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Cytokine profiles of HIV patients with pulmonary tuberculosis resulting from adjunct immunotherapy with herbal phytoconcentrates Dzherelo and Anemin

Contents lists available at ScienceDirect
CYTOKINE
journal homepage: www.elsevier.com/locate/issn/10434666
Lyudmila G. Nikolaeva a'*, Tatiana V. Maystata, Volodymyr S. Pylypchukb, Yuri L. Volyanskiic, Galyna A. Kutsyna d'*
a Kharkov Regional AIDS Prophylaxis and Prevention Center, Kharkov Medical Academy of Postgraduate Education, 6 Bor'by £$reet, Kharkov 61044, Ukraine
b Ekomed^LC, 80-A Prospect Pravdy, Kiev 04208, Ukraine
c I.I. Mechnikov Institute of Microbiology and Immunology, 14 Pushkinskaya street, Kharkov 61057, Ukraine   
d Luhansk Regional AIDS Center and Luhansk State Medical University, p0-Years of Defense ofLuhansk Street, Luhansk 91045, Ukraine
ARTICLE    INFO                                               ABSTRACT              

Article history:

Received 31 August 2008
Received in revised form 4 October 2008
Accepted 10 October 2008
Available online xxxx

Keywords:
AIDS
Botanical
Herbal
Immunotherapy
XDR
MDR
Mycobacterium tuberculosis               
Phytoconcentrate
Phytomedicine
Phytotherapy
Ukraine   
                   
Dzherelo and Anemin when combined with standard anti-tuberculosis therapy (ATT) were shown to produce better clinical outcome than chemotherapy alone. Sixty HIV-positive patients with active pulmonary TB were equally divided into three matched groups to receive either ATT, ATT + Dzherelo, or ATT + Dzherelo + Anemin. Peripheral blood samples were measured by ELISA for plasma levels of IL-2, IL-6, TNF-a, IFN-y, and IFN-a. After 6 months of follow-up Dzherelo and Dzherelo + Anemin combinations produced 61% (P = 0.005) and 44.4% (P =0.06) higher levels of IL-2, whereas in ATT group they were 33.1%_(P = 0.002). The levels of IL-6 increased by 17% (P = 0.15) in ATT group, but declined in both immune intervention groups by 26.2% (P = 0.007) and 21.3% (P = 0.22). TNF-a was suppressed in two immunotherapy groups by 19.1% £P = 0.06) and 76.3% (P = CJX)2)' respectively, but had risen by 14%(P = 0.42) in ATT patients. The pattern of production of IFN-y was opposite to that of TNF-a, but statistical significance was stronger in patients receiving ATT and Dzherelo + Anemin than in Dzherelo group: ^34% (P =^.004), +31.9% (P = 0.008), and +17.3% (P =0.33), respectively. Moderately decreased levels of IFN-a were observed in all treatment arms (range (j.9-16.6%) but differences were not significant. Despite considerable intra-group variation in cytokine production, the baseline inter-group averages were not statistically different indicating that the results were not biased by sample heterogeneity. Immunomodulators used in this study possibly act by enhancing natural immune response against TB. Expanded study of other cytokines and correlates relevant to control and protection from TB and HIV is needed in order to identify biomarkers of favorable treatment outcome, which may aid design of better immune interventions and vaccines.
                                    © 2008 Published by Elsevier Ltd.                 
 

1. Introduction

Mycobacterium tuberculosis is a ubiquitous pathogen with roughly one-third of the world's population carrying the bacillus. However, the vast majority of persons infected with the mycobacte-rium will never develop clinical symptoms of the infection [1].ltis agreed that the balance between Th1 and Th2 cytokine expression influences the course of disease in individuals with pulmonary TB [1-3]. It is generally understood that severity of TB is associated with diminished production of Th1 type cytokines such as lFN-y, TNF-a and lL-2. Cytokines of Th2 type such as lL-4, lL-5, IL-6, lL-10,1L12, TGF-p, and lL-13 have been also described as being involved in mycobacterial immunopathogenesis. Nonetheless, conflicting opinions still exist in the literature about importance of particular cytokines of either Th types in the immune response against TB [1-6]. The host response to M. tuberculosis is a complex interplay between multiple pro- and anti-inflammatory cytokines. This complexity presents a considerable challenge in distinguishing those that play more influential role in protective immunity.
