Background Whether vexing clinical decision-making dilemmas can be partly addressed by recent advances in genomics is unclear. For example, when to initiate highly active antiretroviral therapy (HAART) during HIV-1 infection remains a clinical dilemma. This decision relies heavily on assessing AIDS risk based on the CD4+ T cell count and plasma viral load. However, the trajectories of these two laboratory markers are influenced, in part, by polymorphisms in CCR5, the major HIV coreceptor, and the gene copy number of CCL3L1, a potent CCR5 ligand and HIV-suppressive chemokine. Therefore, we determined whether accounting for both genetic and laboratory markers provided an improved means of assessing AIDS risk. Methods and Findings In a prospective, single-site, ethnically-mixed cohort of 1,132 HIV-positive subjects, we determined the AIDS risk conveyed by the laboratory and genetic markers separately and in combination. Subjects were assigned to a low, moderate or high genetic risk group (GRG) based on variations in CCL3L1 and CCR5. The predictive value of the CCL3L1-CCR5 GRGs, as estimated by likelihood ratios, was equivalent to that of the laboratory markers. GRG status also predicted AIDS development when the laboratory markers conveyed a contrary risk. Additionally, in two separate and large groups of HIV+ subjects from a natural history cohort, the results from additive risk-scoring systems and classification and regression tree (CART) analysis revealed that the laboratory and CCL3L1-CCR5 genetic markers together provided more prognostic information than either marker alone. Furthermore, GRGs independently predicted the time interval from seroconversion to CD4+ cell count thresholds used to guide HAART initiation. Conclusions The combination of the laboratory and genetic markers captures a broader spectrum of AIDS risk than either marker alone. By tracking a unique aspect of AIDS risk distinct from that captured by the laboratory parameters, CCL3L1-CCR5 genotypes may have utility in HIV clinical management. These findings illustrate how genomic information might be applied to achieve practical benefits of personalized medicine.
References
[1]
Lederman MM, Penn-Nicholson A, Cho M, Mosier D (2006) Biology of CCR5 and its role in HIV infection and treatment. Jama 296: 815–826.
[2]
Townson JR, Barcellos LF, Nibbs RJ (2002) Gene copy number regulates the production of the human chemokine CCL3-L1. Eur J Immunol 32: 3016–3026.
[3]
Menten P, Struyf S, Schutyser E, Wuyts A, De Clercq E, et al. (1999) The LD78beta isoform of MIP-1alpha is the most potent CCR5 agonist and HIV-1-inhibiting chemokine. J Clin Invest 104: R1–5.
[4]
Xin X, Shioda T, Kato A, Liu H, Sakai Y, et al. (1999) Enhanced anti-HIV-1 activity of CC-chemokine LD78beta, a non-allelic variant of MIP-1alpha/LD78alpha. FEBS Lett 457: 219–222.
[5]
Gonzalez E, Kulkarni H, Bolivar H, Mangano A, Sanchez R, et al. (2005) The influence of CCL3L1 gene-containing segmental duplications on HIV-1/AIDS susceptibility. Science 307: 1434–1440.
[6]
Dybul M, Fauci AS, Bartlett JG, Kaplan JE, Pau AK (2002) Guidelines for using antiretroviral agents among HIV-infected adults and adolescents. Recommendations of the Panel on Clinical Practices for Treatment of HIV. MMWR Recomm Rep 51: 1–55.
[7]
Yeni PG, Hammer SM, Hirsch MS, Saag MS, Schechter M, et al. (2004) Treatment for adult HIV infection: 2004 recommendations of the International AIDS Society-USA Panel. Jama 292: 251–265.
[8]
http://aidsinfo.nih.gov (2005) Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents.
[9]
http://www.aidsinfo.nih.gov/ContentFiles？/AdultandAdolescentGL.pdf (2008) Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents: Department of Health and Human Services.
[10]
Holmberg SD, Palella FJ Jr, Lichtenstein KA, Havlir DV (2004) The case for earlier treatment of HIV infection. Clin Infect Dis 39: 1699–1704.
[11]
Cohen CJ, Boyle BA (2004) Antiretroviral therapy: the “when to start” debates. Clin Infect Dis 39: 1705–1708.
