Haemophilia, human immunodeficiency virus and human immunodeficiency virus pathogenesis

Michael M. Lederman

doi:10.1160/TH10-02-0096

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2010; 104(05): 911-914
DOI: 10.1160/TH10-02-0096

Theme Issue Article

Schattauer GmbH

Haemophilia, human immunodeficiency virus and human immunodeficiency virus pathogenesis

Michael M. Lederman

¹Case Western Reserve University School of Medicine, University Hospitals/Case Medical Center, Cleveland, Ohio, USA

› Author Affiliations

Abstract

Summary

In July 1982, the occurrence of three cases of acquired immunodeficiency syndrome (AIDS) in men with haemophilia was an immediate signal to Oscar Ratnoff that AIDS was transmissible through blood products. Work that he led provided important and clear indication that the AIDS agent was transmissible through pooled plasma products and had rapidly infected many men who had haemophilia. Before the blood supply was protected, the risk for infection in haemophilia was related directly to the intensity of therapy with pooled anti-haemophilic factor concentrates. Studies performed among the small proportion of haemophiliacs who remained uninfected despite heavy exposure to these plasma products revealed that the rare protective genotype – homozygosity for the 32 base pair deletion in the CCR5 gene was heavily concentrated in this population. Among those who did not have this protective genotype, a state of diminished immune activation distinguished these high risk uninfected haemophiliacs from haemophiliacs who later acquired human immunodeficiency virus (HIV) infection and from healthy uninfected controls. Immune activation state may not only predict risk for HIV acquisition but also appears to be an important predictor and likely determinant of HIV disease progression. The potential drivers of immune activation in chronic HIV infection include HIV itself, other co-infecting pathogens, homeostatic responses to cytopenia as well as the recently recognised phenomenon of translocation of microbial products across a damaged gut mucosal surface. This latter process is particularly compelling as clinical studies have shown a good relationship between indices of microbial translocation and markers of both immune activation and T cell homeostasis in chronic HIV infection. More recently, we have also found evidence that these microbial products also may drive a heightened tendency to thrombus formation in HIV infection via induction of monocyte tissue factor expression. Thus systemic exposure to microbial elements that are translocated through a gut mucosa damaged in the first few weeks of HIV infection may contribute to the pathogenesis of both immune deficiency and the heightened risk for vascular events that have been noted in persons with HIV infection.

