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Title: Bioinformatic analysis of neurotropic HIV envelope sequences identifies polymorphisms in the gp120 bridging sheet that increase macrophage-tropism through enhanced interactions with CCR5

Macrophages express low levels of the CD4 receptor compared to T-cells. Macrophage-tropic HIV strains replicating in brain of untreated patients with HIV-associated dementia (HAD) express Envs that are adapted to overcome this restriction through mechanisms that are poorly understood. Here, bioinformatic analysis of env sequence datasets together with functional studies identified polymorphisms in the β3 strand of the HIV gp120 bridging sheet that increase M-tropism. D197, which results in loss of an N-glycan located near the HIV Env trimer apex, was detected in brain in some HAD patients, while position 200 was estimated to be under positive selection. D197 and T/V200 increased fusion and infection of cells expressing low CD4 by enhancing gp120 binding to CCR5. These results identify polymorphisms in the HIV gp120 bridging sheet that overcome the restriction to macrophage infection imposed by low CD4 through enhanced gp120–CCR5 interactions, thereby promoting infection of brain and other macrophage-rich tissues. - Highlights: • We analyze HIV Env sequences and identify amino acids in beta 3 of the gp120 bridging sheet that enhance macrophage tropism. • These amino acids at positions 197 and 200 are present in brain of some patients with HIV-associated dementia. • D197 results in loss of amore » glycan near the HIV Env trimer apex, which may increase exposure of V3. • These variants may promote infection of macrophages in the brain by enhancing gp120–CCR5 interactions.« less
Authors:
 [1] ;  [2] ;  [2] ;  [1] ;  [3]
  1. Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA (United States)
  2. Northwestern University Medical School, Chicago, IL (United States)
  3. (Microbiology and Immunobiology), Harvard Medical School, Boston, MA (United States)
Publication Date:
OSTI Identifier:
22470176
Resource Type:
Journal Article
Resource Relation:
Journal Name: Virology; Journal Volume: 481; Other Information: Copyright (c) 2015 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; AIDS VIRUS; AMINO ACIDS; ANIMAL TISSUES; BRAIN; BRIDGES; COMPARATIVE EVALUATIONS; DATASETS; INTERACTIONS; MACROPHAGES; NERVOUS SYSTEM DISEASES; PATIENTS; RECEPTORS; STRAINS