A 54-year-old man with HIV is part of a large clinical study. He was diagnosed with HIV-1 infection 5 years ago. Blood samples are obtained periodically to perform sequencing analysis of the viral genome. Current testing reveals a large number of isolates with mutation in the pol gene compared to the previous analyses. This finding is most closely associated with which of the following?

Question

A 54-year-old man with HIV is part of a large clinical study.  He was diagnosed with HIV-1 infection 5 years ago.  Blood samples are obtained periodically to perform sequencing analysis of the viral genome.  Current testing reveals a large number of isolates with mutation in the pol gene compared to the previous analyses.  This finding is most closely associated with which of the following?

Quizplus · Accepted Answer

HIV reverse transcriptase does not have a proofreading mechanism. This allows the virus to rapidly accumulate mutations (~1 nucleotide base pair per replication cycle) that may make it resistant to antiretroviral monotherapy. However, the consistent use of combination antiretroviral therapy, which contains medications that target multiple steps in the HIV replication cycle, effectively prevents the development of resistant strains. This patient was found to have a large number of viral isolates with new mutations to the pol gene, which encodes for the major HIV enzymes protease, reverse transcriptase, and integrase. Most first-line antiretroviral medications, including protease inhibitors, reverse transcriptase inhibitors, and integrase strand transfer inhibitors, target these enzymes. The emergence of a new predominant strain with mutation to the pol gene suggests that this patient has become resistant to his antiretroviral therapy. Nearly all cases of acquired antiretroviral resistance are due to inconsistent use (transmitted resistance can also occur when an individual is inoculated with a resistant strain). This patient will likely need a new antiretroviral regimen and should be encouraged to take it as prescribed. (Choice A) HIV infection results in the generation of antibodies that can reduce free virus in the circulatory system but cannot eliminate the infection due to viral integration into the host genome. The primary target of neutralizing antibodies against HIV is the surface glycoprotein GP120, which is encoded by the env gene, not the pol gene. (Choice C) The HIV nef gene encodes for a protein that downregulates major histocompatibility complex class I proteins, reducing the ability of cytotoxic T cells to recognize host cells infected with HIV. Pol gene mutations are unlikely to directly influence the ability of CD8 cells to respond to the infection. (Choice D) HIV infection triggers CD4 cell apoptosis through many mechanisms, including chronic immunologic stimulation, activation of the CD4 receptor by envelope glycoproteins (during viral attachment), and increased production of cytotoxic ligands by immune cells. Mutations to the pol gene are unlikely to result in a reduction in CD4 apoptosis. (Choice E) Viral replication rate is generally positively correlated with the mutation rate. Educational objective: HIV pol gene mutations are responsible for acquired resistance to reverse transcriptase inhibitors, protease inhibitors, and integrase strand transfer inhibitors. Mutations of the env gene enable escape from host-neutralizing antibodies. __________ References: HIV-1 antiretroviral resistance: scientific principles and clinical applications. (http://www.ncbi.nlm.nih.gov/pubmed/22686620)

A 54-Year-Old Man with HIV Is Part of a Large