[12]
Hughes MD, Daniels MJ, Fischl MA, Kim S, Schooley RT (1998) CD4 cell count as a surrogate endpoint in HIV clinical trials: a meta-analysis of studies of the AIDS Clinical Trials Group. Aids 12: 1823–1832.
[13]
(2000) Human immunodeficiency virus type 1 RNA level and CD4 count as prognostic markers and surrogate end points: a meta-analysis. HIV Surrogate Marker Collaborative Group. AIDS Res Hum Retroviruses 16: 1123–1133.
[14]
Dean M, Carrington M, Winkler C, Huttley GA, Smith MW, et al. (1996) 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, Multicenter Hemophilia Cohort Study, San Francisco City Cohort, ALIVE Study. Science 273: 1856–1862.
[15]
Martin MP, Dean M, Smith MW, Winkler C, Gerrard B, et al. (1998) Genetic acceleration of AIDS progression by a promoter variant of CCR5. Science 282: 1907–1911.
[16]
O'Brien SJ, Nelson GW (2004) Human genes that limit AIDS. Nat Genet 36: 565–574.
[17]
Kaslow RA, Dorak T, Tang JJ (2005) Influence of host genetic variation on susceptibility to HIV type 1 infection. J Infect Dis 191: Suppl 1S68–77.
[18]
Gonzalez E, Bamshad M, Sato N, Mummidi S, Dhanda R, et al. (1999) Race-specific HIV-1 disease-modifying effects associated with CCR5 haplotypes. Proc Natl Acad Sci U S A 96: 12004–12009.
[19]
Mangano A, Gonzalez E, Dhanda R, Catano G, Bamshad M, et al. (2001) Concordance between the CC chemokine receptor 5 genetic determinants that alter risks of transmission and disease progression in children exposed perinatally to human immunodeficiency virus. J Infect Dis 183: 1574–1585.
[20]
Dolan MJ, Kulkarni H, Camargo JF, He W, Smith A, et al. (2007) CCL3L1 and CCR5 influence cell-mediated immunity and affect HIV-AIDS pathogenesis via viral entry-independent mechanisms. Nat Immunol 8: 1324–1336.
[21]
O'Brien TR, McDermott DH, Ioannidis JP, Carrington M, Murphy PM, et al. (2000) Effect of chemokine receptor gene polymorphisms on the response to potent antiretroviral therapy. Aids 14: 821–826.
[22]
Hunt P, Carrington M (2008) Host genetic determinants of HIV pathogenesis: an immunologic perspective. Immune correlates of protection, activation and exhaustion. Current Opinion in HIV & AIDS 3: 342–348.
[23]
Ahuja SK, Kulkarni H, Catano G, Agan BK, Camargo JF, et al. (2008) CCL3L1-CCR5 genotype influences durability of immune recovery during antiretroviral therapy of HIV-1-infected individuals. Nat Med 14: 413–420.
[24]
Carrington M, O'Brien SJ (2003) The influence of HLA genotype on AIDS. Annu Rev Med 54: 535–551.
[25]
Telenti A, Carrington M (2008) Host factors associated with outcome from primary human immunodeficiency virus-1 infection. Current Opinion in HIV & AIDS 3: 28–35.
[26]
Douek DC, Picker LJ, Koup RA (2003) T cell dynamics in HIV-1 infection. Annu Rev Immunol 21: 265–304.
[27]
Kaufmann GR, Furrer H, Ledergerber B, Perrin L, Opravil M, et al. (2005) Characteristics, determinants, and clinical relevance of CD4 T cell recovery to <500 cells/microL in HIV type 1-infected individuals receiving potent antiretroviral therapy. Clin Infect Dis 41: 361–372.
[28]
Florence E, Lundgren J, Dreezen C, Fisher M, Kirk O, et al. (2003) Factors associated with a reduced CD4 lymphocyte count response to HAART despite full viral suppression in the EuroSIDA study. HIV Med 4: 255–262.
[29]
Moore RD, Keruly JC (2007) CD4+ cell count 6 years after commencement of highly active antiretroviral therapy in persons with sustained virologic suppression. Clin Infect Dis 44: 441–446.