Keywords

Infectious diseases - immunity - viral infection

Full Text

References

References
1 Anonymous.. 1982. Pneumocystis carinii Pneumonia among persons with Hemophilia A. Morbidity and Mortality Weekly Report 31: 365-367.
2 Lederman MM, Ratnoff OD, Scillian JJ. et al. Impaired cell-mediated immunity in patients with classic hemophilia. N Engl J Med 1983; 308: 79-83.
3 Menitove JE, Aster RH, Casper JT. et al. T-lymphocyte subpopulations in patients with classic hemophilia treated with cryoprecipitate and lyophilized concentrates. N Engl J Med 1983; 308: 83-86.
4 Lederman MM, Ratnoff OD, Evatt BL. et al. Acquisition of antibody to lymphadenopathy-associated virus in patients with classic hemophilia (factor VIII deficiency). Ann Int Med 1985; 102: 753-757.
5 Kroner BL, Rosenberg PS, Aledort LM. et al. HIV-1 infection incidence among persons with hemophilia in the United States and western Europe, 1978–1990. Multicenter Hemophilia Cohort Study. J AIDS 1994; 07: 279-286.
6 Salkowitz JR, Purvis SF, Meyerson H. et al. Characterization of high-risk HIV-1 seronegative hemophiliacs. Clinical Immunology 2001; 98: 200-211.
7 Alkhatib G, Combadiere C, Broder CC. et al. CC CKR5: a RANTES, MIP-1alpha, MIP-1beta receptor as a fusion cofactor for macrophage-tropic HIV-1. Science NY 1996; 272: 1955-1958.
8 Arenzana-Seisdedos F, Virelizier JL, Rousset D. et al. HIV blocked by chemokine antagonist. Nature 1996; 383: 400.
9 Choe H, Farzan M, Sun Y. et al. The beta-chemokine receptors CCR3 and CCR5 facilitate infection by primary HIV-1 isolates. Cell 1996; 85: 1135-1148.
10 Dragic T, Litwin V, Allaway GP. et al. HIV-1 entry into CD4+ cells is mediated by the chemokine receptor CC- CKR-5. Nature 1996; 381: 667-673.
11 Feng Y, Broder CC, Kennedy PE. et al. HIV-1 entry cofactor: functional cDNA cloning of a seven-transmembrane, G protein-coupled receptor. Science NY 1996; 272: 872-877.
12 Dean M, Carrington M, Winkler C. et al. Genetic restriction of HIV-1 infection and progression to AIDS by a deletion allele of the CKR5 structural gene. Hemophilia Growth and Development Study, Multicenter AIDS Cohort Study, Multi-center Hemophilia Cohort Study, San Francisco City Cohort, ALIVE Study. Science NY 1996; 273: 1856-1862.
13 Huang Y, Paxton WA, Wolinsky SM. et al. The role of a mutant CCR5 allele in HIV-1 transmission and disease progression. Nature Med 1996; 02: 1240-1243.
14 Zimmerman PA, Buckler-White A, Alkhatib G. et al. Inherited resistance to HIV-1 conferred by an inactivating mutation in CC chemokine receptor 5: studies in populations with contrasting clinical phenotypes, defined racial background, and quantified risk. Mol Med 1997; 03: 23-36.
15 Card CM, McLaren PJ, Wachihi C. et al. Decreased immune activation in resistance to HIV-1 infection is associated with an elevated frequency of CD4(+)CD25(+)FOXP3(+) regulatory T cells. J Infect Dis 2009; 199: 1318-1322.
16 Koning FA, Jansen CA, Dekker J. Ret al. Correlates of resistance to HIV-1 infection in homosexual men with high-risk sexual behaviour. Aids 2004; 18: 1117-1126.
17 Deeks SG, Kitchen CM, Liu L. et al. Immune activation set point during early HIV infection predicts subsequent CD4+ T-cell changes independent of viral load. Blood 2004; 104: 942-947.
18 Giorgi JV, Hultin LE, McKeating JA. et al. Shorter survival in advanced human immunodeficiency virus type 1 infection is more closely associated with T lymphocyte activation than with plasma virus burden or virus chemokine coreceptor usage. J Infect Dis 1999; 179: 859-870.
19 Liu Z, Cumberland WG, Hultin LE. et al. CD8+ T-lymphocyte activation in HIV-1 disease reflects an aspect of pathogenesis distinct from viral burden and immuno-deficiency. J Acquir Immune Defic Syndr Hum Retrovirol 1998; 18: 332-340.
20 Silvestri G, Paiardini M, Pandrea I. et al. Understanding the benign nature of SIV infection in natural hosts. J Clin Invest 2007; 117: 3148-3154.
21 Heil F, Hemmi H, Hochrein H. et al. Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8. Science 2004; 303: 1526-1529.
22 Herbeuval JP, Nilsson J, Boasso A. et al. Differential expression of IFN-alpha and TRAIL/DR5 in lymphoid tissue of progressor versus nonprogressor HIV-1-infected patients. Proc Natl Acad Sci USA 2006; 103: 7000-7005.
23 Lempicki RA, Kovacs JA, Baseler MW. et al. Impact of HIV-1 infection and highly active antiretroviral therapy on the kinetics of CD4+ and CD8+ T cell turnover in HIV-infected patients. Proc Natl Acad Sci USA 2000; 97: 13778-13783.
