE Approximately 1% of people infected with HIV control virus replication without taking antiviral medications. These subjects, termed elite controllers (ECs), are known to have stronger immune responses targeting HIV than the typical HIV-infected subject, but the exact mechanisms of how their immune responses control infection are not known. In this study, we identified five soluble immune signaling molecules (cytokines) in the blood that were higher in ECs than in subjects with typical chronic HIV infection. We demonstrated that these cytokines can activate CD4 ϩ T cells, the target cells for HIV infection. Furthermore, these five EC-

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Cytokines Elevated in HIV Elite Controllers Reduce HIV ReplicationIn Vitroand Modulate HIV Restriction Factor Expression

Jacobs

Keating

Abdel‐Mohsen

et al. 2017

J Virol

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“…Phytohemagglutinin (PHA)-activated CD4 + T cells from ES are susceptible to infection (7,8,(26)(27)(28)(29)(30), but studies that have used CD3 stimulation to activate CD4 + T cells from ES have yielded conflicting results. One study suggested that cells from ES were resistant to infection because of selective up-regulation of cyclin-dependent kinase inhibitor p21 (31), whereas another study also found resistance of ES CD4 + T cells to HIV-1 infection but showed that p21 plays no role in this phenomenon (32). A third study found that CD4 + T cells from ES were as susceptible to infection as CD4 + T cells from HIV-1 seronegative donors (9).…”

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confidence: 96%

CD4⁺T cells from elite suppressors are more susceptible to HIV-1 but produce fewer virions than cells from chronic progressors

O’Connell¹,

Rabi²,

Siliciano

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Elite suppressors/controllers (ES) are HIV-1-infected individuals who maintain stable CD4 + T-cell counts and viral loads of <50 copies/mL without antiretroviral therapy. Research has predominantly focused on immune factors contributing to the control of viral replication in these patients. A more fundamental question, however, is whether there are differences in the nature of CD4 + Tcell infection in ES compared with viremic patients. Here, we compare chronic progressor (CP), ES, and uninfected donors in terms of three aspects of CD4 + T-cell infection: cellular susceptibility to infection, death of infected cells, and production of virus from infected cells. Using multiple methods of infection and both single-cycle and replication-competent virus, we show that unmanipulated CD4 + T-cell populations from ES are actually more susceptible to HIV-1 infection than those populations from CP. Depletion of highly susceptible cells in CP may contribute to this difference. Using 7AAD and AnnexinV staining, we show that infected cells die more rapidly than uninfected cells, but the increased death of infected cells from CP and ES is proportional. Finally, using an assay for measuring virus production, we show that virus production by cells from CP is high compared with virus production by cells from ES or uninfected donors. This higher virus production is linked to cellular activation levels. These data identify fundamental differences in chronic infection of ES and CP that likely contribute to differential HIV-1 disease progression.burst size | cell death

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“…While low-level viral replication appears to occur in these patients, known as elite controllers or elite suppressors (ES) (40), the quantity of total (24,30,46) and integrated (23) proviral DNA and replication-competent HIV-1 (8) in circulating CD4 ϩ T cells is small compared to HIV-1-infected patients on HAART. The frequency of HIV-1-infected monocytes in the peripheral blood of ES has not been determined, and the role HIV-1-infected macrophages play in viral persistence in ES is unknown.…”

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confidence: 99%

Circulating Monocytes Are Not a Major Reservoir of HIV-1 in Elite Suppressors

Spivak

Salgado

Rabi

et al. 2011

J Virol

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Restriction of HIV-1 replication in macrophages and CD4+ T cells from HIV controllers

Cited by 104 publications

References 53 publications

Cytokines Elevated in HIV Elite Controllers Reduce HIV ReplicationIn Vitroand Modulate HIV Restriction Factor Expression

Cytokines Elevated in HIV Elite Controllers Reduce HIV ReplicationIn Vitroand Modulate HIV Restriction Factor Expression

CD4⁺T cells from elite suppressors are more susceptible to HIV-1 but produce fewer virions than cells from chronic progressors

Circulating Monocytes Are Not a Major Reservoir of HIV-1 in Elite Suppressors

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Restriction of HIV-1 replication in macrophages and CD4+ T cells from HIV controllers

Cited by 104 publications

References 53 publications

Cytokines Elevated in HIV Elite Controllers Reduce HIV ReplicationIn Vitroand Modulate HIV Restriction Factor Expression

Cytokines Elevated in HIV Elite Controllers Reduce HIV ReplicationIn Vitroand Modulate HIV Restriction Factor Expression

CD4+T cells from elite suppressors are more susceptible to HIV-1 but produce fewer virions than cells from chronic progressors

Circulating Monocytes Are Not a Major Reservoir of HIV-1 in Elite Suppressors

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CD4⁺T cells from elite suppressors are more susceptible to HIV-1 but produce fewer virions than cells from chronic progressors