The only known case of HIV cure
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The only known case of HIV cure
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[post_date] => 2024-12-23 17:51:33
[post_date_gmt] => 2024-12-23 22:51:33
[post_content] => Practice Passage (Question 1-6)
*This passage is the property of Khan Academy and has been reformatted into an AAMC-style interface in their entirety by MedLife Mastery. MedLife Mastery does not endorse and is not an affiliate of Khan Academy.
HIV is a cytopathic retrovirus – it carries its genetic information in RNA enclosed in a protein envelope surrounded by a heavy layer of glycosylation. The main target cells of the virus are CD4 T cells, also known as T helper cells. HIV glycoproteins gp120 and gp41 must bind the T cell’s CD4 receptor and a coreceptor to enable viral entry. Most often, this coreceptor is chemokine receptor 5 (CCR-5) coded for by the CCR-5 gene.
Figure 1 Basic structure of HIV virus; adapted from wikimedia image courtesy of the US National Institute of Health
Individuals homozygous or heterozygous for a mutation known as CCR-5Δ32 have shown resistance to certain strains of the virus. However, this mutation is only found in a small portion of the population. The mutated sequence is shown in Figure 2.
Figure 2 Nucleotide sequence of CCR-5 wildtype (WT) and CCR-5Δ32
The only case of HIV being cured is that of the so-called Berlin Patient. In 2006, about 10 years after discovering he had HIV, Timothy Ray Brown was diagnosed with acute leukemia while living in Berlin. As part of his cancer therapy, Mr. Brown received two stem cell transplants from a donor who was homozygous for the CCR-5Δ32 mutation. At this time, he also stopped taking his antiretroviral therapy (ART) treatment, yet within a year of the transplants, HIV was undetectable and the patient’s white blood cell counts drastically increased. His CCR-5 expression before and after stem cell transplantation is shown in Figure 3.
Figure 3 Gel electrophoresis of control and patient samples
Data adapted from: Hutter, G. (2009). Long-Term Control Of HIV ByDelta32/Delta32 Stem-Cell Transplantation. New England Journal of Medicine, 692-698. Liu R, Paxton WA et al. (1996). Homozygous defect in HIV-1 coreceptor accounts for resistance of some multiply-exposed individuals to HIV-1 infection. Cell, 86: 367-77.
[post_title] => The only known case of HIV cure
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[question] => What sort of mutation is CKR-5 Δ32?
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[answer] => 3
[description] => Reason for Correct Answer:
Compare the CCR-5 Δ32 sequence to the CCR-5 WT sequence to determine its mutation type.
It appears as though the sequences differ significantly following this point:
This is not a missense mutation, which results in one amino acid substitution because that type of mutation would only result in one different codon.
This is not a nonsense mutation, which introduces a stop codon because no new stop codons are shown in the mutated version. Stop codons could be identified by TAG, TGA, or TAA DNA sequences corresponding to UAG, UGA, and UAA stop codons on mRNA.
This cannot be a frameshift mutation, because that would result in the same sequence shifted over by one or a few nucleotides. However, the sequences following the point shown above are not that similar.
The best option is a deletion for this mutation – as shown here, the red portion is deleted in the mutation. (In fact, the Δ notation represents a deletion, and you can see the deletion here.) But you could have eliminated the other answer choices if this was hard to find.
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[answers] => Array
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[0] => Array
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[each_answer] => A. Nonsense
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[each_answer] => B. Missense
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[each_answer] => C. Deletion
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[each_answer] => D. Frameshift
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[1] => Array
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[quiz_unique_key] => 1403770772
[question] => Which of the following features of HIV does NOT hinder the immune response?
[value] => Array
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[answer] => 4
[description] => Reason for Correct Answer:
The outer envelope protects the protein capsid from being lysed by the immune system.
The error-prone reverse transcriptase means that HIV has a very high mutation rate. This makes it difficult for the immune system to fight every version of it.
HIV directly targets immune cells (specifically CD4 T cells), hindering the immune response.
The immune system has evolved defenses against both RNA and DNA viruses. Thus, out of the four options, only the virus RNA genome is a feature that would not specifically hinder the immune response.
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[answers] => Array
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[0] => Array
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[each_answer] => A. The error-prone reverse transcriptase
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[each_answer] => B. The identity of HIV’s target cells
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[2] => Array
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[each_answer] => C. The glycosylated outer envelope
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[each_answer] => D. The viral RNA genome
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[2] => Array
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[quiz_unique_key] => 1403770772
[question] => How did the Berlin Patient’s cells transform after treatment?
