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The Journal of Immunology, 2006, 177: 5775-5778.
Copyright © 2006 by The American Association of Immunologists, Inc.

CUTTING EDGE

Cutting Edge: Rapid Recovery of NKT Cells upon Institution of Highly Active Antiretroviral Therapy for HIV-1 Infection1

Hans J. J. van der Vliet2,*,{dagger}, Marit G. A. van Vonderen*, Johan W. Molling{dagger},{ddagger}, Hetty J. Bontkes{dagger},{ddagger}, Martine Reijm{ddagger}, Peter Reiss§, Michiel A. van Agtmael*, Sven A. Danner*, Alfons J. M. van den Eertwegh{dagger}, B. Mary E. von Blomberg{ddagger} and Rik J. Scheper{dagger},{ddagger}

* Department of Internal Medicine, {dagger} Department of Medical Oncology, and {ddagger} Department of Pathology, Vrije Universiteit Medical Center, Amsterdam, The Netherlands; and § Department of Infectious Diseases, Tropical Medicine, and AIDS, Academic Medical Center, Amsterdam, The Netherlands


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 Disclosures
 References
 
CD1d-restricted NKT cells play important regulatory roles in various immune responses and are rapidly and selectively depleted upon infection with HIV-1. The cause of this selective depletion is incompletely understood, although it is in part due to the high susceptibility of CD4+ NKT cells to direct infection and subsequent cell death by HIV-1. Here, we demonstrate that highly active antiretroviral therapy (HAART) results in the rapid recovery of predominantly CD4– NKT cells with kinetics that are strikingly similar to those of mainstream T cells. As it is well known that the early recovery of mainstream T cells in response to HAART is due to their redistribution from tissues to the circulation, our data suggest that the selective depletion of circulating NKT cells is likely due to a combination of cell death and tissue sequestration and indicates that HAART can improve immune functions by reconstituting both conventional T cells and immunoregulatory NKT cells.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 Disclosures
 References
 
Natural killer T cells constitute an evolutionary, highly conserved, immunoregulatory T cell subset that is restricted by the CD1d Ag-presenting molecule. NKT cells display an extremely restricted TCR repertoire in humans consisting of a V{alpha}24 chain preferentially paired to Vbeta11 and play crucial roles in various immune responses, including antitumor, autoimmune, allergic, and antimicrobial immune responses (1, 2).

Infection with HIV-1 results in the rapid and selective depletion of NKT cells (3, 4, 5, 6). Although CD4+ NKT cells have been shown to be highly susceptible to direct infection and subsequent cell death by HIV-1, it is important to note that the majority of NKT cells do not express CD4 and that the depletion of NKT cells involves both CD4+ and CD4– subsets (4, 5, 6, 7). Therefore, although the preferential infection of CD4+ NKT cells probably contributes to the depletion of NKT cells during HIV-1 infection, it provides an incomplete explanation.

It is well established that treatment of HIV-1 infection with highly active antiretroviral therapy (HAART)3 results in a rapid (2–3 mo) increase in conventional T cell numbers that reflects redistribution of previously sequestered memory lymphocytes from lymphoid tissue to the circulation (8, 9). Because NKT cells express much higher levels of inflammatory lymphocyte chemokine receptors than other memory or effector T cell subsets (10), we hypothesized that tissue redistribution could be a major factor involved in the depletion of NKT cells during HIV-1 infection.