[30]
Grabar S, Le Moing V, Goujard C, Leport C, Kazatchkine MD, et al. (2000) Clinical outcome of patients with HIV-1 infection according to immunologic and virologic response after 6 months of highly active antiretroviral therapy. Ann Intern Med 133: 401–410.
[31]
Tarwater PM, Margolick JB, Jin J, Phair JP, Detels R, et al. (2001) Increase and plateau of CD4 T-cell counts in the 3(1/2) years after initiation of potent antiretroviral therapy. J Acquir Immune Defic Syndr 27: 168–175.
[32]
Hunt PW, Deeks SG, Rodriguez B, Valdez H, Shade SB, et al. (2003) Continued CD4 cell count increases in HIV-infected adults experiencing 4 years of viral suppression on antiretroviral therapy. Aids 17: 1907–1915.
[33]
Moore DM, Hogg RS, Yip B, Wood E, Tyndall M, et al. (2005) Discordant immunologic and virologic responses to highly active antiretroviral therapy are associated with increased mortality and poor adherence to therapy. J Acquir Immune Defic Syndr 40: 288–293.
[34]
Valdez H, Connick E, Smith KY, Lederman MM, Bosch RJ, et al. (2002) Limited immune restoration after 3 years' suppression of HIV-1 replication in patients with moderately advanced disease. Aids 16: 1859–1866.
[35]
Podlekareva D, Mocroft A, Dragsted UB, Ledergerber B, Beniowski M, et al. (2006) Factors associated with the development of opportunistic infections in HIV-1-infected adults with high CD4+ cell counts: a EuroSIDA study. J Infect Dis 194: 633–641.
[36]
http://www.clinicaltrials.gov.
[37]
Zimmerman PA, Buckler-White A, Alkhatib G, Spalding T, Kubofcik J, et al. (1997) 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 3: 23–36.
[38]
McDermott DH, Zimmerman PA, Guignard F, Kleeberger CA, Leitman SF, et al. (1998) CCR5 promoter polymorphism and HIV-1 disease progression. Multicenter AIDS Cohort Study (MACS). Lancet 352: 866–870.
[39]
Hladik F, Liu H, Speelmon E, Livingston-Rosanoff D, Wilson S, et al. (2005) Combined effect of CCR5-Delta32 heterozygosity and the CCR5 promoter polymorphism -2459 A/G on CCR5 expression and resistance to human immunodeficiency virus type 1 transmission. J Virol 79: 11677–11684.
[40]
Valdez H, Purvis SF, Lederman MM, Fillingame M, Zimmerman PA (1999) Association of the CCR5delta32 mutation with improved response to antiretroviral therapy. Jama 282: 734.
[41]
Hendrickson SL, Jacobson LP, Nelson GW, Phair JP, Lautenberger J, et al. (2008) Host genetic influences on highly active antiretroviral therapy efficacy and AIDS-free survival. J Acquir Immune Defic Syndr 48: 263–271.
[42]
Ketas TJ, Kuhmann SE, Palmer A, Zurita J, He W, et al. (2007) Cell surface expression of CCR5 and other host factors influence the inhibition of HIV-1 infection of human lymphocytes by CCR5 ligands. Virology 364: 281–290.
[43]
Sadam M, Karki T, Huik K, Avi R, Rüütel K, et al. (2008) CCL3L1 Variable Gene Copy Number Influence on the Susceptibility to HIV-1/AIDS Among Estonian Intravenous Drug User. 15th Conference on Retroviruses and Opportunistic Infections. Abstract 296:
[44]
Nakajima T, Ohtani H, Naruse T, Shibata H, Mimaya JI, et al. (2007) Copy number variations of CCL3L1 and long-term prognosis of HIV-1 infection in asymptomatic HIV-infected Japanese with hemophilia. Immunogenetics 59: 793–798.
[45]
Kuhn L, Schramm DB, Donninger S, Meddows-Taylor S, Coovadia AH, et al. (2007) African infants' CCL3 gene copies influence perinatal HIV transmission in the absence of maternal nevirapine. Aids 21: 1753–1761.
