Can HIV-1-Specific ADCC Assist the Clearance of Reactivated Latently Infected Cells?

Lee, Wen Shi; Parsons, Matthew S.; Kent, Stephen J.; Lichtfuss, Marit

doi:10.3389/fimmu.2015.00265

Cited by 25 publications

(28 citation statements)

References 55 publications

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“…Given that cumulative signals are important determinants of ADCC susceptibility, future research should assess if target cells infected with viruses coding for wild-type Nef become susceptible to ADCC after blockade of inhibitory NK cell receptors. Such studies could generate potential therapeutic avenues for eliminating HIV-1-infected cells important for curative efforts to eliminate reactivated HIV-1 (39). Finally, whether ligands for other activating or coactivating receptors expressed on HIV-1-infected cells also participate in this cumulative activating signal and modulate ADCC susceptibility remain to be determined.…”

Section: Discussionmentioning

confidence: 99%

Impaired Downregulation of NKG2D Ligands by Nef Proteins from Elite Controllers Sensitizes HIV-1-Infected Cells to Antibody-Dependent Cellular Cytotoxicity

Alsahafi

Richard

Prévost

et al. 2017

J Virol

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HIV-1 Nef clones isolated from a rare subset of HIV-1-infected elite controllers (EC), with the ability to suppress viral load to undetectable levels in the absence of antiretroviral therapy, are unable to fully downregulate CD4 from the plasma membrane of CD4 ϩ T cells. Residual CD4 left at the plasma membrane allows Env-CD4 interaction, which leads to increased exposure of Env CD4-induced epitopes and increases susceptibility of infected cells to antibody-dependent cellular cytotoxicity (ADCC). ADCC is mediated largely by natural killer (NK) cells, which control their activation status through the cumulative signals received through activating and inhibitory receptors. Recently, the activating NKG2D receptor was demonstrated to positively influence ADCC responses. Since HIV-1 Nef has been reported to reduce the expression of NKG2D ligands, we evaluated the relative abilities of Nef from EC and progressors to downmodulate NKG2D ligands. Furthermore, we assessed the impact of EC and progressor Nef on the ADCC susceptibility of HIV-1-infected cells. We observed a significantly increased expression of NKG2D ligands on cells infected with viruses coding for Nef from EC. Importantly, NKG2D ligand expression levels correlated with enhanced susceptibility of HIV-1-infected cells to ADCC. The biological significance of this correlation was corroborated by the demonstration that antibody-mediated blockade of NKG2D significantly reduced ADCC of cells infected with viruses carrying Nef from EC. These results suggest the involvement of NKG2D-NKG2D ligand interactions in the enhanced susceptibility of EC HIV-1-infected cells to ADCC responses.IMPORTANCE Attenuated Nef functions have been reported in HIV-1 isolated from EC. The inability of elite controller Nef to fully remove CD4 from the surface of infected cells enhanced their susceptibility to elimination by ADCC. We now show that downregulation of NKG2D ligands by HIV-1 Nef from EC is inefficient and leaves infected cells susceptible to ADCC. These data suggest a critical role for NKG2D ligands in anti-HIV-1 ADCC responses.KEYWORDS HIV-1, Nef, elite controllers, ADCC, NKG2D, gp120, CD4

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Section: Discussionmentioning

confidence: 99%

Impaired Downregulation of NKG2D Ligands by Nef Proteins from Elite Controllers Sensitizes HIV-1-Infected Cells to Antibody-Dependent Cellular Cytotoxicity

Alsahafi

Richard

Prévost

et al. 2017

J Virol

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“…Non-NAbs capable of mediating ADCC by recruiting Fcγ receptor (FcγR) IIIa–bearing cells such as, NK cells, are of interest as immune therapies to reduce the size of the latent reservoir because these antibodies can target Env on the surface of primary virus–infected cells [44]. The use of mAb-based molecules that can recognize and promote infected cell killing combined with cART is a promising new strategy for treating HIV-1 infection [45–47].…”

Section: Hurdles In Eliminating the Latent Reservoirmentioning

confidence: 99%

Humoral and Innate Antiviral Immunity as Tools to Clear Persistent HIV Infection

Ferrari¹,

Pollara²,

Tomaras³

et al. 2017

The Journal of Infectious Diseases

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Human immunodeficiency virus (HIV) type 1 uses the CD4 molecule as its principal receptor to infect T cells. HIV-1 integrates its viral genome into the host cell, leading to persistent infection wherein HIV-1 can remain transcriptionally silent in latently infected CD4+ T cells. On reactivation of replication-competent provirus, HIV-1 envelope glycoproteins (Env) are expressed and accumulate on the cell surface, allowing infected cells to be detected and targeted by endogenous immune responses or immune interventions. HIV-1 Env-specific antibodies have the potential to bind HIV-1 cell surface Env and promote elimination of infected CD4+ T cells by recruiting cytotoxic effector cells, such as natural killer cells, monocytes, and polymorphonuclear cells. Harnessing humoral and innate cellular responses has become one focus of research to develop innovative strategies to recruit and redirect cytotoxic effector cells to eliminate the HIV-1 latently infected CD4+ T-cell reservoir.

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“…Cytolysis of reactivated cells harboring HIV-1 provirus could theoretically be achieved via antibody-dependent cellular cytotoxicity (ADCC) (10). Anti-HIV-1 antibodies trigger ADCC upon binding cell surface viral proteins and the IgG constant region receptor, Fc␥RIIIa or CD16, of effector cells such as natural killer (NK) cells and monocytes (11)(12)(13).…”

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confidence: 99%

Antibody-Dependent Cellular Cytotoxicity against Reactivated HIV-1-Infected Cells

Lee

Richard

Lichtfuss

et al. 2016

J Virol

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Can HIV-1-Specific ADCC Assist the Clearance of Reactivated Latently Infected Cells?

Cited by 25 publications

References 55 publications

Impaired Downregulation of NKG2D Ligands by Nef Proteins from Elite Controllers Sensitizes HIV-1-Infected Cells to Antibody-Dependent Cellular Cytotoxicity

Impaired Downregulation of NKG2D Ligands by Nef Proteins from Elite Controllers Sensitizes HIV-1-Infected Cells to Antibody-Dependent Cellular Cytotoxicity

Humoral and Innate Antiviral Immunity as Tools to Clear Persistent HIV Infection

Antibody-Dependent Cellular Cytotoxicity against Reactivated HIV-1-Infected Cells

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