A 45-year-old woman with advanced HIV infection has been receiving antiretroviral therapy for several years. When treatment was first initiated, the patient's viral load rapidly decreased to undetectable levels and her CD4+ cell count remained above 200/mm³. However, recent HIV RNA levels have increased above the detection threshold. After undergoing drug resistance testing, she is started on an integrase inhibitor, and her viral load decreases precipitously. Which of the following steps of viral replication is most likely to be inhibited as a result of this patient's new treatment?

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11ec160b_3bf3_88b6_9249_2766a144f777_MD0001_00 After an HIV virion enters a host cell, viral RNA is released from the nucleocapsid and transcribed into double-stranded DNA by reverse transcriptase. The viral DNA then enters the nucleus and, through the actions of integrase, permanently inserts into the host cell's chromosomes to become a provirus. RNA polymerase II then transcribes viral mRNA from the proviral DNA. Once synthesized, HIV mRNA exits through the nuclear pores into the cytoplasm, where it uses the host cell's ribosomes to translate the enzymes, glycoproteins, structural proteins, and regulatory proteins needed to promote viral replication and transmission. The full-length mRNA also serves as the viral genome that is packaged into newly synthesized virions. Raltegravir is an integrase inhibitor that disrupts the ability of double-stranded HIV DNA to integrate into the host cell's chromosomes. In the absence of integration, the viral genome cannot be transcribed by host cellular machinery and is eventually degraded by nucleases. (Choice A) Most of the proteins necessary for HIV replication are translated into a polyprotein precursor that is then cleaved into individual proteins by viral and cellular protease enzymes. The action of viral protease can be directly prevented by protease inhibitors such as saquinavir. (Choice B) Complementary DNA synthesis from the HIV RNA template is directly impaired by nucleoside and non-nucleoside reverse transcriptase inhibitors. (Choice C) Drugs that bind to gp41, HIV's transmembrane envelope protein, are known as fusion inhibitors (eg, enfuvirtide). These drugs prevent gp41 from undergoing the conformational changes necessary for viral membrane fusion with the host cell membrane. (Choice E) For HIV to infect a cell, the envelope glycoprotein gp120 must bind to both a CD4 molecule and a chemokine receptor (eg, CXCR4 or CCR5). CCR5 antagonists, such as maraviroc, exert their antiviral activity against HIV by blocking attachment and entry of CCR5-tropic viruses into CD4+ T cells and macrophages. Educational objective: Integration of double-stranded HIV DNA into the host cell's chromosomes is necessary to induce viral gene expression and prevent degradation of the viral genome. Raltegravir is an integrase inhibitor that disrupts HIV genome integration, preventing synthesis of viral mRNA. __________ References: Raltegravir: the first HIV-1 integrase strand transfer inhibitor in the HIV armamentarium. (http://www.ncbi.nlm.nih.gov/pubmed/21434946)

A 45-Year-Old Woman with Advanced HIV Infection Has Been Receiving