[46]
Meddows-Taylor S, Donninger SL, Paximadis M, Schramm DB, Anthony FS, et al. (2006) Reduced ability of newborns to produce CCL3 is associated with increased susceptibility to perinatal human immunodeficiency virus 1 transmission. J Gen Virol 87: 2055–2065.
[47]
Shalekoff S, Meddows-Taylor S, Schramm DB, Donninger SL, Gray GE, et al. (2008) Host CCL3L1 gene copy number in relation to HIV-1-specific CD4+ and CD8+ T-cell responses and viral load in South African women. J Acquir Immune Defic Syndr 48: 245–254.
[48]
Kalish RS, Askenase PW (1999) Molecular mechanisms of CD8+ T cell-mediated delayed hypersensitivity: implications for allergies, asthma, and autoimmunity. J Allergy Clin Immunol 103: 192–199.
[49]
Kniker WT, Anderson CT, McBryde JL, Roumiantzeff M, Lesourd B (1984) Multitest CMI for standardized measurement of delayed cutaneous hypersensitivity and cell-mediated immunity. Normal values and proposed scoring system for healthy adults in the U.S.A. Ann Allergy 52: 75–82.
[50]
Birx DL, Brundage J, Larson K, Engler R, Smith L, et al. (1993) The prognostic utility of delayed-type hypersensitivity skin testing in the evaluation of HIV-infected patients. Military Medical Consortium for Applied Retroviral Research. J Acquir Immune Defic Syndr 6: 1248–1257.
[51]
Gordin FM, Hartigan PM, Klimas NG, Zolla-Pazner SB, Simberkoff MS, et al. (1994) Delayed-type hypersensitivity skin tests are an independent predictor of human immunodeficiency virus disease progression. Department of Veterans Affairs Cooperative Study Group. J Infect Dis 169: 893–897.
[52]
Dolan MJ, Clerici M, Blatt SP, Hendrix CW, Melcher GP, et al. (1995) In vitro T cell function, delayed-type hypersensitivity skin testing, and CD4+ T cell subset phenotyping independently predict survival time in patients infected with human immunodeficiency virus. J Infect Dis 172: 79–87.
[53]
Maas JJ, Roos MT, Keet IP, Mensen EA, Krol A, et al. (1998) In vivo delayed-type hypersensitivity skin test anergy in human immunodeficiency virus type 1 infection is associated with T cell nonresponsiveness in vitro. J Infect Dis 178: 1024–1029.
[54]
Gibbs RA, Rogers J, Katze MG, Bumgarner R, Weinstock GM, et al. (2007) Evolutionary and biomedical insights from the rhesus macaque genome. Science 316: 222–234.
[55]
Deeks SG, Walker BD (2007) Human immunodeficiency virus controllers: mechanisms of durable virus control in the absence of antiretroviral therapy. Immunity 27: 406–416.
[56]
Gonzalez E, Dhanda R, Bamshad M, Mummidi S, Geevarghese R, et al. (2001) Global survey of genetic variation in CCR5, RANTES, and MIP-1alpha: impact on the epidemiology of the HIV-1 pandemic. Proc Natl Acad Sci U S A 98: 5199–5204.
[57]
Gonzalez E, Rovin BH, Sen L, Cooke G, Dhanda R, et al. (2002) HIV-1 infection and AIDS dementia are influenced by a mutant MCP-1 allele linked to increased monocyte infiltration of tissues and MCP-1 levels. Proc Natl Acad Sci U S A 99: 13795–13800.
[58]
Silverberg MJ, Wegner SA, Milazzo MJ, McKaig RG, Williams CF, et al. (2006) Effectiveness of highly-active antiretroviral therapy by race/ethnicity. Aids 20: 1531–1538.
[59]
Gallagher EJ (1998) Clinical utility of likelihood ratios. Ann Emerg Med 31: 391–397.
[60]
Langdorf MI, Rudkin SE, Dellota K, Fox JC, Munden S (2002) Decision rule and utility of routine urine toxicology screening of trauma patients. Eur J Emerg Med 9: 115–121.
