Master of Science
Pathology and Laboratory Medicine
Poon, Art F.Y.
Insertions and deletions (indels) in the HIV-1 gp120 variable loops modulate sensitivity to neutralizing antibodies and are therefore implicated in HIV-1 immune escape. However, the rates and characteristics of variable loop indels have not been investigated within hosts. Here, I report a within-host phylogenetic analysis of gp120 variable loop indels, with mentions to my preceding study on these indels among hosts.
We processed longitudinally-sampled gp120 sequences collected from a public database (n = 11,265) and the Novitsky Lab (n=2,541). I generated time-scaled within-host phylogenies using BEAST, extracted indels by reconstructing ancestral sequences in Historian, and estimated variable loop indel rates by applying a Poisson-based model to indel counts and time data.
Variable loop indel rates appeared higher within hosts than among hosts in subtype C. Our findings improve understanding of indel evolution in HIV-1 gp120 and enable the evaluation of models describing indels, which I present as work in progress.
Summary for Lay Audience
The Human Immunodeficiency Virus (HIV) attaches to our immune cells using a protein on its surface called gp120. The nucleotide sequence that produces the gp120 protein undergoes numerous changes (mutations), with one type being the insertion or deletion of nucleotides (indels). Indels are most frequently found in five specific regions of the gp120 nucleotide sequence, or gene, that produce five sugar-covered loop structures (V1-V5) on the surface of this protein, referred to as “variable loops”. Since gp120 is exposed on the surface of HIV, the human immune system commonly designs cells and proteins that target key patterns on the gp120 variable loops in order to detect and eliminate HIV. Importantly, indel mutations can change the shapes, lengths, and sugar positions of the gp120 variable loops, thereby altering the same targeted patterns on these loops until they become unrecognizable to the immune system. This process, known as “immune escape”, occurs repeatedly during HIV infection, allowing the virus to remain unaffected by the immune response and continue to cause disease.
Rates of mutations provide an indication of how quickly an organism, or virus, can change itself to adapt to its environment, like in the process of immune escape in HIV, for example. In the gp120 variable loops, indels are involved in immune escape; however, indel rates have not been studied in these regions. This work provides the first estimates of indel rates in the gp120 variable loops of HIV by using computer software to estimate the amount of historical time between different virus samples. I first estimated variable loop indel rates at the population scale (among hosts) by analyzing one HIV nucleotide sequence per person worldwide. My main study then estimated indel rates by analyzing multiple sequences collected from a single individual (within hosts). I found that indel rates appear higher within hosts than among hosts. This work contributes to a better understanding of an important type of mutation within the gp120 variable loops that helps HIV adapt to our immune system. It does this by quantifying how frequently indels occur and their contributions to both variable loop changes and immune escape.
Palmer, John Lawrence, "Rates and patterns of indels in HIV-1 gp120 within and among hosts" (2020). Electronic Thesis and Dissertation Repository. 7308.
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