9.10B: HIV Attachment and Host Cell Entry
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The attachment and fusion of HIV virons to host cells are crucial to HIV infection.
- Define the unique aspects of HIV attachment and host cell entry
- HIV proteins bind to specific receptors of host cells, most importantly HIV coat proteins gp41 and gp160.
- After attaching to the host, many of the receptors on both the cell and invading virus bind together for fusion of the virus with its host.
- Because HIV attachment is critical for the HIV replication cycle, understanding the specific mechanisms by which HIV attachment occurs has implications for potential treatments of HIV.
- glycoprotein: A protein with covalently bonded carbohydrates.
- macrophages: A type of white blood cell that targets foreign material, including bacteria and viruses.
- capsid: The outer protein shell of a virus.
- chemokine: Any of various cytokines, produced during inflammation, that organize the leukocytes.
- T cells: A lymphocyte, from the thymus, that can recognise specific antigens and can activate or deactivate other immune cells.
HIV entry is the earliest stage of infection in the HIV viral life cycle, occurring when the HIV virus comes into contact with the host cell and introduces viral material into the cell. HIV enters macrophages and CD4-positive T cells (CD4 is a glycoprotein receptor found on cells) by the adsorption of glycoproteins on its surface to receptors on the target cell, followed by fusion of the viral envelope with the cell membrane and the release of the HIV capsid into the cell.
Entry to the cell begins through interaction of the trimeric envelope complex and both CD4 and a chemokine receptor on the host cell on the cell surface. The HIV coat protein, gp120, binds to integrin α4β7, activating LFA-1 (the central integrin involved in the establishment of bridges known as “virological synapses”) which facilitate efficient cell-to-cell spreading of HIV-1.
After attachment, the HIV viron must next fuse with the host cell. The first step in fusion begins after the attachment of the CD4 binding domains of gp120 to CD4. Once gp120 is bound with the CD4 protein, the envelope complex undergoes a structural change, exposing the chemokine binding domains of gp120 and allowing them to interact with the target chemokine receptor. This allows for a more stable two-pronged attachment, which allows the N-terminal fusion peptide gp41 to penetrate the cell membrane. Repeat sequences in gp41, known as HR1 and HR2, then interact, causing the collapse of the extracellular portion of gp41 into a hairpin. This loop structure brings the virus and cell membranes close together, allowing fusion of the membranes and subsequent entry of the viral capsid.
After HIV has bound to the target cell, the HIV RNA and various enzymes (including reverse transcriptase, integrase, ribonuclease, and protease) are injected into the cell. Because HIV attachment is critical for the HIV replication cycle, understanding the specific mechanisms through which HIV attachment occurs has implications for potential treatments of HIV.