Aberrant natural killer (NK) cell activation and dysfunction among ART-treated HIV-infected adults in an African cohort

Nabatanzi, Rose; Bayigga, Lois; Cose, Stephen; Rowland‐Jones, Sarah; Canderan, Glenda; Joloba, Moses; Nakanjako, Damalie

doi:10.1016/j.clim.2019.02.010

Cited by 38 publications

(35 citation statements)

References 34 publications

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“…Unfortunately, both T and NK cells’ effector responses often become dysfunctional upon HIV infection ( 22 , 23 ), and do not completely recover even after ART treatment ( 24 , 25 ), which historically has been initiated during the chronic phase of infection. However, there exists rare PLWH that can naturally control HIV in the absence of ART through immune-mediated mechanisms.…”

Section: Introductionmentioning

confidence: 99%

Deep Phenotypic Analysis of Blood and Lymphoid T and NK Cells From HIV+ Controllers and ART-Suppressed Individuals

et al. 2022

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T and natural killer (NK) cells are effector cells with key roles in anti-HIV immunity, including in lymphoid tissues, the major site of HIV persistence. However, little is known about the features of these effector cells from people living with HIV (PLWH), particularly from those who initiated antiretroviral therapy (ART) during acute infection. Our study design was to use 42-parameter CyTOF to conduct deep phenotyping of paired blood- and lymph node (LN)-derived T and NK cells from three groups of HIV+ aviremic individuals: elite controllers (N = 5), and ART-suppressed individuals who had started therapy during chronic (N = 6) vs. acute infection (N = 8), the latter of which is associated with better outcomes. We found that acute-treated individuals are enriched for specific subsets of T and NK cells, including blood-derived CD56-CD16+ NK cells previously associated with HIV control, and LN-derived CD4+ T follicular helper cells with heightened expansion potential. An in-depth comparison of the features of the cells from blood vs. LNs of individuals from our cohort revealed that T cells from blood were more activated than those from LNs. By contrast, LNs were enriched for follicle-homing CXCR5+ CD8+ T cells, which expressed increased levels of inhibitory receptors and markers of survival and proliferation as compared to their CXCR5- counterparts. In addition, a subset of memory-like CD56brightTCF1+ NK cells was enriched in LNs relative to blood. These results together suggest unique T and NK cell features in acute-treated individuals, and highlight the importance of examining effector cells not only in blood but also the lymphoid tissue compartment, where the reservoir mostly persists, and where these cells take on distinct phenotypic features.

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Section: Introductionmentioning

confidence: 99%

Deep Phenotypic Analysis of Blood and Lymphoid T and NK Cells From HIV+ Controllers and ART-Suppressed Individuals

et al. 2022

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“…The ADCC involves both the antibodies and effector cells like NK cells. It is known that HIV-infected individuals are known to have compromised NK cell function ( 45 ). Although ADCC antibodies can effectively identify HIV-1-infected cells, the NK cells in these patients may not be able to lyse the reactivated reservoir ( 46 ).…”

Section: Discussionmentioning

confidence: 99%

HIV-gp140-Specific Antibodies Generated From Indian Long-Term Non-Progressors Mediate Potent ADCC Activity and Effectively Lyse Reactivated HIV Reservoir

2022

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Strategies to reduce the human immunodeficiency virus (HIV) reservoir are urgently required. The antibody-dependent cellular cytotoxicity (ADCC)-mediating anti-HIV antibodies have shown an association with HIV control. We assessed if such antibodies can be generated in vitro and whether the generated antibodies can facilitate the reduction of reactivated HIV reservoir. We isolated HIV-1-gp140-specific memory B cells from HIV-1-infected long-term non-progressors (LTNPs) with or without plasma ADCC and cultured them to generate anti-HIV antibodies. The ability of the generated antibodies to mediate ADCC and facilitate NK cell-mediated lysis of reactivated HIV reservoir was assessed by the rapid fluorometric antibody-dependent cellular cytotoxicity assay and a flow-based novel latency reduction assay, respectively. All LTNPs showed the presence of gp140-specific memory B cells [median: 0.79% (0.54%–1.225%)], which were successfully differentiated into plasma cells [median 72.0% (68.7–82.2%)] in an in-vitro culture and secreted antibodies [median OD: 0.253 (0.205–0.274)]. The HIV-gp140-specific antibodies were generated from 11/13 LTNPs irrespective of their plasma ADCC status. The generated antibodies from LTNPs with plasma ADCC showed higher ADCC potency (median: 37.6%, IQR: 32.95%–51%) and higher reduction in reactivated HIV reservoir (median: 62.5%, IQR: 58.71%–64.92%) as compared with the antibodies generated from LTNPs without plasma ADCC (ADCC: median: 8.85%, IQR: 8%–9.7%; and % p24 reduction median: 13.84, IQR: 9.863%–17.81%). The potency of these antibodies to reduce latent reservoir was two-fold higher than the respective plasma ADCC. The study showed that the potent ADCC-mediating antibodies could be generated from memory B cells of the LTNPs with plasma ADCC activity. These antibodies also showed potent ability to facilitate NK cell-mediated lysis of reactivated HIV reservoirs. It also indicated that memory B cells from individuals with plasma ADCC activity should be preferentially used for such antibody generation. The important role of these antibodies in the reduction of latent reservoirs needs to be further evaluated as a useful strategy to obtain a functional cure for HIV infection.

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“…NKG2D is an activating receptor that binds to the surface ligand NKG2DL to mediate the killing function of NK cells. Numerous studies have reported a general decrease in NKG2D expression in HIV-infected individuals ( 21 , 60 ). In addition, NKG2D expression is negatively correlated with viral set point ( 56 ), and the capacity of NK cells to kill target cells decreases with decreased NKG2D ( 61 ).…”

Section: Nk Cell Dysfunction During Hiv Infectionmentioning

confidence: 99%

Negative Regulation and Protective Function of Natural Killer Cells in HIV Infection: Two Sides of a Coin

2022

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Natural killer (NK) cells play an important immunologic role, targeting tumors and virus-infected cells; however, NK cells do not impede the progression of human immunodeficiency virus (HIV) infection. In HIV infection, NK cells exhibit impaired functions and negatively regulate other immune cell responses, although NK cells can kill HIV-infected cells and thereby suppress HIV replication. Considerable recent research has emerged regarding NK cells in the areas of immune checkpoints, negative regulation, antibody-dependent cell-mediated cytotoxicity and HIV reservoirs during HIV infection; however, no overall summary of these factors is available. This review focuses on several important aspects of NK cells in relation to HIV infection, including changes in NK cell count, subpopulations, and immune checkpoints, as well as abnormalities in NK cell functions and NK cell negative regulation. The protective function of NK cells in inhibiting HIV replication to reduce the viral reservoir and approaches for enhancing NK cell functions are also summarized.

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Aberrant natural killer (NK) cell activation and dysfunction among ART-treated HIV-infected adults in an African cohort

Cited by 38 publications

References 34 publications

Deep Phenotypic Analysis of Blood and Lymphoid T and NK Cells From HIV+ Controllers and ART-Suppressed Individuals

Deep Phenotypic Analysis of Blood and Lymphoid T and NK Cells From HIV+ Controllers and ART-Suppressed Individuals

HIV-gp140-Specific Antibodies Generated From Indian Long-Term Non-Progressors Mediate Potent ADCC Activity and Effectively Lyse Reactivated HIV Reservoir

Negative Regulation and Protective Function of Natural Killer Cells in HIV Infection: Two Sides of a Coin

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