Objective: HIV-infected immunological nonresponders (InRs) patients fail to show satisfactory CD4+ T-cell recovery despite virologically effective HAART. We propose that NKp44L, the cellular ligand of an activating natural killer (NK) receptor, expressed only on uninfected bystander CD4+ T cells from HIV-1 infected patients, could play a major role in this phenomenon by sensitizing these cells to NK killing.
Design: Phenotype and multifunctional status of CD4+ T cells, especially the subsets expressing and not expressing NKp44L, were characterized for HIV-infected patients receiving HAART for at least 2 years, during which their viral load remained less than 40 copies/ml; 53 were InRs (CD4 cell count always <350 cells/μl), and 82 immunological responders (CD4 cell count always ≥350 cells/μl). Flow cytometry determined NKp44L expression in association with specific markers of proliferation, maturation, activation, homeostasis, and intracellular cytokine production. Degranulation of NKp44+ determined the functional capacity of NK cells.
Results: InRs exhibited high levels of NKp44L+CD4+ T cells. Compared with NKp44L negative cells, the frequency of naive CD45RA+CCR7+ T cells expressing NKp44L fell (P < 0.001) and their proliferative capacity grew. Moreover, apoptosis and a unique ability to produce multiple cytokines (IL-2, IFN-γ, and TNF-α) without or after phytohemagglutinin or anti-CD3/CD28 stimulation distinguished NKp44L+ T cells.
Conclusion: InR status is associated to a significant expansion of highly differentiated, multifunctional and apoptotic CD4+ T cells expressing NKp44L. This could explain a rapid CD4+ T-cell turnover in InR preventing immune recovery. These data suggest a new target for developing therapeutic strategies to prevent NKp44L expression and then stimulating immune recovery in InRs.
aINSERM UMR-S 945, Hôpital Pitié-Salpêtrière Paris
bUniversité Pierre et Marie Curie (Paris-6)
cInnaVirVax SA, Evry
dAP-HP, Département d’Immunologie Hôpital La Pitié-Salpêtrière, Paris
eAP-HP, Service des Maladies Infectieuses, Hôpital La Pitié-Salpêtrière
fAP-HP, Service de Médecine Interne. Hôpital La Pitié-Salpêtrière Paris, France.
Correspondence to Vincent Vieillard, PhD, Laboratoire Immunité and Infection, Université, Pierre and Marie Curie, INSERM UMR-S 945, Hôpital Pitié-Salpêtrière, 83 boulevard de l’Hôpital, Bâtiment CERVI, 75013 Paris, France. Tel: +33 1 42 17 75 24; fax: +33 1 42 17 74 90; e-mail: firstname.lastname@example.org
Received 7 January, 2013
Revised 21 March, 2013
Accepted 27 March, 2013
This work was supported in part by the Institut National de la Recherche Médicale (INSERM), and the Université Pierre et Marie Curie, Paris. Alexis Sennepin is supported by a CIFRE fellowship from the Association Nationale de la Recherche et de la Technologie (ANRT) and InnaVirVax SA (#846/2009)
Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (http://www.AIDSonline.com).