Persistence of high levels of blood soluble human leukocyte antigen-G is associated with rapid progression of HIV infection
Lajoie, Juliea,b; Fontaine, Juliea,b; Tremblay, Cécileb; Routy, Jean-Pierrec; Poudrier, Johannea,b; Roger, Michela,b
aLaboratoire d'immunogénétique, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Canada
bDépartement de Microbiologie et Immunologie de l'Université de Montréal, Canada
cResearch Institute of the McGill University Health Centre, Montreal, Québec, Canada.
Received 22 February, 2009
Revised 7 April, 2009
Accepted 17 April, 2009
Correspondence to Michel Roger, MD, PhD, Département de microbiologie, Hôpital Notre-Dame du CHUM, 1560 Sherbrooke Est, Montréal, Québec, Canada H2L 4M1. Tel: +1 514 890 8000 (25802); fax: +1 514 412 7512; e-mail: firstname.lastname@example.org
Human leukocyte antigen-G is an important suppressor of the immune response, and HIV can modulate its expression. Longitudinal monitoring of soluble human leukocyte antigen-G plasma levels in patients with primary HIV infection undergoing different rates of disease progression showed that levels were elevated in the early phases of infection and remained high throughout follow-up in rapid progressors who responded to antiretroviral therapy but were restored to normal levels in the chronic phase of infection in both untreated normal progressors and long-term nonprogressors.
Human leukocyte antigen-G (HLA)-G is a nonclassical major histocompatibility class I protein characterized by limited polymorphism and tissue-restricted distribution. HLA-G is expressed as membrane-bound (HLA-G1, HLA-G2, HLA-G3 and HLA-G4) and soluble (HLA-G5, HLA-G6 and HLA-G7) isoforms as a result of alternative splicing . HLA-G expression is involved in maternal–fetal tolerance and can be induced in pathological conditions such as autoimmune diseases, cancers, transplantations and viral infections. The major isoforms present in the plasma are soluble HLA-G (sHLA-G)1 and HLA-G5 that are generated by shedding or proteolytic cleavage of membrane-bound HLA-G1 isoform and by secretion of a soluble form, respectively. These two isoforms share immunological functions such as inhibition of natural killer (NK) and CD8+ T lymphocytes cytotoxic activity, as well as inhibition of CD4+ T-cell functions [2–4]. The immunosuppressive properties of HLA-G might contribute to the susceptibility and persistence of HIV infection. Recent studies have shown that functionally active HLA-G polymorphisms are associated with susceptibility to heterosexual [5,6] and vertical [7,8] transmission of HIV-1. Blood sHLA-G levels  and monocytes and T lymphocytes HLA-G surface expression are elevated in HIV-1-infected individuals . However, no data are available on sHLA-G expression in the context of HIV disease progression. We have, therefore, performed a longitudinal study of plasma levels of sHLA-G in HIV-infected individuals with different rates of clinical progression to investigate whether sHLA-G expression is associated HIV disease progression.
Twenty-four HIV-infected patients were selected from the Montreal Primary HIV Infection (PHI) cohort: 10 were classified as rapid and 14 as normal progressors. The date of infection was estimated based on clinical and laboratory results using criteria established by the Acute HIV Infection and Early Disease Research Program. Rapid progressors were defined as having CD4+ T-cell counts of less than 250 cells/μl within 2 years of infection. Blood samples of rapid progressors were assessed during the acute (0–3 months), early (5–8 months) and chronic phases of infection: 3–6 months and 9–12 months after the initiation of antiretroviral therapy (ART). Normal progressors were ART-naive patients whose CD4+ T-cell counts remained more than 500 cells/μl during the first 2 years of infection. Blood samples of normal progressors were obtained in the acute, early and chronic phases (24 months) of infection. Also included were blood samples from 12 long-term nonprogressors (LTNPs) infected for at least 8 years with CD4+ T-cell counts of more than 500 cells/μl and low to undetectable viral loads in the absence of ART and 20 age-matched HIV-negative volunteers. None of the study participants had syphilis or hepatitis B or C infection. Informed consent was obtained from all participants, and the research conformed to ethical guidelines of all authors' institutions. sHLA-G plasma levels were measured using a Human sHLA-G Immunoassay kit (Alexis Biochemicals, San Diego, California, USA), which allows detection of HLA-G1 and HLA-G5 soluble proteins. Statistical analyses were performed using the GraphPad PRISM 5.0 (GraphPad Software Inc., San Diego, California, USA).
