Sequence variation in the CC-chemokine ligand 2 promoter of pigtailed macaques is not associated with the incidence or severity of neuropathology in a simian immunodeficiency virus model of human immunodeficiency virus central nervous system disease.
Increased expression of CC-chemokine ligand 2 (CCL2) in the cerebrospinal fluid (CSF) and brain is consistently observed in human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) central nervous system (CNS) disease. The molecular basis for the correlation between increased expression of CCL2 and HIV neuropathogenesis has been linked to a polymorphism at -2578 in the promoter of human CCL2, which was reported to influence the rate of progression to acquired immunodeficiency syndrome (AIDS) and the predisposition of HIV-infected individuals to develop HIV-associated dementia. However, because the rate of neurological deterioration essentially parallels the progression of immunosuppression, it is inherently difficult to uncouple the influence of this polymorphism on increased progression to AIDS from increased propensity to develop CNS complications. To further investigate the correlation between CCL2 and HIV/SIV CNS disease, the authors sequenced the CCL2 promoter of 29 pigtailed macaques examined in their accelerated and consistent SIV model in which all infected macaques develop AIDS but only 69% developed moderate/severe CNS lesions. Sequence analysis identified 39 sites of nucleotide variation in the pigtailed macaque CCL2 promoter/enhancer regions, with the resulting consensus sequence aligning with 94.7% homology to the human CCL2 promoter. After genetic analyses, no variation was found to correlate with the incidence or severity of CNS lesions or with levels of CCL2 in plasma or CSF. These findings suggest that the determinants of neuropathogenesis in this SIV model are distinct from variation in these regions of the CCL2 promoter.
Wright
Edward K
EK
McKusick-Nathans Institute of Genetic Medicine, Baltimore, Maryland, USA.
Clements
Janice E
JE
Barber
Sheila A
SA
D000163:Acquired Immunodeficiency Syndrome / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D001921:Brain / Q000473:pathology*; D018932:Chemokine CCL2 / Q000032:analysis / Q000235:genetics*; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D020022:Genetic Predisposition to Disease; D006678:HIV; D006801:Humans; D008254:Macaca nemestrina; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic / Q000235:genetics*; D017422:Sequence Analysis, DNA; D012689:Sequence Homology, Nucleic Acid; D016097:Simian Acquired Immunodeficiency Syndrome / Q000235:genetics* / Q000473:pathology; D015302:Simian Immunodeficiency Virus
D018932:Chemokine CCL2