USMLE® Step 1 style questions USMLE
USMLE® Step 2 style questions USMLE
A 52-year-old HIV positive man with a past medical history of dyslipidemia and a current white blood cell count of 500 comes to his primary care physician for a routine check up. He states that he is feeling well overall and has no new complaints. He also mentions that he is in a new relationship and is concerned about passing the virus on to his partner, who is aware of his HIV status. The patient is started on antiretroviral therapy. One year later, he presents with a “hump” on the back of his neck (see image below). Which of the following drugs is most strongly associated with this finding?
Content Reviewers:Yifan Xiao, MD
Protease inhibitors, or PIs, work by inhibiting the enzyme HIV-1 protease, which prevents the formation of new viruses and further infection of the host’s cells.
HIV is a single-stranded, positive-sense, enveloped RNA retrovirus that targets cells in the immune system that have molecules called CD4 on their membranes.
These include macrophages, dendritic cells, and especially CD4+ T-helper cells.
HIV attaches to the CD4 molecule via a protein called gp120 found on its envelope.
Now, inside its envelope, HIV contains a nucleocapsid which is a capsule containing a single-stranded RNA and some viral enzymes, like reverse transcriptase, integrase, and aspartate protease, also known as a mature HIV-1 protease.
As HIV binds to the receptors, the viral envelope fuses with the cell membrane of the immune cell, releasing the contents of the nucleocapsid into the helpless host cell’s cytoplasm.
Once it’s inside the CD4+ cell, reverse transcriptase gets to work immediately.
It uses the single-stranded viral RNA as a template and uses the nucleotides present in the cytoplasm of the CD4+ cell to transcribe a complementary double-stranded “proviral” DNA.
This proviral DNA enters the T-helper cell’s nucleus and pops itself into the cell’s DNA, ready to be transcribed into messenger RNA (mRNA).
These mRNA travel to the ribosomes which translate this into long Gag-Pol polyproteins, which are a bunch of viral proteins joined together.
Now, human cells don’t come with the equipment to process these long polyprotein chains, but one of the enzymes that HIV releases into the cell is a protease called aspartate protease, or HIV-1 protease.
This enzyme cuts the polyprotein into individual, functional viral proteins.
These proteins are then packed together to form new HIV viruses, which bud off from the cell membrane to infect more cells. Very sneaky indeed!
Over time, more and more immune cells are infected, and the immune system begins to fail, which is called immunodeficiency, and this increases the risk of infections and tumors that a healthy immune system would usually be able to fend off.
These complications are referred to as AIDS, or acquired immunodeficiency syndrome.
Now, in order to prevent the formation of new HIV viruses and further infection of the host’s cells, we can use protease inhibitors, or PIs.
As their name implies, protease inhibitors bind and inhibit HIV-1 protease, thereby making it incapable of processing the Gag-Pol polyproteins so new viruses can’t be made.
These medications are rarely used alone since HIV quickly develops resistance to them by point mutations of the pol gene, which is the gene that encodes HIV-1 protease.
Typically, protease inhibitors are used as a part of the highly active antiretroviral therapy, or HAART, along with nucleoside reverse transcriptase inhibitors, or NRTIs, like tenofovir.
This is so that, if HIV were to develop a mutation making it resistant to protease inhibitors, then it can still be killed by the NRTIs.
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