Sociodemographic and clinical characteristics of HIV-infected individuals were described elsewhere . Briefly, the study groups were similar with respect to sex, race and modes of HIV acquisition. The mean age of LTNPs was higher (P < 0.0001). Rapid progressors had lower CD4+ T-cell counts (P < 0.0001) and higher viremia levels (P = 0.04) than did normal progressors during the acute and early phases of infection. During the chronic phase of infection, ART-treated rapid progressors had similar levels of CD4+ T cells and lower viral loads (P = 0.02) than did untreated normal progressors. There was no significant correlation between CD4+ T-cell counts or viral loads and sHLA-G levels either within groups or among all patients during acute or chronic infection as determined by the Spearman's rank test (data not shown).
Longitudinal assessment of plasma sHLA-G levels in HIV-1-infected individuals with different rates of disease progression is depicted in Fig. 1. The relative level of sHLA-G was similar in both untreated rapid and normal progressors but higher than normal during the acute and early phases of infection. Levels of sHLA-G remained elevated throughout follow-up in rapid progressors who responded to ART but were restored to normal levels in the chronic phase of infection in both untreated normal progressors and LTNPs. In fact, during the chronic phase of infection, rapid progressors had higher levels of sHLA-G than did normal progressors (P = 0.0004) and LTNPs (P = 0.0006).
The relative high level of plasma sHLA-G observed in HIV-infected individuals is in agreement with previous findings . However, our longitudinal study in PHI patients allowed us to show, for the first time, that sHLA-G levels are elevated during the very early stage of infection but are restored to normal levels in the chronic phase of infection in both untreated normal progressors and LTNPs, demonstrating the capacity of their immune system to control, at least to a certain extent, the infection. Conversely, in rapid progressors, sHLA-G levels remained higher than normal throughout the course of infection, despite the suppression of viremia and the replenishment of CD4+ T cells with ART. Monocytes/macrophages together with myeloid and plasmacytoid dendritic cells are the major producers of sHLA-G . We have recently shown that the blood levels of mature (HLA-DR++ CD86+) plasmacytoid dendritic cells during the chronic phase of infection were higher in rapid progressors than in HIV-negative individuals (P < 0.05) . Moreover, levels of serum interleukin-10, a potent inducer of HLA-G expression , were higher in rapid progressors than in HIV-negative individuals (P < 0.05) (unpublished data). It has been suggested that ART itself could induce surface expression of HLA-G on peripheral monocytes from HIV-infected patients . However, this does not seem to apply to the secretion of sHLA-G, as in our study, the levels were similar before and after ART (Fig. 1, left).
Our results show that sHLA-G is elevated in the very early stage of HIV infection, and its production is associated with rate of disease progression. The maintenance of relatively high levels of sHLA-G, in rapid progressors, may contribute to the tolerogenic environment favoring viral immune escape and dissemination as reflected by the rapid course of disease progression in these individuals.
We are grateful to the members of the Montreal PHI and Canadian Cohort of HIV Slow Progressors Study Groups: M. Legault (coordinator); J. Allan, N. Bernard, J. Cox, J. Falutz, N. Gilmore, M. Klein, R.G. Lalonde, R. Leblanc, J. MacLeod, M. Potter, G. Smith and C. Tsoukas (McGill University Health Center); J. Bruneau, C. Fortin, A. de Pokomandy and D. Rouleau (Centre Hospitalier de l'Université de Montréal); R. Thomas, B. Trottier, F. Asselin, M. Boissonnault, L. Charest, H. Dion, S. Lavoie, D. Legault, D. Longpré, P.J. Maziade, M.E. Morin, D. Murphy, V.K. Nguyen, R. O'Brien and S. Vézina (Clinique médicale l'Actuel); J.G. Baril, P. Côté, S. Dufresne, P. Junod, F. Laplante, D. Poirier, Y. Parent, M.A. Charron, B. Lessard, D. Tessier, É. Sasseville, A. Talbot and M.S. Joyal (Clinique médicale du Quartier Latin); N. Lapointe (Hôpital Ste-Justine); A. Dascal (Jewish General Hospital); M. Munoz [local community service centre (CLSC) Cote des Neiges]. We also thank Marie-Pierre Boisvert, Maryse Lainesse, Rebecca Bordi, Véronique Lafontaine, Bader Yassine-Diab and Younes Chouick for processing the blood samples.
J.L. wrote the article and performed HLA-G measurements and analysis. J.F. provided the data analysis on the sociodemographic and clinical characteristics of HIV-infected individuals. J-P.R and C.T. are principal investigators of the Montreal PHI and LTNP study groups, respectively, that recruited the study participants. J.P. supervised the experiments and revised the article. M.R. generated the concept, wrote the article and coordinated all aspects of this study.
