A 45-year-old woman is hospitalized due to severe Pneumocystis pneumonia. The patient has a history of injection drug use and was diagnosed with HIV 10 years ago. She does not adhere to antiretroviral therapy and has developed resistance to multiple antiretroviral medications. Laboratory evaluation reveals severe immunosuppression with a high HIV viral load. After the patient is adequately treated for pneumonia, HIV genotypic analysis is performed. The viral isolates are found to have a mutation in the variable (V3) region of the env gene, which makes the virus capable of infecting T cells with a specific surface receptor, but infection of macrophages is inefficient. Which of the following antiretroviral medications is most likely to be ineffective in this patient?

Question

A 45-year-old woman is hospitalized due to severe Pneumocystis pneumonia.  The patient has a history of injection drug use and was diagnosed with HIV 10 years ago.  She does not adhere to antiretroviral therapy and has developed resistance to multiple antiretroviral medications.  Laboratory evaluation reveals severe immunosuppression with a high HIV viral load.  After the patient is adequately treated for pneumonia, HIV genotypic analysis is performed.  The viral isolates are found to have a mutation in the variable (V3) region of the env gene, which makes the virus capable of infecting T cells with a specific surface receptor, but infection of macrophages is inefficient.  Which of the following antiretroviral medications is most likely to be ineffective in this patient?

Quizplus · Accepted Answer

11ec160b_3bf6_e419_9249_21c05ef3d1fc_MD0001_00 HIV binds to host cells using the host CD4 receptor and a chemokine coreceptor (either CCR5 or CXCR4). The virus preferentially targets T lymphocytes, dendritic cells, and macrophages because these cells contain high surface concentrations of CD4. However, each of these cell types contains different surface concentrations of the 2 chemokine receptors. HIV is considered tropic for a certain cell type, depending on whether it preferentially binds to CCR5 or CXCR4 for viral entry, as follows: R5 virus uses CCR5 for viral entry and is considered macrophage-tropic because CCR5 is expressed in high concentrations on both macrophages and lymphocytes. R5 is the predominant HIV type. X4 virus uses CXCR4 for viral entry and is considered T lymphotropic because CXCR4 is expressed primarily on T lymphocytes but only minimally on macrophages. HIV trophism is determined by a gene sequence in the variable (V3) region of the env gene, which encodes for the HIV surface glycoprotein 120. This glycoprotein mediates viral attachment to the CD4 receptor and chemokine coreceptor. The laboratory results in this case indicate an X4 virus (T lymphotropic with minimal macrophage invasion). Patients with X4 virus cannot be treated with HIV medications that target CCR5 (eg, maraviroc) because the X4 virus uses CXCR4, not CCR5, to enter cells. (Choice A) Protease inhibitors (eg, atazanavir, indinavir, darunavir) inhibit HIV protease from cleaving HIV polyproteins into the individual, functional proteins that compose the virus. This results in the formation of immature, noninfectious virions that are unable to infect T cells or macrophages. (Choices B and F) Non-nucleoside reverse transcriptase inhibitors (eg, efavirenz, nevirapine) allosterically bind reverse transcriptase, which alters its shape and prevents it from converting the HIV RNA genome into complementary DNA (cDNA). Nucleoside reverse transcriptase inhibitors (eg, tenofovir, emtricitabine) competitively bind reverse transcriptase and are integrated into growing cDNA strands, which results in chain termination. Both of these HIV medication classes truncate viral replication but do not affect viral attachment or fusion. (Choice C) Enfuvirtide is an HIV fusion inhibitor that binds to the HIV transmembrane surface protein glycoprotein 41 and prevents the virus from fusing with the host cell membrane. Fusion inhibitors would inhibit the ability of HIV to invade both lymphocytes and macrophages. (Choice E) Integrase inhibitors (eg, raltegravir, dolutegravir) prevent the HIV enzyme integrase from incorporating viral cDNA into the host chromosome, which prevents viral replication. They do not affect viral attachment or fusion. Educational objective: R5 strains (macrophage-tropic) of HIV attach to the host CD4 receptor and CCR5 chemokine coreceptor; CCR5 inhibitors such as maraviroc can be used in the treatment of R5 virus. X4 strains (T lymphotropic) of HIV bind to the CD4 receptor and CXCR4 chemokine receptor; X4 virus cannot be treated with CCR5 inhibitors.

A 45-Year-Old Woman Is Hospitalized Due to Severe Pneumocystis Pneumonia