High CD56++CD16- natural killer (NK) cells among suboptimal immune responders after four years of suppressive antiretroviral therapy in an African adult HIV treatment cohort.
BACKGROUND
Up to 40% of HIV-infected individuals receiving Highly Active Antiretroviral Therapy (HAART) have poor CD4+ T-cell recovery. The role of natural killer (NK) cells in immune recovery during HAART is not well understood. We described the profiles of NK cell subsets and their expression of activating receptor, NKG2D and cytotoxicity receptor NKp46 among suboptimal immune responders to despite four years of suppressive HAART.


METHODS
A case control study utilized frozen peripheral blood mononuclear cells (PBMC) from a cohort of HIV-infected adults that initiated HAART in 2004/5, at CD4 < 200 cells/μl. Cases were 'suboptimal' responders; patients within the lowest quartile of CD4+ T-cell reconstitution, with a median CD4 count increase of 129 (-43-199) cells/μl (difference between CD4 count at baseline and after 4 years of HAART) and controls were 'super-optimal' responders; patients within the highest quartile of CD4 T-cell reconstitution with a median CD4 count increase of 528 (416-878) cells/μl). Expression of NK cell lineage markers (CD56+/-CD16+/-) and receptors NKG2D and NKp46, was measured among PBMC from 29 cases of 'suboptimal' responders' and 23 controls of 'super-optimal responders', and compared among 'suboptimal' and 'super-optimal' responders. NK cell populations were compared using the Holm Sidak multiple comparison test and p values < 0.05 were considered statistically significant. Data was analyzed using FLOWJO and GraphPad Prism 6.


RESULTS
'Suboptimal responders' had a higher proportion of cytokine producing CD56(++)CD16(+/-) (CD56bri) NK cells than the 'super-optimal responders' p = 0.017, and CD56(neg) NK cells were lower among suboptimal than super-optimal responders (p = 0.007). The largest NK cell subset, CD56(dim), was comparable among suboptimal responders and 'super-optimal immune responders'. Expression of NKG2D and NKp46 receptors on NK cell subsets (CD56(bri), CD56(neg) and CD56(dim)), was comparable among 'suboptimal' and 'super-optimal' immune responders.


CONCLUSIONS
The pro-inflammatory CD56++CD16-- NK cells were higher among 'suboptimal' responders relative to 'super-optimal' responders, despite four years of suppressive HAART. Alteration of NK cell populations could inhibit host immune responses to infections among suboptimal responders. We recommend further analysis of NK cell function among suboptimal immune responders in order to inform targeted interventions to optimize immune recovery among HAART-treated adults.
Lois
L
Bayigga
Rose
R
Nabatanzi
Prossy Naluyima
PN
Sekiziyivu
Harriet
H
Mayanja-Kizza
Moses R
MR
Kamya
Andrew
A
Kambugu
Joseph
J
Olobo
Agnes
A
Kiragga
Sam
S
Kirimunda
Moses
M
Joloba
Department of Internal Medicine, Makerere University College of Health Sciences, Makerere University, Kampala, Uganda. dnakanjako@gmail.com.
Damalie
D
Nakanjako
D000328:Adult; D023241:Antiretroviral Therapy, Highly Active; D044383:Black People; D019002:CD56 Antigen / Q000378:metabolism; D016022:Case-Control Studies; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism* / Q000821:virology; D006801:Humans; D016130:Immunophenotyping; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000378:metabolism; D055627:Natural Cytotoxicity Triggering Receptor 1 / Q000378:metabolism; D010641:Phenotype; D017452:Receptors, IgG / Q000378:metabolism
D019002:CD56 Antigen; C527085:KLRK1 protein, human; C112260:NCR1 protein, human; D055655:NK Cell Lectin-Like Receptor Subfamily K; D055627:Natural Cytotoxicity Triggering Receptor 1; D017452:Receptors, IgG