[61]
Lemon SC, Roy J, Clark MA, Friedmann PD, Rakowski W (2003) Classification and regression tree analysis in public health: methodological review and comparison with logistic regression. Ann Behav Med 26: 172–181.
[62]
Li L, Huang J, Sun S, Shen J, Unverzagt FW, et al. (2004) Selecting pre-screening items for early intervention trials of dementia–a case study. Stat Med 23: 271–283.
[63]
Province MA, Shannon WD, Rao DC (2001) Classification methods for confronting heterogeneity. Adv Genet 42: 273–286.
[64]
Vlahou A, Laronga C, Wilson L, Gregory B, Fournier K, et al. (2003) A novel approach toward development of a rapid blood test for breast cancer. Clin Breast Cancer 4: 203–209.
[65]
Zhang ZQ, Schleif WA, Casimiro DR, Handt L, Chen M, et al. (2004) The impact of early immune destruction on the kinetics of postacute viral replication in rhesus monkey infected with the simian-human immunodeficiency virus 89.6P. Virology 320: 75–84.
[66]
Mellors JW, Munoz A, Giorgi JV, Margolick JB, Tassoni CJ, et al. (1997) Plasma viral load and CD4+ lymphocytes as prognostic markers of HIV-1 infection. Ann Intern Med 126: 946–954.
[67]
Lifson JD, Rossio JL, Arnaout R, Li L, Parks TL, et al. (2000) Containment of simian immunodeficiency virus infection: cellular immune responses and protection from rechallenge following transient postinoculation antiretroviral treatment. J Virol 74: 2584–2593.
[68]
Mummidi S, Bamshad M, Ahuja SS, Gonzalez E, Feuillet PM, et al. (2000) Evolution of human and non-human primate CC chemokine receptor 5 gene and mRNA. Potential roles for haplotype and mRNA diversity, differential haplotype-specific transcriptional activity, and altered transcription factor binding to polymorphic nucleotides in the pathogenesis of HIV-1 and simian immunodeficiency virus. J Biol Chem 275: 18946–18961.
[69]
Thomas SM, Tse DB, Ketner DS, Rochford G, Meyer DA, et al. (2006) CCR5 expression and duration of high risk sexual activity among HIV-seronegative men who have sex with men. Aids 20: 1879–1883.
[70]
Salkowitz JR, Bruse SE, Meyerson H, Valdez H, Mosier DE, et al. (2003) CCR5 promoter polymorphism determines macrophage CCR5 density and magnitude of HIV-1 propagation in vitro. Clin Immunol 108: 234–240.
[71]
Kawamura T, Gulden FO, Sugaya M, McNamara DT, Borris DL, et al. (2003) R5 HIV productively infects Langerhans cells, and infection levels are regulated by compound CCR5 polymorphisms. Proc Natl Acad Sci U S A 100: 8401–8406.
[72]
Reynes J, Baillat V, Portales P, Clot J, Corbeau P (2003) Low CD4+ T-cell surface CCR5 density as a cause of resistance to in vivo HIV-1 infection. J Acquir Immune Defic Syndr 34: 114–116.
[73]
Reynes J, Portales P, Segondy M, Baillat V, Andre P, et al. (2000) CD4+ T cell surface CCR5 density as a determining factor of virus load in persons infected with human immunodeficiency virus type 1. J Infect Dis 181: 927–932.
[74]
Reynes J, Portales P, Segondy M, Baillat V, Andre P, et al. (2001) CD4 T cell surface CCR5 density as a host factor in HIV-1 disease progression. Aids 15: 1627–1634.
[75]
Gervaix A, Nicolas J, Portales P, Posfay-Barbe K, Wyler CA, et al. (2002) Response to treatment and disease progression linked to CD4+ T cell surface CC chemokine receptor 5 density in human immunodeficiency virus type 1 vertical infection. J Infect Dis 185: 1055–1061.
[76]
Vincent T, Portales P, Baillat V, Eden A, Clot J, et al. (2006) The immunological response to highly active antiretroviral therapy is linked to CD4+ T-cell surface CCR5 density. J Acquir Immune Defic Syndr 43: 377–378.
