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Special Communication |

Current Evidence and Future Directions for Targeting HIV Entry:  Therapeutic and Prophylactic Strategies

M. Patricia D'Souza, PhD; J. Scott Cairns, PhD; Susan F. Plaeger, PhD
JAMA. 2000;284(2):215-222. doi:10.1001/jama.284.2.215.
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Great strides have been made in developing potent antiretroviral regimens that block human immunodeficiency virus (HIV) transcription and assembly. Despite these therapeutic advances, problems of drug resistance, latent viral reservoirs, and drug-induced toxic effects that compromise effective viral control point to the need for new classes of anti-HIV drugs with different modes of action. One promising approach involves blocking HIV entry into human cells, a complex process that involves multiple protein interactions. The process of HIV entry begins with binding of the viral envelope glycoprotein to both the CD4 receptor and one of several chemokine receptors and ends with fusion of viral and cell membranes. Conceptually, there are 3 steps in the HIV entry process that could serve as therapeutic targets: binding of the viral envelope glycoprotein with the CD4 receptor, binding of the envelope-CD4 complex to chemokine receptors, and fusion of the viral and cell membranes. Preclinical and clinical assessment of these entry inhibitors is ongoing and will determine if they possess properties required for drug licensure. Moreover, the worldwide epidemic is largely occurring in developing countries that cannot afford these drugs: a prophylactic vaccine is necessary and urgent. New knowledge of the HIV-envelope glycoprotein has also provided insight into possibilities for the design of novel HIV vaccines.

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Figure. Steps in the Process of HIV Entry Into a Cell
Graphic Jump Location
A, The HIV-1 envelope structure gp 160 consists of glycoproteins gp 120 and gp 41. Upon interaction of gp 120 with cellular receptors (CD4 and a chemokine receptor), the envelope complex undergoes a conformational change. B, Formation of a prehairpin intermediate in which the fusion peptide has inserted into the target membrane, though the C peptide (component of C-helices) has not yet associated with the N peptide (component of N-helices) and is subject to peptide inhibition. C, The prehairpin intermediate resolves to the fusion-active hairpin structure when the C and N peptides interact, pulling the cell and viral membranes into close proximity and culminating in membrane fusion. The precise location of the gp 120 at this point is unknown; one possibility is that it may be shed following fusion. D, Blocking the conformational change with a peptide inhibitor such as T-20 prevents membrane fusion. Adapted from Chan and Kim2 with permission.

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