T cell Activation does not drive CD4 decline in longitudinally followed HIV-infected Elite Controllers

Kamya, Philomena; Tsoukas, Christos; Boulet, Salix; Routy, Jean Pierre; Thomas, Réjean; Côté, Pierre; Boulassel, Mohamed Rachid; Lessard, Bernard; Kaul, Rupert; Ostrowski, Mario; Kovacs, Colin; Tremblay, Cécile; Bernard, Nicole F.

doi:10.1186/1742-6405-8-20

Cited by 20 publications

(17 citation statements)

References 27 publications

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“…Elite controllers have been shown to have a greater magnitude of immune activation compared to those with suppressed viral load on ART [24]. Despite this finding, however, one study showed that T cell activation was not a driver of CD4 decline in elite controllers [26]. Since HIV is a chronic inflammatory disease, the development of a therapeutic vaccine that can reduce immune activation as well as reduce plasma viremia would be highly advantageous.…”

Section: Elite Controllers and Ltnp As Models For Functional Cure Of mentioning

confidence: 86%

Elite Controllers and Long-term Nonprogressors: Models for HIV Vaccine Development?

Okulicz¹

2012

J AIDS Clinic Res

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Section: Elite Controllers and Ltnp As Models For Functional Cure Of mentioning

confidence: 86%

Elite Controllers and Long-term Nonprogressors: Models for HIV Vaccine Development?

Okulicz¹

2012

J AIDS Clinic Res

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“…Tolerance to self and the state of activation of NK cells is determined by an ontogenic process known as education, which requires the interaction of inhibitory NK receptors (iNKRs) with their cognate HLA ligands on neighboring cells . Education is a complex process whereby functionality is tuned by the number of iNKRs engaged, the strength of interactions between iNKRs and their ligands and whether activating NK cell receptors (aNKRs) are also engaged . NK cells lacking iNKRs for self‐HLA ligands remain uneducated and hyporesponsive .…”

Section: Introductionmentioning

confidence: 99%

Differential contribution of education through KIR2DL1, KIR2DL3, and KIR3DL1 to antibody-dependent (AD) NK cell activation and ADCC

Lisovsky

Kant

Tremblay‐McLean

et al. 2019

Journal of Leukocyte Biology

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The engagement of activating NK receptors (aNKR) stimulates NK cell activity, provided that interactions between inhibitory NK receptors (iNKR) with their HLA ligands do not override them. Abs bound to target cells can also activate NK cells by engaging the CD16 aNKR. NK cell education status is an important factor for Ab‐dependent NK cell activation (ADNKA) of some NK cell subsets. However, whether NK cell education also influences Ab‐dependent cellular cytotoxicity (ADCC) levels is not fully known. ADCC‐GranToxiLux (GTL) assays measured ADCC activity as the frequency of granzyme B positive (%GzB+) target cells. Target cells were anti‐HIV Immunoglobulin G (HIVIG)‐opsonized CEM‐NKr.CCR5 (CEM) cells. Lymphocytes and sorted single positive (SP) NKG2A+, KIR2DL1+, KIR2DL3+, and KIR3DL1+ NK cells, to self‐ and nonself HLA, were used as effectors in ADCC‐GTL assays to examine how education status influenced ADCC activity. ADNKA activity was assessed by stimulating lymphocytes with HIVIG‐opsonized CEMs and measuring the frequency of NK cell populations defined by their expression of iNKRs, along with IFN‐γ, CCL4, and CD107a functions. ADCC: the %GzB+ CEM cells generated by self‐ versus nonself HLA‐specific SPiNKR did not differ. ADNKA: More NK cells educated through KIR2DL1 and KIR3DL1, but not KIR2DL3, responded to ADNKA than their uneducated counterparts. CD16 engagement induced ADCC and ADNKA activity. With the proviso that groups’ sizes were small, our results support the notion that NK cell education does not influence ADCC levels but does contribute to ADNKA activity.

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“…In the majority of these patients, this spontaneous control of HIV-1 is associated with normal CD4 T cells, however, a small proportion of elite controllers develops declining number of CD4 T cells despite undetectable levels of HIV-1 viremia[12–15]. Here, we comprehensively assessed naïve T cell subsets, thymic output and frequencies of recent thymic emigrants in a cohort of EC with normal or low CD4 T cell counts.…”

Section: Introductionmentioning

confidence: 99%

CD4 T-cell regeneration in HIV-1 elite controllers

Yang

Al-Mozaini²,

Buzón³

et al. 2012

Aids

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Background Elite controllers spontaneously control HIV-1 replication, which in many cases is associated with preservation of normal CD4 T cell counts. However, a subset of elite controllers has progressive CD4 T cell losses despite undetectable viral loads, for reasons that remain undefined. Here, we assessed mechanisms of CD4 T cell homeostasis in elite controllers with progressive vs. non-progressive HIV-1 disease courses. Methods Flow cytometry assays were used to determine the proliferation, activation and apoptosis levels of naïve T cells in elite controllers with high or low CD4 T cell counts, and reference cohorts of HIV-1 negative and HAART-treated persons. Thymic output was measured by sjTREC/βTREC ratios, and the frequency of circulating recent thymic emigrants was flow-cytometrically determined by surface expression of protein tyrosine kinase 7 (PTK7). Results Proportions of naïve T cells in elite controllers were severely reduced and closely resemble those of HIV-1 patients with progressive disease. Despite reductions of naïve T cells, most elite controllers were able to maintain normal total CD4 T-cell counts by preservation of uncompromised thymic function in conjunction with extrathymic processes that led to elevated levels of circulating recent thymic emigrants. In contrast, elite controllers with low CD4 T-cell counts had reduced thymic output that mirrored thymic dysfunction during untreated progressive HIV-1 infection. Conclusion These results indicate that both thymic and extrathymic mechanisms contribute to CD4 T cell maintenance in elite controllers and support the idea that CD4 T-cell homeostasis and control of viral replication are distinct, but frequently coinciding processes

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T cell Activation does not drive CD4 decline in longitudinally followed HIV-infected Elite Controllers

Cited by 20 publications

References 27 publications

Elite Controllers and Long-term Nonprogressors: Models for HIV Vaccine Development?

Elite Controllers and Long-term Nonprogressors: Models for HIV Vaccine Development?

Differential contribution of education through KIR2DL1, KIR2DL3, and KIR3DL1 to antibody-dependent (AD) NK cell activation and ADCC

CD4 T-cell regeneration in HIV-1 elite controllers

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