Researchers develop a novel drug to treat HIV infection. In an in vitro experiment, wild-type viral isolates are cultured with human CD4 T lymphocytes in the presence of the drug. Microscopic evaluation of these cells reveals no cytopathic changes, and no intracellular viral particles can be detected. Further analysis reveals that in the presence of the drug the virus attaches to the cellular membrane, but fusion of the viral and cell membranes does not occur. Which of the following is the most likely target of this medication?

Question

Researchers develop a novel drug to treat HIV infection.  In an in vitro experiment, wild-type viral isolates are cultured with human CD4 T lymphocytes in the presence of the drug.  Microscopic evaluation of these cells reveals no cytopathic changes, and no intracellular viral particles can be detected.  Further analysis reveals that in the presence of the drug the virus attaches to the cellular membrane, but fusion of the viral and cell membranes does not occur.  Which of the following is the most likely target of this medication?

Quizplus · Accepted Answer

11ec160b_3831_2986_9249_a5d0d22af90a_MD0001_00 HIV attaches to host cells using the viral surface glycoprotein gp120. This glycoprotein binds to the CD4 molecule as the primary receptor and the chemokine receptor CCR5 (or CXCR4) as a coreceptor. Binding of the primary receptor and coreceptor induces a conformational change in gp120 that exposes the underlying transmembrane glycoprotein gp41, which mediates viral fusion to the host cell and release of the viral capsid into the cytoplasm. The drug described in this case does not interfere with viral attachment but does interfere with viral fusion. This implies that gp120 is still able to bind to the primary CD4 receptor but may be blocked from binding to the chemokine coreceptor, which would prevent the conformational change to gp120 required for viral fusion. Chemokine receptor antagonists (eg, maraviroc) block this step in the HIV replication cycle. The drug described in this case could also be a fusion inhibitor (eg, enfuvirtide), which blocks gp41 from fusing the viral and host plasma membranes. (Choices B and C) Nef and tat are HIV regulatory genes. The nef gene product downregulates the expression of class I major histocompatibility complex proteins on the surface of infected cells, which limits immune recognition by cytotoxic T cells. The tat gene product is a transcriptional activator that promotes viral gene expression. (Choice A) HIV integrase is a viral enzyme that inserts the viral cDNA into the host cell chromosome. (Choice D) The CD3 receptor is found on the surface of mature T lymphocytes. Monoclonal antibodies against CD3 are being investigated for autoimmune disorders, but this receptor does not play a role in HIV entry. (Choice F) CTLA4 (CD-152) is a negative regulator of T-cell activation. Antagonists of CTLA4 are used as immune checkpoint inhibitors in cancer therapy (eg, melanoma). Educational objective: The chemokine receptor CCR5 is a coreceptor that enables the HIV virus to enter cells. Blockade of CCR5 by chemokine receptor antagonists prevents viral entry into host cells.

Researchers Develop a Novel Drug to Treat HIV Infection