Dzherelo is a multi-herbal, oral immunomodulator recommended by the health authorities of Ukraine as an adjunct therapy for TB [7]. Anemin is another phytoconcentrate used in Ukraine— mainly for correcting anemia—a condition common in TB patients. We and others have conducted several clinical trials involving TB patients the results of which indicated that when Dzherelo and anti-tuberculosis therapy (ATT) are combined, it improves clinical symptoms and produces higher cure rate than in TB patients on ATT alone. It has been shown to achieve faster and superior rate of mycobacterial clearance, reduce HIV burden, accelerate healing of pulmonary lesions, decrease inflammation markers and liver damage, improve hematology picture, i.e., increased hemoglobin levels, CD4 counts, and enhance significantly quality of life such as  weight gain, fever, respiratory function, physical fitness, well-being and better mood. The details of these beneficial outcomes were published earlier [7-12]. The patient population presented in this study has been investigated earlier for changes in peripheral blood cell subsets and viral load as a result of Dzherelo intervention [11,12]. In this study, we evaluated whether changes in cytokine production profiles resulting from our immune-based intervention may reveal specific immune correlates associated with positive clinical outcome.

2. Materials and methods
2.1. Patients
Male patients, aged 20-49 years, have been selected and divided into three matching groups, each consisting of 20 individuals by exclusion/inclusion criteria such as age bracket, gender, TB infection type, HIV disease stage, alcohol/drug abuse, prior treatment, and disease stage. Another inclusion criterion was the lack of any form of anti-retroviral therapy prior to and during the trial. Active pulmonary tuberculosis was certified by a medical history and clinical findings compatible with pulmonary tuberculosis, a chest X-ray showing lung involvement, and positive sputum smear for acid-fast bacilli or the culture of M. tuberculosis. The participation in this trial was voluntary and patients were enrolled only after signing the written consent indicating that they were free to withdraw from the study at any time. The conduct of the trial was approved by the Ethics board of Kharkov Medical Academy of Postgraduate Education, Kharkov, Ukraine.
2.2. Treatment regimens
All patients received standard anti-tuberculosis therapy (ATT) administered under DOTS schedule which consisted of once daily dose of Isoniazid (H) 300 mg, Rimfapicin (R) 600 mg, Pyrazinamide (Z) _2000/mg, Streptomycin (S) ^000mg and jEthambutol (E)
 ^200 mg. All anti-TB drugs were procured through the centralized national supply system of Ukraine. Before initiation of herbal therapy the patients received anti-tuberculous drugs for 6 months. The first group, which served as a control, continued receiving ATT. The second group of patients received, in addition to HRZSE, twice per day dose of Dzherelo which was given as 50 drops diluted in 100 ml of water. The third group received in addition to Dzherelo a same dose of another herbal supplement, Anemin. First two groups of patients were evaluated by us earlier on our comparative study assessing changes in peripheral blood cells and viral load [11,12]. The over-the-counter phytoconcentrates were generously supplied by Ekomed company. Dzherelo contains concentrated aqueous-alcohol extract from medicinal plants such as aloe (Aloe arborescens), common knotgrass (Polygonum aviculare), yarrow (Achillea millefolium), purple coneflower (Echinacea purpurea), St.
John's wort (Hypericum perforatum), centaury (Centaurium erythraea), snowball tree berries (Viburnum opulus), nettle (Urtica dioica), dandelion (Taraxacum officinale), sweet-sedge (Acorus calamus), oregano (Oreganum majorana), marigold (Calendula nofficinalis),    seabuckthorn   berries   (Hippophae   rhamnoides), elecampane (Inula helenium), tormentil (Potentilla erecta), greater plantain (Plantago major), wormwood (Artemisia sp.), Siberian golden root (Rhodiola rosea), cudweed (Gnaphalium uliginosum), licorice (Glycyrrhiza glabra), fennel (Foeniculum vulgare), chaga (Inonotus   obliquus),   thyme   (Thymus   vulgaris),   three-lobe beggarticks (Bidens tripartite), sage (Salvia officinalis), dog rose (Rosa carina), and juniper berries (Juniperus communis).
