Macrophage entry mediated by HIV Envs from brain and lymphoid tissues is determined by the capacity to use low CD4 levels and overall efficiency of fusion.
HIV infects macrophages and microglia in the central nervous system (CNS), which express lower levels of CD4 than CD4+ T cells in peripheral blood. To investigate mechanisms of HIV neurotropism, full-length env genes were cloned from autopsy brain and lymphoid tissues from 4 AIDS patients with HIV-associated dementia (HAD). Characterization of 55 functional Env clones demonstrated that Envs with reduced dependence on CD4 for fusion and viral entry are more frequent in brain compared to lymphoid tissue. Envs that mediated efficient entry into macrophages were frequent in brain but were also present in lymphoid tissue. For most Envs, entry into macrophages correlated with overall fusion activity at all levels of CD4 and CCR5. gp160 nucleotide sequences were compartmentalized in brain versus lymphoid tissue within each patient. Proline at position 308 in the V3 loop of gp120 was associated with brain compartmentalization in 3 patients, but mutagenesis studies suggested that P308 alone does not contribute to reduced CD4 dependence or macrophage-tropism. These results suggest that HIV adaptation to replicate in the CNS selects for Envs with reduced CD4 dependence and increased fusion activity. Macrophage-tropic Envs are frequent in brain but are also present in lymphoid tissues of AIDS patients with HAD, and entry into macrophages in the CNS and other tissues is dependent on the ability to use low receptor levels and overall efficiency of fusion.
Thomas
Elaine R
ER
Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA, USA.
Dunfee
Rebecca L
RL
Stanton
Jennifer
J
Bogdan
Derek
D
Taylor
Joann
J
Kunstman
Kevin
K
Bell
Jeanne E
JE
Wolinsky
Steven M
SM
Gabuzda
Dana
D
D015526:AIDS Dementia Complex / Q000821:virology*; D000222:Adaptation, Physiological; D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000821:virology; D015704:CD4 Antigens / Q000378:metabolism; D002451:Cell Compartmentation; D002460:Cell Line; D015686:Gene Products, env / Q000235:genetics*; D015699:HIV Envelope Protein gp120 / Q000235:genetics / Q000378:metabolism; D015658:HIV Infections; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D008221:Lymphoid Tissue / Q000821:virology; D008264:Macrophages / Q000378:metabolism / Q000821:virology*; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism; D010802:Phylogeny; D019713:Receptors, CCR5 / Q000378:metabolism*; D016415:Sequence Alignment; D013045:Species Specificity; D014779:Virus Replication
D015704:CD4 Antigens; D015686:Gene Products, env; D015699:HIV Envelope Protein gp120; C059762:HIV envelope protein gp120 (305-321); D010446:Peptide Fragments; D019713:Receptors, CCR5