In this study, we evaluated circulating T and NKT cell responses in HIV-1-infected individuals during their first year of HAART. Initiation of HAART resulted in a remarkably similar and rapid recovery in both circulating T and NKT cell numbers, indicating that the depletion of circulating NKT cells during HIV-1 infection is probably at least in part due to tissue sequestration.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results and Discussion
 Disclosures
 References
 
Patients

Twenty-six male antiretroviral therapy naive HIV-1 infected subjects (mean age, 41 years; range, 27–58); mean CD4+ T cell count 212 cells/µl (range 19–601); median NKT cell count 90 cells/ml (interquartile range, 31–270); and mean viral load, 176,190 copies/ml (range, 13,063–916,000, limit of detection, 50)) were studied. The number of patients classified in Centers for Disease Control stages A, B, and C was 14, 7, and 5, respectively. This study is a substudy of a randomized controlled multicenter trial called MEDICLAS (Metabolic Effects of Different Classes of Antiretrovirals) in which patients received either lopinavir-ritonavir and nevirapine or lopinavir-ritonavir, zidovudine, and lamivudine and included all randomized patients that, at the time of analysis, had received at least one year of HAART.

Flow cytometry and cell culture

Lymphocyte numbers were calculated from heparinized peripheral blood samples using MultiTEST reagents in combination with MultiSET software (BD Biosciences). The following mAbs were used: FITC-labeled V{alpha}24 and PE- and biotin-labeled Vbeta11 (Immunotech); R-PE-Cy5-labeled streptavidin (DakoCytomation); PerCP-Cy5.5-labeled CD3, allophycocyanin-labeled CD4, PE-labeled IL-4, and IFN-{gamma} (BD Biosciences); and PE-labeled CXCR6 and PE-labeled CCR2 (R&D Systems). NKT cells were defined by coexpression of CD3, V{alpha}24, and Vbeta11, because this combination has been shown to be highly specific for {alpha}-galactosylceramide ({alpha}-GalCer)-reactive, CD1d-restricted NKT cells (11). The cytokine profile of NKT cells and the expression of CCR2 and CXCR6 by NKT cells were separately tested in healthy controls and in HIV-1 infected patients who were not included in the randomized controlled trial. The cytokine profile of NKT cells was assessed as described previously (12). In short, NKT cells were enriched from PBMC by magnetic isolation of V{alpha}24+ T cells (Miltenyi Biotec) and subsequently cultured for 7 days in the presence of {alpha}-GalCer-pulsed monocyte derived dendritic cells. Cells were then washed and NKT cell cytokine production was determined by intracellular flow cytometry after a 5-h coculture with CD1d-transfected HeLa cells in the presence of 100 ng/ml {alpha}-GalCer (KRN7000; Kirin Pharmaceutical Research Laboratory) and 1 µl/ml GolgiPlug (BD Biosciences). Flow cytometry was performed on a FACSCalibur device (BD Biosciences).

Statistical analysis

Statistical analyses were performed using Student t tests and a Spearman rank correlation test. p < 0.05 was considered significant.


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
Disclosures
 References
 
HIV-1 RNA viral load and circulating T and NKT cell numbers were evaluated in 26 male HIV-1-infected subjects before and after 3 and 12 mo of HAART. Institution of HAART resulted in a decrease in the viral load from 176,190 ± 41,260 (mean ± SEM) to 337 ± 112 copies/ml at 3 mo (undetectable in 9, p = 0.0002; paired t test) and 52 ± 2 copies/ml at 12 mo (undetectable in 22, p = 0.0002). As expected, this reduction in viral load was accompanied by a significant increase in circulating CD4+ T cell numbers (fold increase of 1.90 ± 0.18 (p < 0.0001) at 3 mo and 2.41 ± 0.33 (p = 0.0002) at 12 mo; Fig. 1, open bars). Importantly, circulating NKT cell numbers similarly increased (2.07 ± 0.36-fold at 3 mo (p = 0.007) and 2.09 ± 0.43-fold at 12 mo (p = 0.02); Fig. 1, closed bars). It is well established that HAART results in a rapid first phase increase in conventional T cells due to redistribution of lymphocytes from tissue sites, followed by a second phase characterized by continuous slow repopulation with newly produced naive T cells (8, 9). Because the vast part of the increase in NKT cells occurred early after the initiation of HAART, our data suggest that this increase is likewise due to redistribution from tissue sites, though we cannot formally exclude the possibility that the recovery of NKT cells is due to NKT cell neogenesis that may follow the HAART-induced reduction of immune activation and the subsequent reduction in activation-induced cell death of NKT cells (13). Interestingly, a recent paper by Moll et al. (14) demonstrated an increase in circulating NKT cell numbers in patients with primary HIV-1 infection treated with a combination of HAART and the T and NKT cell growth factor IL-2, but little reconstitution of NKT cells during HAART alone. However, because circulating NKT cell numbers in that study were still in the normal range before the institution of HAART, it seems reasonable to assume that in patients with primary HIV-1 infection no substantial NKT cell depletion and tissue redistribution has yet occurred and, thus, HAART cannot result in NKT cell reconstitution but can prevent the decline in NKT cells that is expected to occur with progressing HIV-1 infection (3).


