title: Bioinformatic analysis of neurotropic HIV envelope sequences identifies polymorphisms in the gp120 bridging sheet that increase macrophage-tropism through enhanced interactions with CCR5.
abstract: 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.
authors: Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA, USA. Electronic address: megan_mefford@hms.harvard.edu.
authors: Megan E
authors: ME
authors: Mefford
authors: Northwestern University Medical School, Chicago, IL, USA. Electronic address: kunstman@northwestern.edu.
authors: Kevin
authors: K
authors: Kunstman
authors: Northwestern University Medical School, Chicago, IL, USA. Electronic address: s-wolinsky@northwestern.edu.
authors: Steven M
authors: SM
authors: Wolinsky
authors: Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Neurology (Microbiology and Immunobiology), Harvard Medical School, Boston, MA, USA. Electronic address: dana_gabuzda@dfci.harvard.edu.
authors: Dana
authors: D
authors: Gabuzda
mesh_terms: D000595:Amino Acid Sequence; D001921:Brain / Q000378:metabolism / Q000821:virology*; D019295:Computational Biology; D015699:HIV Envelope Protein gp120 / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D015658:HIV Infections / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D015497:HIV-1 / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008264:Macrophages / Q000378:metabolism / Q000821:virology*; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide; D011485:Protein Binding; D017433:Protein Structure, Secondary; D019713:Receptors, CCR5 / Q000235:genetics / Q000378:metabolism*; D016415:Sequence Alignment; D056189:Viral Tropism
chemical_list: D015699:HIV Envelope Protein gp120; D019713:Receptors, CCR5
keywords: Bridging sheet; CCR5; CD4; Envelope; HIV; Macrophage; Tropism; V1/V2 stem