[77]
Taub DD, Turcovski-Corrales SM, Key ML, Longo DL, Murphy WJ (1996) Chemokines and T lymphocyte activation: I. Beta chemokines costimulate human T lymphocyte activation in vitro. J Immunol 156: 2095–2103.
[78]
Karpus WJ, Lukacs NW, Kennedy KJ, Smith WS, Hurst SD, et al. (1997) Differential CC chemokine-induced enhancement of T helper cell cytokine production. J Immunol 158: 4129–4136.
[79]
Zou W, Borvak J, Marches F, Wei S, Galanaud P, et al. (2000) Macrophage-derived dendritic cells have strong Th1-polarizing potential mediated by beta-chemokines rather than IL-12. J Immunol 165: 4388–4396.
[80]
Pinto LA, Williams MS, Dolan MJ, Henkart PA, Shearer GM (2000) Beta-chemokines inhibit activation-induced death of lymphocytes from HIV-infected individuals. Eur J Immunol 30: 2048–2055.
[81]
Luther SA, Cyster JG (2001) Chemokines as regulators of T cell differentiation. Nat Immunol 2: 102–107.
[82]
Abdelwahab SF, Cocchi F, Bagley KC, Kamin-Lewis R, Gallo RC, et al. (2003) HIV-1-suppressive factors are secreted by CD4+ T cells during primary immune responses. Proc Natl Acad Sci U S A 100: 15006–15010.
[83]
Lillard JW Jr, Singh UP, Boyaka PN, Singh S, Taub DD, et al. (2003) MIP-1alpha and MIP-1beta differentially mediate mucosal and systemic adaptive immunity. Blood 101: 807–814.
[84]
Rot A, von Andrian UH (2004) Chemokines in innate and adaptive host defense: basic chemokinese grammar for immune cells. Annu Rev Immunol 22: 891–928.
[85]
Molon B, Gri G, Bettella M, Gomez-Mouton C, Lanzavecchia A, et al. (2005) T cell costimulation by chemokine receptors. Nat Immunol 6: 465–471.
[86]
Castellino F, Huang AY, Altan-Bonnet G, Stoll S, Scheinecker C, et al. (2006) Chemokines enhance immunity by guiding naive CD8+ T cells to sites of CD4+ T cell-dendritic cell interaction. Nature 440: 890–895.
[87]
Friedman RS, Jacobelli J, Krummel MF (2006) Surface-bound chemokines capture and prime T cells for synapse formation. Nat Immunol 7: 1101–1108.
[88]
Lin YL, Mettling C, Portales P, Reynes J, Clot J, et al. (2002) Cell surface CCR5 density determines the postentry efficiency of R5 HIV-1 infection. Proc Natl Acad Sci U S A 99: 15590–15595.
[89]
Amella CA, Sherry B, Shepp DH, Schmidtmayerova H (2005) Macrophage inflammatory protein 1alpha inhibits postentry steps of human immunodeficiency virus type 1 infection via suppression of intracellular cyclic AMP. J Virol 79: 5625–5631.
[90]
Tyner JW, Uchida O, Kajiwara N, Kim EY, Patel AC, et al. (2005) CCL5-CCR5 interaction provides antiapoptotic signals for macrophage survival during viral infection. Nat Med 11: 1180–1187.
[91]
Rodriguez B, Sethi AK, Cheruvu VK, Mackay W, Bosch RJ, et al. (2006) Predictive value of plasma HIV RNA level on rate of CD4 T-cell decline in untreated HIV infection. Jama 296: 1498–1506.
[92]
Mayer H, Van der Ryst E, Saag M, Clotet B, Fatkenheuer G, et al. (2006) Safety and efficacy of maraviroc (MVC), a novel CCR5 antagonist, when used in combination with optimized background therapy (OBT) for the treatment of antiretroviral-experienced subjects infected with dual/mixed-tropic HIV-1: 24-week results of a phase 2b exploratory trial.
[93]
Lalezari J, Yadavalli GK, Para M, Richmond G, Dejesus E, et al. (2008) Safety, pharmacokinetics, and antiviral activity of HGS004, a novel fully human IgG4 monoclonal antibody against CCR5, in HIV-1-infected patients. J Infect Dis 197: 721–727.
