Objective. During the course of HIV infection, progressive immune deficiency occurs. The aim of this prospective substudy was to evaluate the recovery of functional immunity in a subset of patients from the GRACE (Gender, Race, And Clinical Experience) study treated with a DRV/r-based regimen. Methods. The recovery of functional immunity with a darunavir/ritonavir-based regimen was assessed in a subset of treatment-experienced, HIV-1 infected patients from the GRACE study. Results. 19/32 patients (59%) enrolled in the substudy were virologically suppressed (<50 copies/mL). In these patients, median (range) CD4+ cell count increased from 222 (2, 398) cells/mm3 at baseline to 398 (119, 812) cells/mm3 at Week 48. CD8+% decreased significantly from baseline to Week 48 ( ). Proliferation of CD4+ lymphocytes in response to CD3+/CD28+, phytohemagglutinin, and pokeweed was significantly increased ( ) by Week 12. Proliferation in response to Candida and tetanus was significantly increased by Week 48 ( and , resp.). Staphylococcal enterotoxin B-stimulated tumor necrosis factor-alpha and interleukin-2 in CD4+ cells was significantly increased by Week 12 ( ) and Week 48 ( ), respectively. Conclusions. Darunavir/ritonavir-based therapy demonstrated improvements in CD4+ cell recovery and association with progressive functional immune recovery over 48 weeks. This trial is registered with NCT00381303. 1. Introduction During the course of HIV-1 infection, multifactorial T-lymphocyte (T-cell)-mediated mechanisms contribute to the progressive loss of host immune function [1–5]. In infected individuals, immune dysregulation occurs early and is characterized by a decrease in CD4+ cell count, a concurrent rise in CD8+ cells, a progressive decline in the CD4+/CD8+ ratio, and defective thymocyte proliferation . During late-stage disease, loss of T-cell homeostasis also occurs [7, 8]. T cells are chronically activated throughout the course of HIV infection, as indicated by an increase in the expression of the antigens Ki67, CD38, and human leukocyte antigen (HLA)-DR, with CD38 recognized as the most reliable marker of immune activation [1–3, 5, 9]. Immune activation provides the virus with a steady pool of target cells and has been linked with increased polyclonal T-cell proliferation and turnover, as well as increases in the apoptotic marker CD95 [10–13] and activation-induced cell death [12, 14–16]. Concomitant with the decline of CD4 cells in the peripheral blood, the frequency of the CD4+ CD28 null subset increases with disease progression and eventual progression to
L. Kestens, G. Vanham, C. Vereecken et al., “Selective increase of activation antigens HLA-DR and CD38 on CD4+ CD45RO+ T lymphocytes during HIV-1 infection,” Clinical and Experimental Immunology, vol. 95, no. 3, pp. 436–441, 1994.
M. Levacher, F. Hulstaert, S. Tallet, S. Ullery, J. J. Pocidalo, and B. A. Bach, “The significance of activation markers on CD8 lymphocytes in human immunodeficiency syndrome: staging and prognostic value,” Clinical and Experimental Immunology, vol. 90, no. 3, pp. 376–382, 1992.
J. V. Giorgi, H.-N. Ho, K. Hirji et al., “CD8+ lymphocyte activation at human immunodeficiency virus type 1 seroconversion: development of HLA-DR+ CD38- CD8+ cells is associated with subsequent stable CD4+ cell levels,” Journal of Infectious Diseases, vol. 170, no. 4, pp. 775–781, 1994.
S. A. Klein, J. M. Dobmeyer, T. S. Dobmeyer et al., “Demonstration of the Th1 to Th2 cytokine shift during the course of HIV-1 infection using cytoplasmic cytokine detection on single cell level by flow cytometry,” AIDS, vol. 11, no. 9, pp. 1111–1118, 1997.
Z. Liu, W. G. Cumberland, L. E. Hultin, H. E. Prince, R. Detels, and J. V. Giorgi, “Elevated CD38 antigen expression on CD8+ T cells Is a stronger marker for the risk of chronic HIV disease progression to AIDS and death in the multicenter AIDS Cohort study than CD4+ cell count, soluble immune activation markers, or combinations of HLA-DR and CD38 expression,” Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology, vol. 16, no. 2, pp. 83–92, 1997.
J. B. Margolick, A. Munoz, A. D. Donnenberg, et al., “Failure of T-cell homeostasis preceding AIDS in HIV-1 infection. The Multicenter AIDS Cohort study,” Nature Medicine, vol. 1, no. 7, pp. 674–680, 1995.
S. P. Aries, B. Schaaf, C. Muller, R. H. Dennin, and K. Dalhoff, “Fas (CD95) expression on CD4+ T cells from HIV-infected patients increases with disease progression,” Journal of Molecular Medicine, vol. 73, no. 12, pp. 591–593, 1995.
Z. Grossman, M. Meier-Schellersheim, W. E. Paul, and L. J. Picker, “Pathogenesis of HIV infection: what the virus spares is as important as what it destroys,” Nature Medicine, vol. 12, no. 3, pp. 289–295, 2006.
L. A. Trimble, P. Shankar, M. Patterson, J. P. Daily, and J. Lieberman, “Human immunodeficiency virus-specific circulating CD8 T lymphocytes have down-modulated CD3ζ and CD28, key signaling molecules for T-cell activation,” Journal of Virology, vol. 74, no. 16, pp. 7320–7330, 2000.