Figure 1
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  		FIGURE 1. Recovery of circulating CD4+ T cells and NKT cells upon institution of HAART. Bars show fold increase in CD4+ T cells (open bars; 1.90 ± 0.18-fold (mean ± SEM) at 3 mo (p < 0.0001) and 2.41 ± 0.33-fold at 12 mo (p = 0.0002)) and NKT cells (black bars; 2.07 ± 0.36-fold at 3 mo (p = 0.007) and 2.09 ± 0.43-fold at 12 mo (p = 0.02)) after 3 and 12 mo of HAART. Bars labeled "pre" represent cells before institution of HAART.

 
Although these data demonstrate that HAART can result in the recovery of both CD4+ T and NKT cells, it is important to note that although all patients showed a virologic response upon initiation of HAART, not all patients showed a concomitant increase in CD4+ T cell numbers. This phenomenon of incomplete immune reconstitution despite successful suppression of plasma HIV-1 viremia is well known and has been attributed to ongoing increased immune activation and turnover (15). To evaluate whether NKT cell recovery differed depending on the extent of CD4+ T cell recovery, patients were divided into two groups based on the presence (n = 21) or absence (n = 5) of a >10% increase in CD4+ T cell counts after 3 mo of HAART. We focused on the first 3 mo of HAART because changes in the size of the CD4+ T and NKT cell population predominantly occurred during this period (Fig. 1). Fig. 2A shows that patients responding to HAART with a >10% increase in CD4+ T cells also had an increase in their NKT cell numbers at 3 mo (a fold increase of 2.51 ± 0.65 (p = 0.0017) and an absolute increase of 126 ± 43 cells/ml (p = 0.009)). In contrast, in all patients with a poor initial CD4+ T cell response a further decrease in NKT cell numbers was observed (a fold change of 0.54 ± 0.09 (p = 0.006) and an absolute decrease of 345 ± 244 cells/ml (p = 0.23)). In accordance, we found that there was a strong correlation between the absolute recovery of CD4+ T cells and NKT cells (correlation coefficient (r) = 0.67, p = 0.0004; Spearman rank correlation test) as illustrated in Fig. 2B. Altogether, these results indicate that the response of NKT cells and CD4+ T cells to HAART is not only strikingly similar in timing but also in occurrence. To evaluate whether the reconstituted NKT cells were functional, we analyzed their capacity to produce IFN-{gamma} and IL-4 in response to antigenic stimulation with the glycolipid {alpha}-GalCer and CD1d-transfected HeLa cells. Importantly, the IFN-{gamma}/IL-4 ratio of NKT cells from HAART-treated HIV-1-infected patients (5.2 ± 3.2, mean ± SD, n = 4) was within the range of that of healthy controls (18.2 ± 15.2, n = 3, p = 0.15; unpaired t test (not shown)). Furthermore, as CD4– NKT cells were previously reported to be more Th1 biased than CD4+ NKT cells (16, 17), we also determined the cytokine profile of CD4+ and CD4– NKT cell subsets and found that the CD4– subset of reconstituted NKT cells contained similar numbers of IL-4-producing cells (9.7 ± 8.3% of CD4– and 14.7 ± 7.6% of CD4+ NKT cells, n = 4, p = 0.28; paired t test) but significantly more IFN-{gamma} producing cells (46.2 ± 13.5% of CD4– and 27.1 ± 11.7% of CD4+ NKT cells, n = 4, p = 0.04), further supporting the view that the reconstituted NKT cells of HIV-1 infected patients are functional and that subsets have retained their biased cytokine profile.


