Brain-derived HIV-1 tat sequences from AIDS patients with dementia show increased molecular heterogeneity.
HIV-1 infection results in a dementing illness affecting 20% of patients with AIDS. Several HIV-1 genes have been implicated in the pathogenesis of HIV-induced neurological disease. To search for distinct HIV-1 sequences associated with the development of dementia, brain-derived tat, env, and pol sequences were examined from AIDS patients defined pre-mortem as demented (HIV-D)[n=5] or non-demented (HIV-ND)[n=5]. Estimations of evolutionary distances and frequency of non-synonymous mutation rates revealed significant differences between brain-derived tat, env, and pol-encoded reverse transcriptase sequences. However, established zidovudine-associated resistance mutations in reverse transcriptase sequences were identified in only one HIV-D and one HIV-ND patient despite prolonged treatment of some patients. Non-synonymous/synonymous substitution rates among the tat sequences derived from patients with HIV-D were significantly higher compared to the HIV-ND group (P < 0.001). The ratios of transversions to transitions were also significantly higher among the HIV-D tat sequences (P< 0.01). Phylogenetic analyses showed clustering of sequences from each clinical group among the brain-derived tat and env sequences. These studies indicated that differing selective forces act on individual HIV-1 genes in the brain which may influence the development of dementia.
Bratanich
A C
AC
Department of Medical Microbiology, University of Manitoba, Winnipeg, Canada.
Liu
C
C
McArthur
J C
JC
Fudyk
T
T
Glass
J D
JD
Mittoo
S
S
Klassen
G A
GA
Power
C
C
D015526:AIDS Dementia Complex / Q000821:virology*; D001921:Brain / Q000821:virology*; D004279:DNA, Viral / Q000032:analysis; D005814:Genes, Viral / Q000235:genetics; D015756:Genes, tat / Q000235:genetics*; D018740:Genetic Heterogeneity; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D010802:Phylogeny; D017386:Sequence Homology, Amino Acid
D004279:DNA, Viral