Feedback between glial tumor necrosis factor-alpha and gp120 from HIV-infected cells helps maintain infection and destroy neurons.
An envelope glycoprotein, gp20, of the human immunodeficiency virus (HIV) interacts with host systems to promote HIV replication. gp120 is also involved in tissue-destructive positive feedback cycles that contribute to HIV-related but non-lymphocytic-, non-immunodeficiency-related tissue-destructive morbidity. Exposure to gp120 results in tumor necrosis factor-alpha (TNF) upregulation, particularly in cells of monocyte lineage. The resultant increased TNF in the microenvironment of the TNF-producing monocyte lineage cells results in increased occupancy of TNF receptors on nearby lymphocytes, monocytes or glia in which HIV does replicate. Such TNF binding increases HIV replication. Increased replication results in increased gp120 available to bind to monocyte lineage cells, further increasing or maintaining those cells' TNF production in the face of other TNF suppressive forces. A trophic environment (TNF) for HIV replication is thereby maintained. gp120 raises cAMP levels. Increased cAMP is inherently TNF-suppressive. This is a moderating negative feedback element embedded within the larger positive feedback cycle. HIV does not effectively replicate in neurons yet many HIV infections show significant neuron loss. gp120 stimulates glia to synthesize TNF. Increased TNF stimulates HIV to replicate in the cells present in which HIV is able to replicate. TNF also damages nearby neurons. The resultant increased gp120 would further stimulate glia, and the stimulated glia's TNF would damage local neurons. Damaged neurons make factors that activate glia to upregulate TNF synthesis. These feedback cycles centering on gp120 and TNF contribute to HIV pathophysiology, neuron loss and maintenance of infection.
Kast
Richard E
RE
Department of Psychiatry, University of Vermont, Burlington, VT 05401, USA. rekast@email.com
D025461:Feedback, Physiological / Q000276:immunology; D015699:HIV Envelope Protein gp120 / Q000378:metabolism*; D015658:HIV Infections / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D009457:Neuroglia / Q000276:immunology / Q000378:metabolism / Q000821:virology*; D015213:Neuroimmunomodulation / Q000276:immunology; D009474:Neurons / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D015699:HIV Envelope Protein gp120; D014409:Tumor Necrosis Factor-alpha