Author Affiliations: Branches of Vaccine Clinical Research (Dr D'Souza), Targeted Interventions (Dr Cairns), and Pathogenesis and Basic Sciences (Dr Plaeger), Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
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.
D'Souza MP, Cairns JS, Plaeger SF. Current Evidence and Future Directions for Targeting HIV EntryTherapeutic and Prophylactic Strategies. JAMA. 2000;284(2):215-222. doi:10.1001/jama.284.2.215