J. H. Vingerhoets, G. L. Vanham, L. L. Kestens et al., “Increased cytolytic T lymphocyte activity and decreased B7 responsiveness are associated with CD28 down-regulation on CD8+ T cells from HIV-infected subjects,” Clinical and Experimental Immunology, vol. 100, no. 3, pp. 425–433, 1995.
S. T. Parish, J. E. Wu, and R. B. Effros, “Sustained CD28 expression delays multiple features of replicative senescence in human CD8 T lymphocytes,” Journal of Clinical Immunology, vol. 30, no. 6, pp. 798–805, 2010.
J. V. Giorgi, Z. Liu, L. E. Hultin, W. G. Cumberland, K. Hennessey, and R. Detels, “Elevated levels of CD38+CD8+ T cells in HIV infection add to the prognostic value of low CD4+ T cell levels: results of 6 years of follow-up,” Journal of Acquired Immune Deficiency Syndromes, vol. 6, no. 8, pp. 904–912, 1993.
B. Autran, G. Carcelain, T. S. Li et al., “Positive effects of combined antiretroviral therapy on CD4+ T cell homeostasis and function in advanced HIV disease,” Science, vol. 277, no. 5322, pp. 112–116, 1997.
J. Estaquier, J.-D. Leliévre, F. Petit et al., “Effects of antiretroviral drugs on human immunodeficiency virus type 1-induced CD4+ T-cell death,” Journal of Virology, vol. 76, no. 12, pp. 5966–5973, 2002.
A. D. Badley, K. Parato, D. W. Cameron et al., “Dynamic correlation of apoptosis and immune activation during treatment of HIV infection,” Cell Death and Differentiation, vol. 6, no. 5, pp. 420–432, 1999.
M. Goicoechea, D. M. Smith, L. Liu et al., “Determinants of CD4+ T cell recovery during suppressive antiretroviral therapy: association of immune activation, T cell maturation markers, and cellular HIV-1 DNA,” Journal of Infectious Diseases, vol. 194, no. 1, pp. 29–37, 2006.
M. Pichenot, S. Deuffic-Burban, L. Cuzin, and Y. Yazdanpanah, “Efficacy of new antiretroviral drugs in treatment-experienced HIV-infected patients: a systematic review and meta-analysis of recent randomized controlled trials,” HIV Medicine, vol. 13, no. 3, pp. 148–155, 2012.
J. M. Llibre, M. J. Buzón, M. Massanella et al., “Treatment intensification with raltegravir in subjects with sustained HIV-1 viraemia suppression: a randomized 48-week study,” Antiviral Therapy, vol. 17, no. 2, pp. 355–364, 2012.
H. Hatano, T. L. Hayes, V. Dahl et al., “A randomized, controlled trial of raltegravir intensification in antiretroviral-treated, HIV-infected patients with a suboptimal CD4+ T cell response,” Journal of Infectious Diseases, vol. 203, no. 7, pp. 960–968, 2011.
H. Byakwaga, M. Kelly, D. F. J. Purcell et al., “Intensification of antiretroviral therapy with raltegravir or addition of hyperimmune bovine colostrum in HIV-infected patients with suboptimal CD4+ T-cell response: a randomized controlled trial,” Journal of Infectious Diseases, vol. 204, no. 10, pp. 1532–1540, 2011.
J. B. Angel, K. G. Parato, A. Kumar et al., “Progressive human immunodeficiency virus-specific immune recovery with prolonged viral suppression,” Journal of Infectious Diseases, vol. 183, no. 4, pp. 546–554, 2001.
H. Ullum, T. Katzenstein, H. Aladdin et al., “Immunological changes in Human Immunodeficiency Virus (HIV)-infected individuals during HIV-specific protease inhibitor treatment,” Scandinavian Journal of Immunology, vol. 49, no. 5, pp. 539–547, 1999.
R. C. Kaplan, C. M. Parrinello, H. N. Hodis, et al., “Impact of HAART initiation on immune regulation (activation/senescence) in aging HIV-infected women: Women's Interagency HIV study,” in Proceedings of the 19th Conference on Retroviruses and Opportunistic Infections, Seattle, Wash, USA, 2012.
R. T. Steigbigel, D. A. Cooper, P. N. Kumar et al., “Raltegravir with optimized background therapy for resistant HIV-1 infection,” The New England Journal of Medicine, vol. 359, no. 4, pp. 339–354, 2008.
M.-L. Gougeon, H. Lecoeur, and Y. Sasaki, “Apoptosis and the CD95 system in HIV disease: impact of Highly Active Anti-Retroviral Therapy (HAART),” Immunology Letters, vol. 66, no. 1–3, pp. 97–103, 1999.
C. G. Lange, M. M. Lederman, K. Medvik et al., “Nadir CD4+ T-cell count and numbers of CD28+ CD4+ T-cells predict functional responses to immunizations in chronic HIV-1 infection,” AIDS, vol. 17, no. 14, pp. 2015–2023, 2003.
A. Hill, J. Montaner, M. Lederman, A. Cutrell, S. Tortell, and D. Thorborn, “Discordant CD4/RNA responses to HAART are strongly associated with high baseline CD4 count and low HIV RNA: analysis of 406 naive patients,” in Proceedings of the 3rd International Workshop on HIV Drug Resistance and Treatment Strategies, San Diego, Calif, USA, 1999.
R. C. Kaplan, E. Sinclair, A. L. Landay et al., “T cell activation and senescence predict subclinical carotid artery disease in HIV-infected women,” Journal of Infectious Diseases, vol. 203, no. 4, pp. 452–463, 2011.