Anemin is recommended for anemic patients and contains aqueous alcohol extract of succulent aloe leaves (Aloe arborescens), marsh buckbean leaves (Menyanthes trifoliate), nettle leaves (Urtica dioica), common knotgrass (Polygonum aviculare), St. John's wort (Hypericum perforatum), and oregano (Oreganum majorana). Except marsh buckbean other herbs in Anemin preparation are also found in Dzherelo. Both products were approved in 1997 by the Ministry of Health of Ukraine as a dietary herbal supplements. In 1999 Dzherelo was recommended by the Ministry of Health as an immune adjunct to the therapy of pulmonary tuberculosis [7]. In 2006 they received status of a functional food—special category of supplements which can carry medical claims substantiated by clinical evidence.
2.3. Cytokine measurement
Supernatants from peripheral blood of patients were harvested and stored at ^20 °C until enzyme-linked immunosorbent assay (ELISA) measurement. Samples were taken at baseline and two times after, with three-month intervals between. ELISA kits for measuring cytokines 1L-2, IL-6, IFN-y, IFN-a, and TNF-a were purchased from a commercial supplier (ProCon, St. Petersburg, Russia). Assays were carried out according to the manufacturer's protocol.
2.4. Statistical analysis
The obtained results were analyzed with the aid of statistical software STATMOST (Datamost, South Sandy, UT). The baseline values relative to 3rd and 6th months of follow-up were evaluated by paired or unpaired Student t-test. The statistical difference between three sets of data obtained before, during, and at the end of TB therapy was analyzed by repeated measure, two-way ANO- VA. The Kruskal-Wallis and Friedman nonparametric tests were used to test ranked differences between responses among three groups. Wilcoxon signed-rank test was used to compare median values. All statistical analyses were two sided and probability values were considered as significant at the cut-off levels of P 6 0.05.
3. Results
A total of 60 patients were enrolled in this study and equally divided into three matched groups which received either ATT, ATT + Dzherelo or ATT  Dzherelo + Anemin. Blood samples were taken at study initiation and after three and six months. Plasma samples were analyzed by ELISA for the presence of IL-2, IL-6, TNF-a, IFN-y, and IFN-a. The Table 1 shows the dynamics of absolute values (mean ± SD) of these cytokines as expressed in pg/ml. The statistical significance of data presented in this table was evaluated by repeated measure, two-way ANOVA and Friedman's non- parametric ranking test. To better visualize observed changes we have transformed obtained mean values into percentage values in relation to pre-treatment levels considered as zero (Fig. 1). After 6 months of follow-up Dzherelo and Dzherelo + Anemin combination produced significantly higher absolute and relative levels of IL-2, whereas the levels of the same cytokine in ATT group were reduced by one-third (P < 0.002) in comparison to baseline (Table 1 and Fig. 1). The difference between study end results of three groups was statistically significant by Kruskal-Wallis test (P = 0.0004). The levels of IL-6 were increased in ATT group but reduced in both immune intervention groups. However, the statistical difference was observed only in Dzherelo group (P = 0.007). Nevertheless the disparity between inter-group IL-6 levels was significant^P = 0.04). TNF-a was strongly suppressed in two immunotherapy groups with probability values, P = 0.06 and P = 0.02, respectively, but its increase in ATT-treated patients appeared insignificant by ANOVAJ73 = 0.42) while Friedman test revealed significance (P = 0.03).
Table 1 Absolute values of pre- and post-treatment cytokine levels from three TB treatment regimens.

 The independence of results from three groups at 6 months was slightly above cut-off level(P = 0.07). The pattern of production ofIFN-y was opposite to that of TNF-a, but statistical significance was stronger in patients receiving ATT or Dzherelo + Anemin than in Dzherelo group: P < 0.004 and P = 0.008, respectively. Results from Dzherelo were affected by a slight drop in cytokine levels at end of three month (P = 0.33) which had also affected ranking test results (P = 0.07). The output of IFN-a was unremarkable, decreased levels (range 0.9%-16.6%) were observed in all three treatment groups, but these were not statistically significant at any given time.
While there was a considerable intra-group individual variation in levels of cytokines, particularly with TNF-a, observed differences in cytokine production resulting from three different treatment modalities were not due to population heterogeneity at study entry. Unpaired Student t-test comparing independent inter-group averages for every cytokine in each individual group has not shown any statistical difference at baseline. The P values for ATT vs. ATT+ Dzherelovs. ATT + DzhereloAnemin were 0.9080 vs. 0.9186 vs. 0.8351, respectively. Kruskal-Wallis as well as Wilcoxon signed-rank nonparametric tests also failed to reveal any bias in distribution of patients among three matched groups.
