title: Bioinformatic prediction programs underestimate the frequency of CXCR4 usage by R5X4 HIV type 1 in brain and other tissues.
abstract: Human immunodeficiency virus (HIV-1) variants in brain primarily use CCR5 for entry into macrophages and microglia, but dual-tropic (R5X4) HIV-1 has been detected in brain and cerebral spinal fluid (CSF) of some patients with HIV-associated dementia (HAD). Here, we sequenced the gp120 coding region of nine full-length dual-tropic (R5X4) env genes cloned directly from autopsy brain and spleen tissue from an AIDS patient with severe HAD. We then compiled a dataset of 30 unique clade B R5X4 Env V3 sequences from this subject and 16 additional patients (n = 4 brain and 26 lymphoid/blood) and used it to compare the ability of six bioinformatic algorithms to correctly predict CXCR4 usage in R5X4 Envs. Only one program (SVM(geno2pheno)) correctly predicted the ability of R5X4 Envs in this dataset to use CXCR4 with 90% accuracy (n = 27/30 predicted to use CXCR4). The PSSM(SINSI), Random Forest, and SVM(genomiac) programs and the commonly used charge rule correctly predicted CXCR4 usage with >50% accuracy (22/30, 16/30, 19/30, and 25/30, respectively), while the PSSM(X4R5) matrix and "11/25" rule correctly predicted CXCR4 usage in <50% of the R5X4 Envs (10/30 and 13/30, respectively). Two positions in the V3 loop (19 and 32) influenced coreceptor usage predictions of nine R5X4 Envs from patient MACS1 and a total of 12 Envs from the dataset (40% of unique V3 sequences). These results demonstrate that most predictive algorithms underestimate the frequency of R5X4 HIV-1 in brain and other tissues. SVM(geno2pheno) is the most accurate predictor of CXCR4 usage by R5X4 HIV-1.
authors.affiliation: Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
authors.forename: Megan E
authors.initials: ME
authors.lastname: Mefford
authors.forename: Paul R
authors.initials: PR
authors.lastname: Gorry
authors.forename: Kevin
authors.initials: K
authors.lastname: Kunstman
authors.forename: Steven M
authors.initials: SM
authors.lastname: Wolinsky
authors.forename: Dana
authors.initials: D
authors.lastname: Gabuzda
mesh_terms: D015526:AIDS Dementia Complex / Q000821:virology; D000465:Algorithms; D000595:Amino Acid Sequence; D001921:Brain / Q000821:virology*; D019295:Computational Biology / Q000379:methods*; D015699:HIV Envelope Protein gp120 / Q000235:genetics; D015658:HIV Infections / Q000821:virology*; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D010802:Phylogeny; D019718:Receptors, CXCR4 / Q000235:genetics / Q000502:physiology*; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D013154:Spleen / Q000821:virology*; D053586:Virus Internalization
chemical_list: D015699:HIV Envelope Protein gp120; D019718:Receptors, CXCR4; C514793:gp120 protein, Human immunodeficiency virus 1
references.citation: J Virol. 2005 Feb;79(3):1480-6
references.pmid: 15650174
references.citation: J Virol. 2003 Nov;77(22):12336-45
references.pmid: 14581570
references.citation: Virology. 2007 Mar 30;360(1):105-19
references.pmid: 17084877
references.citation: J Clin Invest. 2000 Dec;106(12):1569
references.pmid: 11120764
references.citation: J Virol. 2002 Jun;76(12):6277-92
references.pmid: 12021361
references.citation: J Virol. 1990 May;64(5):2337-44
references.pmid: 2182911
references.citation: J Virol. 1996 Mar;70(3):1651-67
references.pmid: 8627686
references.citation: J Virol. 2000 Dec;74(24):11858-72
references.pmid: 11090186
references.citation: J Microbiol. 2007 Oct;45(5):441-6
references.pmid: 17978804
references.citation: J Virol. 2006 Apr;80(7):3684-91
references.pmid: 16537640
references.citation: Virology. 2007 May 25;362(1):163-78
references.pmid: 17239419
references.citation: J Virol. 2002 Apr;76(8):3852-64
references.pmid: 11907225
references.citation: Virology. 2001 Sep 15;288(1):51-62
references.pmid: 11543657
references.citation: AIDS. 2007 Sep 12;21(14):F17-24
references.pmid: 17721088
references.citation: J Virol. 2003 Dec;77(24):13376-88
references.pmid: 14645592
references.citation: J Virol. 2001 Nov;75(21):10073-89
references.pmid: 11581376
references.citation: AIDS Res Hum Retroviruses. 2007 Mar;23(3):415-26
references.pmid: 17411375
references.citation: AIDS. 1999 Jan 14;13(1):89-96
references.pmid: 10207549
references.citation: J Virol. 2005 Sep;79(18):11848-57
references.pmid: 16140761
references.citation: Curr HIV Res. 2006 Jul;4(3):267-78
references.pmid: 16842080
references.citation: AIDS Res Hum Retroviruses. 2006 Feb;22(2):177-81
references.pmid: 16478400
references.citation: Mol Membr Biol. 1999 Jan-Mar;16(1):57-65
references.pmid: 10332738