This work was supported by the Réseau SIDA et maladies infectieuses from the Fonds de la Recherche en Santé du Québec (FRSQ). J. Lajoie and J. Fontaine hold studentships from the Canadian Institute of Health Research (CIHR). C. Tremblay, J-P Routy and M. Roger are recipients of Research Scholar awards from the FRSQ.
The authors declare no conflict of interest.
1. Ishitani A, Geraghty DE. Alternative splicing of HLA-G transcripts yields proteins with primary structures resembling both class I and class II antigens. Proc Natl Acad Sci U S A 1992; 89:3947–3951.
2. Le Gal FA, Riteau B, Sedlik C, Khalil-Daher I, Menier C, Dausset J, et al. HLA-G-mediated inhibition of antigen-specific cytotoxic T lymphocytes. Int Immunol 1999; 11:1351–1356.
3. Park GM, Lee S, Park B, Kim E, Shin J, Cho K, et al. Soluble HLA-G generated by proteolytic shedding inhibits NK-mediated cell lysis. Biochem Biophys Res Commun 2004; 313:606–611.
4. Lila N, Rouas-Freiss N, Dausset J, Carpentier A, Carosella ED. Soluble HLA-G protein secreted by allo-specific CD4+ T cells suppresses the allo-proliferative response: a CD4+ T cell regulatory mechanism. Proc Natl Acad Sci U S A 2001; 98:12150–12155.
5. Matte C, Lajoie J, Lacaille J, Zijenah LS, Ward BJ, Roger M. Functionally active HLA-G polymorphisms are associated with the risk of heterosexual HIV-1 transmission in African women. AIDS 2004; 18:427–431.
6. Lajoie J, Hargrove J, Zijenah LS, Humphrey JH, Ward BJ, Roger M. Genetic variants in nonclassical MHC class I HLA-E and HLA-G molecules are associated with risk of heterosexual HIV-1 infection. J Infect Dis 2006; 193:298–301.
7. Aikhinonbare FO, Kumaresan K, Shamsa F, Bon VC. HLA-G DNA sequence variants and risk of perinatal HIV-1 infection. AIDS Res Ther 2006; 3:28.
8. Fabris A, Catamo E, Segat L, Morgutti M, Arraes LC, de Lima-Filho JL, et al. Association between HLA-G 3′UTR 14-bp polymorphism and HIV vertical transmission in Brazilian children. AIDS 2009; 23:177–182.
9. Donaghy L, Gros F, Amiot L, Mary C, Maillard A, Guiguen C, et al. Elevated levels of soluble nonclassical major histocompatibility class I molecule human leucocyte antigen (HLA)-G in the blood of HIV-infected patients with or without visceral leishmaniasis. Clin Exp Immunol 2006; 147:236–240.
10. Lozano JM, Gonzalez R, Kindelan JM, Rouas-Freiss N, Cabellos R, Dausset J, et al. Monocytes and T lymphocytes in HIV-1-positive patients express HLA-G molecule. AIDS 2002; 16:347–351.
11. Fontaine J, Coutlée F, Tremblay C, Routy JP, Poudrier J, Roger M. HIV infection affects blood myeloid dendritic cells beyond successful therapy and despite nonprogressing clinical disease. J Infect Dis 2009; 199:1007–1018.
12. Rebmann V, Busemann A, Lindemann M, Grosse-Wilde H. Detection of HLA-G5 secreting cells. Hum Immunol 2003; 64:1017–1024.
13. Moreau P, Adrian-Cabestre F, Menier C, Guiard V, Gourand L, Dausset J, et al. IL-10 selectively induces HLA-G expression in human trophoblasts and monocytes. Int Immunol 1999; 11:803–811.
14. Rivero A, Lozano JM, Gonzalez R, Garcia-Jurado G, Camacho A, Torres-Cisneros J, et al. Nucleoside reverse transcriptase inhibitors are able and protease inhibitors unable to induce the tolerogenic molecule HLA-G1 on monocytes from HIV-1 infected patients. Hum Immunol 2007; 68:303–306.
This article has been cited 2 time(s).
Biomed Research InternationalHLA-G/C, miRNAs, and Their Role in HIV Infection and ReplicationBiomed Research International
Bmc CancerCase-control study of HLA-G promoter methylation status, HPV infection and cervical neoplasia in Curitiba, Brazil: a pilot analysisBmc Cancer
© 2009 Lippincott Williams & Wilkins, Inc.