4. Discussion
Immunotherapy of TB merits more attention than it has previously received [3,13,14]. However, a caution is required so that protective and not harmful aspects of immunity are induced. Various immunotherapeutic approaches as an adjunct to TB.
chemotherapy have been tested including the modulation of cyto-kine levels, administration of environmental Mycobacterium vac-cae, and antibody therapy in order to modulate the host immune response to Mycobacterium tuberculosis [14]. Pro- and anti-inflammatory cytokines play a critical role in protection from mycobacte-rial infection and changes in their production pattern may predict clinical outcome. The immune intervention which we employed in this study appeared to shift cytokine production in a direction that was opposite to cytokine output resulting from chemotherapy in all evaluated cytokines except IFN-a.
Two groups of patients, i.e., those who received ATT and ATT + Dzherelo, were investigated by us earlier for changes in select subsets of peripheral blood leukocytes and viral load at months 1 and 2 post-therapy [11,12]. The results of that study have shown that after 2 months of follow-up the total CD3+ T lymphocytes increased in Dzherelo recipients, whereas in the control group they decreased. The population of CD4 T-cells expanded in Dzherelo arm but declined in ATT group. The CD8 cells fluctuated slightly upward in both groups but changes were not significant. The ratio between CD4/CD8 cells deteriorated in ATT arm but improved in Dzherelo arm. The percent of CD3+HLA-DR+ activated lymphocytes had fallen in ATT group but rose in Dzherelo recipients. The changes in CD20+ B lymphocytes were insignificant in both arms. No difference was seen in the amount of CD3-CD16+CD56+ natural killer (NK) cells in ATT arm, while in Dzherelo recipients they declined significantly. The viral load, measured by plasma RNA-PCR, decreased in 17 out of 20 Dzherelo recipients, but increased in the same number of patients on ATT. Dzherelo thus appeared to have favorable effect on surrogate immune markers and viral burden in HIV/TB patients when given as the immunomodulating adjunct to ATT. In this study we present changes in cytokine production at 6 and 9 months post-therapy. Due to delay in getting cytokine kits we were, unfortunately, unable to conduct this study within the same time period as the cell subset phenotype and viral load studies. For this reason results from this investigation are not directly correlated with prior findings.
At the end of 6 months of treatment Dzherelo and Dzherelo + Anemin combinations produced 61% and 44.4% more of IL-2, whereas the levels of this cytokine in ATT alone group were reduced by 33.1% (Fig. 1). Incidentally, Toossi et^l. reported that patients with pulmonary TB had 81.2% lower output of tuberculin-induced IL-2 as compared with healthy tuberculin reactors. Defective IL-2 production was associated with more extensive disease on chest X-ray implying that administration of this cytokine could be beneficial to patients with TB [15]. The first initial trial of IL-2 had shown encouraging results. However, randomized, placebo-controlled trial of therapeutic interleukin-2 demonstrated significant delays in clearance and conversion rate of M. tuberculosis in sputum culture. This clinical study revealed potential antagonism between TB drugs and immunotherapy and suggested that exogenous supplementation with cytokines will not necessarily fulfill expectations based on mechanistic studies [14]. By the same token, it is unclear whether higher levels of IL-2, originally described as the T-cell growth factor, are responsible for increased CD3+ T lymphocyte levels observed in Dzherelo recipients [12].
Many studies in TB patients and non-TB controls deal with analysis of cytokine production in response to mitogens or mycobacte-rial antigens such as PPD or tuberculin. IL-6 was often found elevated in such assays [16]. Nagabhushanam et^l. reported that excess of IL-6 secreted by mycobacterium-infected macrophages may contribute to the inability of the cellular immune response to eradicate infection viajFN-y dependent pathway [17]. In addition to many other functions IL-6 is considered to be non-specific inflammatory cytokine shown to exacerbate deleterious immune restoration syndrome in tuberculosis and HIV co-infected patients [5,18]. Our results indicate that production of IL-6 was suppressed by Dzherelo (P = 0.007) or Dzherelo + Anemin(P = 0.2) but appears to be increased by ATTj(P = 0.15). As Dzherelo has been found equally effective in treating both TB and HIV our findings support prior studies suggesting that the downregulation ofIL-6 dependent inflammatory process may be beneficial to the host.