Figure 2
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  		FIGURE 2. Correlation between NKT cell recovery and CD4+ T cell recovery upon institution of HAART. A, Bars show fold change in CD4+ T cells and NKT cells after 3 mo of HAART in patients responding to HAART with a greater (open bars, responders (R); change in CD4+ T cells was 2.15 ± 0.20-fold (mean ± SEM, p < 0.0001); change in NKT cells was 2.51 ± 0.65-fold (p = 0.0017)) or smaller (filled bars, nonresponders (NR); change in CD4+ T cells was 0.99 ± 0.05-fold (p = 0.90); change in NKT cells was 0.54 ± 0.09-fold (p = 0.006)) than 10% increase in CD4+ T cells. B, Correlation between absolute changes in circulating NKT cells (number per milliliter of peripheral blood) and CD4+ T cells (number per microliter peripheral blood) after 3 mo of HAART (r = 0.67, p = 0.0004; Spearman rank correlation test).

 
To evaluate whether the recovery of NKT cells was due to the selective recruitment of CD4+ or CD4– NKT cells, we determined the contribution of both subsets to the total NKT cell pool in five patients that showed a virologic, CD4+ T cell, and NKT cell response to HAART. In this group we noted that the increase in NKT cell numbers during HAART resulted from an increase in CD4– NKT cells (p = 0.03; paired t test), but not in CD4+ NKT cells (p = 0.98; Fig. 3). Recently, CXCL16/CXCR6 and CCL2/CCR2 interactions were reported to play a major role in NKT cell trafficking (18, 19, 20). Because both CXCL16 and CCL2 are induced under proinflammatory conditions (21, 22), as occurs during HIV-1 infection, and their receptors have been reported to be predominantly expressed by CD4– NKT cells (23), one could hypothesize that this differential expression of CCR2 and CXCR6 on NKT cell subsets might be involved in the predominant recovery of CD4– NKT cells during HAART. Therefore, we additionally evaluated the expression of CCR2 and CXCR6 on CD4+ and CD4– NKT cells. In healthy volunteers we found that CCR2 was indeed predominantly expressed by CD4– NKT cells (90.8 ± 9.5% of CD4– and 59 ± 23.1% of CD4+ NKT cells, n = 5, p = 0.03; paired t test), but CXCR6 expression was comparable among both NKT cell subsets (79.2 ± 8.7% of CD4– and 67.6 ± 27.3% of CD4+ NKT cells, p = 0.28). Notably, in HIV-1-infected patients that were not treated with HAART the proportion of NKT cells expressing CCR2, and to a lesser extent CXCR6, was substantially decreased (p < 0.0001 and p = 0.03 respectively; unpaired t test), suggesting that NKT cells expressing these chemokine receptors were selectively depleted from the circulation. However, as the proportion of NKT cells expressing CCR2 or CXCR6 was not significantly higher in HAART-treated compared with HAART-untreated HIV-1-infected patients (p = 0.48 for CCR2 and p = 0.50 for CXCR6; unpaired t test), our data do not indicate that HAART-induced modulation of the ligands of these chemokine receptors plays a dominant role in the reconstitution of NKT cells (Fig. 4).