24 Lederman MM, Margolis L. The lymph node in HIV pathogenesis. Semin Immunol 2008; 20: 187-195.
25 Deayton JR, Sabin CA, Johnson MA. et al. Importance of cytomegalovirus viraemia in risk of disease progression and death in HIV-infected patients receiving highly active antiretroviral therapy. Lancet 2004; 363: 2116-2121.
26 Kovacs A, Schluchter M, Easley K. et al. Cytomegalovirus infection and HIV-1 dis-ease progression in infants born to HIV-1-infected women. Pediatric Pulmonary and Cardiovascular Complications of Vertically Transmitted HIV Infection Study Group. N Engl J Med 1999; 341: 77-84.
27 Whalen C, Horsburgh CR, Hom D. et al. Accelerated course of human immuno-deficiency virus infection after tuberculosis. Am J Respir Crit Care Med 1995; 151: 129-135.
28 Okoye A, Meier-Schellersheim M, Brenchley JM. et al. Progressive CD4+ central memory T cell decline results in CD4+ effector memory insufficiency and overt disease in chronic SIV infection. J Exp Med 2007; 204: 2171-2185.
29 Brenchley JM, Schacker TW, Ruff LE. et al. CD4+ T cell depletion during all stages of HIV disease occurs predominantly in the gastrointestinal tract. J Exp Med 2004; 200: 749-759.
30 Veazey RS, DeMaria M, Chalifoux LV. et al. Gastrointestinal tract as a major site of CD4+ T cell depletion and viral replication in SIV infection. Science 1998; 280: 427-431.
31 Brenchley JM, Price DA, Schacker TW. et al. Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med 2006; 12: 1365-1371.
32 Jiang W, Lederman MM, Hunt P. et al. Plasma Levels of Bacterial DNA Correlate with Immune Activation and the Magnitude of Immune Restoration in Persons with Antiretroviral-Treated HIV Infection. J Infect Dis 2009; 199: 1177-1185.
33 Brenchley JM, Price DA, Douek DC. HIV disease: fallout from a mucosal catastrophe?. Nat Immunol 2006; 07: 235-239.
34 Funderburg N, Luciano AA, Jiang W. et al. Toll-like receptor ligands induce human T cell activation and death, a model for HIV pathogenesis. PLoS ONE 2008; 03: e1915.
35 Sieg SF, Bazdar DA, Lederman MM. S-phase entry leads to cell death in circulating T cells from HIV-infected persons. J Leukoc Biol 2008; 83: 1382-1387.
36 Sieg SF, Rodriguez B, Asaad R. et al. Peripheral S-phase T cells in HIV disease have a central memory phenotype and rarely have evidence of recent T cell receptor engagement. J Infect Dis 2005; 192: 62-70.
37 Altfeld M, van Lunzen J, Frahm N. et al. Expansion of pre-existing, lymph node-localized CD8+ T cells during supervised treatment interruptions in chronic HIV-1 infection. J Clin Invest 2002; 109: 837-843.
38 Biancotto A, Grivel JC, Iglehart SJ. et al. Abnormal activation and cytokine spectra in lymph nodes of people chronically infected with HIV-1. Blood 2007; 109: 4272-4279.
39 Cheynier R, Henrichwark S, Hadida F. et al. HIV and T cell expansion in splenic white pulps is accompanied by infiltration of HIV-specific cytotoxic T lymphocytes. Cell 1994; 78: 373-387.
40 Tenner-Racz K, Racz P, Thome C. et al. Cytotoxic effector cell granules recognized by the monoclonal antibody TIA-1 are present in CD8+ lymphocytes in lymph nodes of human immunodeficiency virus-1-infected patients. Am J Pathol 1993; 142: 1750-1758.
41 Shiow LR, Rosen DB, Brdickova N. et al. CD69 acts downstream of interferonalpha/beta to inhibit S1P1 and lymphocyte egress from lymphoid organs. Nature 2006; 440: 540-544.
42 Currier JS. Update on cardiovascular complications in HIV infection. Top HIV Med 2009; 17: 98-103.
43 Stein JH. Cardiovascular risks of antiretroviral therapy. N Engl J Med 2007; 356: 1773-1775.
44 El-Sadr WM, Lundgren JD, Neaton JD. et al. CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med 2006; 355: 2283-2296.
45 Libby P. Inflammation in atherosclerosis. Nature 2002; 420: 868-874.
46 Melnick JL, Adam E, Debakey ME. Cytomegalovirus and atherosclerosis. Eur Heart J 1993; 14 Suppl K 30-38.
47 Valantine HA, Luikart H, Doyle R. et al. Impact of cytomegalovirus hyperimmune globulin on outcome after cardiothoracic transplantation: a comparative study of combined prophylaxis with CMV hyperimmune globulin plus ganciclovir versus ganciclovir alone. Transplantation 2001; 72: 1647-1652.
48 Hsue PY, Hunt PW, Sinclair E. et al. Increased carotid intima-media thickness in HIV patients is associated with increased cytomegalovirus-specific T-cell responses. AIDS 2006; 20: 2275-2283.
49 Funderburg NT, Mayne E, Sieg SF. et al. Increased tissue factor expression on circulating monocytes in chronic HIV infection: relationship to in vivo coagulation and immune activation. Blood 2010; 115: 161-167.