IFN-a is a multifunctional cytokine with established activity in many infectious diseases. IFN-a synergizes with IL-12 and plays an important role in inhibiting Th2 cytokines through antagonizing effect on IL-4, IL-10, or other immunosuppressive cellular factors and by promoting Th1 response via induction of IL-2 and IFN-y [18]. Administration of aerosolized IFN-a to TB patients had shown more favorable effects than in those given chemotherapy alone [19]. In our study, IFN-a was the only cytokine that behaved similarly in all three treatment groups. While tendency to decrease was observed it was not statistically significant. For this reason it is not clear whether this cytokine has contributed to observed increase in IL-2 and IFN-y levels or it plays any role in outcome from therapy. Thus, in case of IFN-a we do not know how to interpret our observation without being biased by an erroneous a priori attribution of cause and effect.
TNF-a is a monocyte-activating cytokine which stimulates anti-mycobacterial activity and helps to maintain the integrity of tuberculous granulomas in which M. tuberculosis is contained [1]. Our results indicate that both Dzherelo and Dzherelo + Anemin combinations cause significant decrease in baseline TNF-a levels by as much as 19.1% (P = 0.02) and 76.3%fP = 0.06) respectively. This effect is opposite to the trend in ATT-treated patients where TNF-a secretion continued to escalate. Since most studies agree that higher levels of TNF-a were associated with favorable clinical prognosis as the immunomodulating adjunct to ATT. In this study we present changes in cytokine production at 6 and 9 months post-therapy. Due to delay in getting cytokine kits we were, unfortunately, unable to conduct this study within the same time period as the cell subset phenotype and viral load studies. For this reason results from this investigation are not directly correlated with prior findings.
At the end of 6 months of treatment Dzherelo and Dzherelo + Anemin combinations produced 61% and 44.4% more of IL-2, whereas the levels of this cytokine in ATT alone group were reduced by 33.1% (Fig. 1). Incidentally, Toossi et^l. reported that patients with pulmonary TB had 81.2% lower output of tuberculin-induced IL-2 as compared with healthy tuberculin reactors. Defective IL-2 production was associated with more extensive disease on chest X-ray implying that administration of this cytokine could be beneficial to patients with TB [15]. The first initial trial of IL-2 had shown encouraging results. However, randomized, placebo-controlled trial of therapeutic interleukin-2 demonstrated significant delays in clearance and conversion rate of M. tuberculosis in sputum culture. This clinical study revealed potential antagonism between TB drugs and immunotherapy and suggested that exogenous supplementation with cytokines will not necessarily fulfill expectations based on mechanistic studies [14]. By the same token, it is unclear whether higher levels of IL-2, originally described as the T-cell growth factor, are responsible for increased CD3+ T lymphocyte levels observed in Dzherelo recipients [12].
Many studies in TB patients and non-TB controls deal with analysis of cytokine production in response to mitogens or mycobacte-rial antigens such as PPD or tuberculin. IL-6 was often found elevated in such assays [16]. Nagabhushanam et^l. reported that excess of IL-6 secreted by mycobacterium-infected macrophages may contribute to the inability of the cellular immune response to eradicate infection viajFN-y dependent pathway [17]. In addition to many other functions IL-6 is considered to be non-specific inflammatory cytokine shown to exacerbate deleterious immune restoration syndrome in tuberculosis and HIV co-infected patients [5,18]. Our results indicate that production of IL-6 was suppressed by Dzherelo (P = 0.007) or Dzherelo + Anemin (P = 0.2) but appears to be increased by ATTj(P = 0.15). As Dzherelo has been found equally effective in treating both TB and HIV our findings support prior studies suggesting that the downregulation ofIL-6 dependent inflammatory process may be beneficial to the host.
IFN-a is a multifunctional cytokine with established activity in many infectious diseases. IFN-a synergizes with IL-12 and plays an important role in inhibiting Th2 cytokines through antagonizing effect on IL-4, IL-10, or other immunosuppressive cellular factors and by promoting Th1 response via induction of IL-2 and IFN-y [18]. Administration of aerosolized IFN-a to TB patients had shown more favorable effects than in those given chemotherapy alone [19]. In our study, IFN-a was the only cytokine that behaved similarly in all three treatment groups. While tendency to decrease was observed it was not statistically significant. For this reason it is not clear whether this cytokine has contributed to observed increase in IL-2 and IFN-y levels or it plays any role in outcome from therapy. Thus, in case of IFN-a we do not know how to interpret our observation without being biased by an erroneous a priori attribution of cause and effect.
