Env gp120 sequence analysis of HIV type 1 strains from diverse areas of the brain shows preponderance of CCR5 usage.
In this study diverse areas of the autopsied brain of 12 HIV-infected patients with and without dementia were analyzed. All brain samples were obtained at autopsy through prior consent. Env C2-V5 region was PCR amplified and sequenced and compared between different brain regions within the same patient and also between patients to find changes, which can discriminate between patients with and without dementia and also identify motifs responsible for coreceptor-mediated entry of HIV into the CNS. For this, the Env gp120 hypervariable V3 region (35 amino acid residues) was subjected to position scoring matrix analyses (PSSM) for predicting coreceptor usage in the brain. These predictions based on the V3 loop sequence were absolutely consistent with the biologically determined viral phenotype at least for the samples, which were successful for virus culture. These data clearly show that the PSSM correlates can be unambiguously applied in determining viral phenotype for entry. The most notable observation is that of 69 V3 region sequences analyzed from 12 patients from diverse brain regions, 64 showed CCR5 usage (93%) as opposed to only five using CXCR4. Comparison of the V3 loop charge failed to show any correlation between charge and coreceptor usage. Given that cells of macrophage lineage predominate in the CNS and also facilitate HIV entry into the CNS, the preponderance of CCR5 usage in brain-derived HIV strains from patients with and without dementia may have important clinical implications.
Shah
Meet
M
Retroviral Genetics Division, Center for Virus Research, Westmead Millennium Institute, Westmead Hospital, The University of Sydney, Darcy Road, Westmead NSW 2145, Australia.
Smit
Theresa K
TK
Morgello
Susan
S
Tourtellotte
Wallace
W
Gelman
Benjamin
B
Brew
Bruce J
BJ
Saksena
Nitin K
NK
D000595:Amino Acid Sequence; D001344:Autopsy; D001921:Brain / Q000473:pathology / Q000821:virology*; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000235:genetics*; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D019713:Receptors, CCR5 / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid
D015699:HIV Envelope Protein gp120; D019713:Receptors, CCR5