[value] => Array
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[answer] => 3
[description] => Reason for Correct Answer:
The patient is CD4+ meaning they have CD4+ T cells; the unknown is whether their T cells express the coreceptor in its normal form (CCR5+) and/or its mutated form (CCR-5Δ32, or CCR5-). To find out where the CCR5+ and CCR-5Δ32 bands show up on electrophoresis, look at the results of electrophoresis from controls who are homozygous for each mutation:
(Note that the heterozygous CCR5+/Δ32 control seems to exhibit two bands around the CCR5+ level, which may reflect the better resolution of its smaller quantities of the protein. This gives the heterozygote a total of 3 bands.)
Before the transplant, the Berlin patient exhibited all three bands, and after the transplant, the patient exhibited just one band.
The patient went from being heterozygous for the wildtype CCRS (CCR5 +/-) to homozygous for the Δ32 mutation (CCR5 -/-).
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[answers] => Array
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[0] => Array
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[each_answer] => A. CD4⁺, CCR5⁺/⁺ → CD4⁺, CCR5⁺/⁻
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[1] => Array
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[each_answer] => B. CD4⁺, CCR5⁺/⁺ → CD4⁺, CCR5⁻/⁻
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[2] => Array
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[each_answer] => C. CD4⁺, CCR5⁺/⁻ → CD4⁺, CCR5⁻/⁻
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[each_answer] => D. CD4⁺, CCR5⁺/⁻ → CD4⁺, CCR5⁺/⁺
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[3] => Array
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[quiz_unique_key] => 1403770772
[question] => If you were to design a vaccine for HIV, which option provides the best hypothetical target according to the reasoning provided?
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[answer] => 2
[description] => Reason for Correct Answer:
Vaccines mimic antigens – distinct parts of the pathogen – to allow the immune system to ready a response in case of later infection.
HIV’s high mutation and proliferation rates mean that large numbers of highly variable forms of the disease attack the body.
The target antigen needs to be conserved (i.e. resistant to mutation), accessible, and must not belong to the host.
Due to its relative structural stability, exterior location, and viral origin, gp120 is an excellent candidate for vaccine trials.
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[answers] => Array
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[0] => Array
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[each_answer] => A. CCR5, because without it the HIV cannot get into the host cell
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[each_answer] => B. Gp120, because its active site remains relatively constant among HIV mutations
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[2] => Array
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[each_answer] => C. Gp41, because without it the gp120 would not be attached to the virus
)
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[each_answer] => D. The protein capsid, because it would destroy the structural integrity of the virus
)
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[4] => Array
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[quiz_unique_key] => 1403770772
[question] => How did the stem cell transplant affect the immune system of the Berlin Patient?
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[answer] => 3
[description] => Reason for Correct Answer:
A stem cell transplant injects new progenitor cells (often bone marrow) into the patient.
HIV destroys white blood cells, but it does not destroy the host’s ability to produce more.
A stem cell transplant can change a host’s genotype – in the case of the Berlin Patient, after his SCT he began to produce white blood cells resistant to HIV – specifically, white blood cells expressing the CCR-5Δ32 mutant protein that HIV could not bind to
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[answers] => Array
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[0] => Array
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[each_answer] => A. The transplant gave the Berlin Patient enough HIV-resistant white blood cells to fight both the cancer and the virus.
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[each_answer] => B. The transplant allowed the Berlin Patient to manufacture white blood cells, which had been halted by HIV.
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[each_answer] => C. The transplant caused the Berlin Patient to begin to make HIV-resistant white blood cells.
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[each_answer] => D. The transplant replaced the HIV target cells with the resistant white blood cells from the donor.
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[quiz_unique_key] => 1115843717
[question] => How could researchers best replicate the effect of the Berlin Patient’s mutation pharmacologically?
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[answer] => 2
[description] => Reason for Correct Answer:
The Berlin patient took on the phenotype of the CCR-5Δ32 mutation after the stem cell transplant, per the electrophoresis results.
The CCR-5Δ32 hypothetically would cause T cells not to bind HIV very well.
While soluble CCR-5 and gp120 may inhibit HIV entry, they are not the most direct ways to replicate the phenotype of the patient. This is because the CCR-5 receptor would remain active in these approaches.
Only a CCR-5 antagonist would best replicate the effect of the CCR-5Δ32 mutation. This would hypothetically block a patient’s CCR5 receptors from binding HIV.
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[answers] => Array
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[each_answer] => A. With a CCR-5 agonist
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[each_answer] => B. With a CCR-5 antagonist
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[each_answer] => C. With soluble CCR-5
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[each_answer] => D. With soluble gp120
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