TNF-a is a monocyte-activating cytokine which stimulates anti-mycobacterial activity and helps to maintain the integrity of tuberculous granulomas in which M. tuberculosis is contained [1]. Our results indicate that both Dzherelo and Dzherelo + Anemin combinations cause significant decrease in baseline TNF-a levels by as much as 19.1% (P = 0.02) and 76.3%fP = 0.06) respectively. This effect is opposite to the trend in ATT-treated patients where TNF-a secretion continued to escalate. Since most studies agree that higher levels of TNF-a were associated with favorable clinical prognosis our findings may appear to contradict common wisdom. On the other hand, the risk of developing TB was 20-fold higher in non-TB patients who were treated with TNF antagonists, e.g., monoclonal anti-TNF antibodies and soluble TNF receptor [20]. Since TNF is a major inflammatory molecule that exacerbates symptoms of AIDS, clinical studies were conducted in which treatment modalities with anti-TNF activity were evaluated in HIV-positive patients co-infected with TB. Interestingly enough a positive trend toward superior resolution of lung infiltrates, closure of lung cavities, improvement in mycobacterial clearance score, and weight gain was observed [14]. Our findings appear to support the opinion that therapies directed at suppression of TNF-a might be beneficial for TB patients, even though in non-TB cases this strategy was associated with higher risk of re-activation of latent tuberculosis.
IFN-y is considered to be most important cytokine in the protective response against TB [21]. JFN-y is an essential component of the activation cascade of other cytokines such as GM-CSF, IL-2, and IL-4 which act as cofactors with anti-TB activity [22]. IFN-gam-ma production is strongly depressed during active TB, correlates inversely with disease severity, and increases during therapy. After 6 months of treatment Dzherelo and Dzherelo + Anemin increased IFN-y production by 17.3% (P = 0.33) and 31.9% (p = ^008), respectively, while in ATT recipients the reverse trend was observed (34%; P = 0.004). Our findings are in line with results of several clinical trials of inhaled or injected IFN-y which have shown positive clinical outcome [14,23,24]. Our findings are also in line with observations that in active-TB patients M. tuberculosis-induced IFN-y and TNF-a production are driven in opposite directions
[1,25,26].
An understanding of cytokine responses that are crucial for control of M. tuberculosis has major implications for the development of immune-based prophylactic and therapeutic interventions [13]. Our investigation of cytokines is limited in scope mostly to Th1 axis components and does not fully explain the mechanism of action of immune modulators used in this study. Th2 response, which is considered equally important, has not been evaluated by us [27]. Other surrogate markers of disease progression and prognosis such as for example, beta2-microglobulin, neopterin, tumor necrosis factor receptor II (TNFRII), CD8/CD38 cells ratio, soluble urokinase plasminogen activator receptor (suPAR), and CXCL10 (IP-10) need to be evaluated as well [28].
Nevertheless, judging from what we have observed so far, our immunomodulators appear to enhance naturally-occurring immune response against TB, perhaps by contributing to the down-regulation of inflammatory reaction [29]. We have shown before that patients receiving conventional chemotherapy with Dzherelo and related botanical supplements had significantly higher and faster cure rate than those given chemotherapy alone [7-12]. Dzherelo induces higher number of CD4 lymphocytes and reduced viral burden—surrogate markers associated with favorable course of HIV infection [11,12]. Expanded study is now required to identify the role of other immune correlates associated with control and protection against M. tuberculosis infection. The results may reveal not only biomarkers related to better clinical outcome but also may help designing better immunotherapies and vaccines [30].
Acknowledgments
We thank all participants who volunteered in this study. The support of clinical staff and technicians who contributed to this study has been of tremendous help to us. We are grateful to other colleagues who shared their insight and provided helpful suggestions based on their own experience with phytoconcentrates used in present study. This work was presented in part at the Keystone Symposia on HIV Pathogenesis and HIV Vaccines, March 27-Apr 1, 2008, Banff, Alberta, Canada, through a grant from Bill and Melinda. Gates Foundation's Global Health Travel Award, which is gratefully  acknowledged.
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