The HIV Env variant N283 enhances macrophage tropism and is associated with brain infection and dementia.
HIV infects tissue macrophages and brain microglia, which express lower levels of CD4 and CCR5 than CD4+ T cells in peripheral blood. Mechanisms that enhance HIV tropism for macrophages in the CNS and other tissues are not well understood. Here, we identify an HIV envelope glycoprotein (Env) variant in the CD4-binding site of gp120, Asn 283 (N283), that is present at a high frequency in brain tissues from AIDS patients with HIV-associated dementia (HAD). N283 increases gp120 affinity for CD4 by decreasing the gp120-CD4 dissociation rate, enhancing the capacity of HIV Envs to use low levels of CD4 for virus entry and increasing viral replication in macrophages and microglia. Structural modeling suggests that the enhanced ability of Envs with N283 to use low levels of CD4 is due to a hydrogen bond formed with Gln 40 of CD4. N283 is significantly more frequent in brain-derived Envs from HAD patients (41%; n=330) compared with non-HAD patients (8%; n=151; P<0.001). These findings suggest that the macrophage-tropic HIV Env variant N283 is associated with brain infection and dementia in vivo, representing an example of a HIV variant associated with a specific AIDS-related complication.
Dunfee
Rebecca L
RL
Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Thomas
Elaine R
ER
Gorry
Paul R
PR
Wang
Jianbin
J
Taylor
Joann
J
Kunstman
Kevin
K
Wolinsky
Steven M
SM
Gabuzda
Dana
D
D015526:AIDS Dementia Complex / Q000276:immunology / Q000473:pathology / Q000821:virology*; D001665:Binding Sites; D001921:Brain / Q000276:immunology / Q000473:pathology / Q000821:virology*; D015704:CD4 Antigens / Q000378:metabolism; D002460:Cell Line; D002465:Cell Movement / Q000276:immunology*; D014644:Genetic Variation; D006678:HIV / Q000235:genetics / Q000472:pathogenicity*; D015699:HIV Envelope Protein gp120 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D008264:Macrophages / Q000276:immunology / Q000473:pathology / Q000821:virology*; D017628:Microglia / Q000276:immunology / Q000473:pathology / Q000821:virology; D008969:Molecular Sequence Data; D011485:Protein Binding
D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120