Figure 3
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  		FIGURE 3. Increase in CD4– NKT cells during HAART. Absolute numbers of circulating CD4– and CD4+ NKT cells (number per microliter of peripheral blood) in five donors before (pre) and after 3 mo of HAART. There was a significant increase in CD4– NKT cell numbers (p = 0.03) but no significant change in CD4+ NKT cell numbers (p = 0.98).

 

Figure 4
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  		FIGURE 4. Expression of CCR2 and CXCR6 on NKT cells. Bars indicate the proportion of NKT cells expressing CCR2 and CXCR6 in healthy controls (open bars; n = 5), HIV-1-infected patients not on HAART (filled bars; n = 5), and HIV-1-infected patients on HAART (hatched bars; n = 5). Significantly lower expression of CCR2 (p < 0.0001) and CXCR6 (p = 0.03) on NKT cells of HAART naive HIV-1-infected patients compared with healthy controls. Data indicate mean and SD.

 
In conclusion, we demonstrate that HAART results in the rapid recovery of both mainstream T and predominantly CD4– NKT cells with striking similarities in occurrence and kinetics. As the early recovery of mainstream T cells in response to HAART has been shown to be due to their redistribution from tissues to the circulation, our data suggest that the observed selective depletion of NKT cells during HIV-1 infection is not only caused by the previously reported loss of CD4+ NKT cells as a consequence of cell death after infection with HIV-1 but may also be attributed in part to tissue sequestration of NKT cells. Recently, it was shown that levels of CD1d are down-regulated by HIV-1 Nef and gp120 proteins and that HAART-induced viral suppression restored CD1d expression levels (24, 25, 26). These data, together with our current data, indicate that the immune reconstitution mediated by HAART is not restricted to conventional CD4+ and CD8+ T cells but also involves reconstitution of an important immunoregulatory axis represented by CD1d and NKT cells.


   Acknowledgments
 
We gratefully acknowledge the following investigators and research nurses for their assistance in recruiting patients for the main study: Dr. K. Brinkman and L. Schrijnders-Gudde (Onze Lieve Vrouwe Gasthuis, Amsterdam, Netherlands); Dr. J. M. Gatell, Dr. E. Martinez, and Dr. A. Milinkovic (Hospital Clinic, Barcelona, Spain); Dr. S.E. Geerlings, Dr. S. Lowe, Dr. E. Hassink, and N. Hulshoff (Academic Medical Center, Amsterdam); Dr. R.M. Perenboom, Dr. F.A.P. Claessen, L.Hegeman, and J. Stadwijk (Vrije Universiteit Medisch Centrum, Amsterdam); Dr. M. Ristola, Dr. J. Sutinen, and O. Debnam (Helsinki University Central Hospital, Helsinki, Finland); Dr. A. van Eeden and J. Tesselaar (Medisch Centrum Jan van Goyen, Amsterdam); Dr. F. Kroon, Dr. L.B.S. Gelinck, and W. Dorama (Leids Universitair Medisch Centrum, Leiden, Netherlands); Dr. M. Youle and A. Carroll (Royal Free Hospital London, U.K.); and Dr. R. ten Kate, M. Schoemaker and A. Kritsos (Kennemer Gasthuis, location Elisabeth Gasthuis, Haarlem, Netherlands).


   Disclosures
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 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 Disclosures
References
 
The authors have no financial conflict of interest.


   Footnotes
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 This work was supported by a Netherlands Organization for Scientific Research TALENT Grant and Grant 920-03-142 and by a Dutch Cancer Society Academic Grant and Grant VU2002-2607. Back

2 Address correspondence and reprint requests to Dr. Hans J. J. van der Vliet, Department of Internal Medicine, Vrije Universiteit Medisch Centrum, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands. E-mail address: jj.vandervliet{at}vumc.nl Back

3 Abbreviations used in this paper: HAART, highly active antiretroviral therapy; {alpha}-GalCer, {alpha}-galactosylceramide. Back

Received for publication December 30, 2005. Accepted for publication August 14, 2006.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 Disclosures
 References
 

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