Clonal Expansion of Infected CD4+ T Cells in People Living with HIV

Key Question Being Explored in This Insight:

HIV infection is not curable with current antiretroviral therapy (ART) because a small fraction of CD4+ T cells infected prior to ART initiation persists. Understanding the nature of this latent reservoir and how it is created is essential to development of potentially curative strategies. John Coffin discusses.

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Institution: Tufts University

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This video is a transcript of a dialogue discussing HIV, its mechanism of persistence in the body, specifically through the integration of its genetic material into host cells, particularly CD4 T cells. Professor John explains that while HIV can be effectively treated with antiretroviral therapy, it can re-emerge after treatment cessation due to the presence of latent cells that harbor the virus's DNA (provirus) without expressing it.

Key points covered include:

1. **Clonal Expansion**: The discussion highlights how CD4 T cells undergo clonal expansion in response to pathogens and how HIV exploits this process for its persistence.

2. **Mechanism of HIV Persistence**: Although most infected cells may die, some remain and can potentially reactivate the virus. The latent HIV cells can proliferate and cause reinfection if treatment stops.

3. **Research Developments**: Professor John discusses studies aimed at identifying these latent reservoirs and the challenges researchers face in eradicating the virus. He emphasizes the importance of understanding how these cells can survive and expand.

4. **Future Directions**: The conversation touches upon potential strategies to activate these latent cells as a method to better target and eliminate them, although this is a complex area with risks of causing autoimmune issues.

5. **HIV and Cancer**: There is also mention of the relationship between HIV infections and an increased risk of certain cancers, specifically lymphomas, and how integration of the provirus into host cell genes may influence cancer development.

The discussion concludes with acknowledgment of the ongoing research efforts and the complexities of targeting these latent reservoirs of HIV effectively.

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Here are some key quotes from the video related to HIV infection, its treatment, and the underlying mechanisms of viral persistence:

1. **HIV Treatment**:
- "HIV infection... can be very, very successfully treated with drugs that block the replication of the virus in the body."
- "One pill a day in many cases."

2. **Viral Persistence**:
- "As soon as you stop therapy, the virus starts to come back again."
- "HIV is a retrovirus... they have to integrate their genetic information into the cell's genetic information."

3. **Mechanism of Infection**:
- "The viruses will always be there as long as that cell lives."
- "A very small residue of cells... remains in which the virus... has effectively been shut off."

4. **T-Cells and Immune Response**:
- "CD four T cells are cells of the immune system that are essential for generating a correct immune response."
- "The damage done to these cells is what causes AIDS."

5. **Viral Reservoirs**:
- "A few of them... can carry the provirus... and have the potential to give rise to more virus even many years after they're infected."

6. **Rekindling of Infection**:
- "When you stop those drugs, that little bit of virus can rekindle the infection, like the embers basically in a... long dead fire."

7. **Research and Observations**:
- "We observed, um, now 10 years ago... to detect not only the presence of these proviruses... but to estimate how many cells actually had the provirus at exactly that site."
- "We think HIV can cause cancer in this way, but it's... quite rare."

8. **Challenges in Eradication**:
- "It really is what makes the virus right now impossible to eradicate."
- "So far, a lot of time and money and effort's been invested in these areas... the virus has proven to be smarter than we are in these regards."

These quotes encapsulate essential elements of the discussion on HIV, emphasizing treatment mechanisms, challenges in management and research, and the complexities of the immune response in the convideo of viral persistence and potential cancer associations.

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And another group, first observed,

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something unexpected.

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I, we should have expected it actually, but we didn't.

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Um, and that is that,

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I have to back up a little bit.

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HHIV infection, I'm sure, as your audience knows,

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can be very, very successfully treated, with drugs

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that block the replication of the virus, in the body.

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It's, it's its ability to be transferred from one cell

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to the next, to the next, to the next.

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And we can do that very, very effectively,

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with modern antiretroviral therapy.

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Uh, one pill a day in many cases.

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Um, but, as as soon

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as you stop therapy, the,

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the virus starts to come back again.

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And the reason it comes back again, is

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that HIV is a retrovirus.

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And retroviruses have the unique property that as part

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of their normal replication pro pathway in a cell,

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they have to integrate their genetic information into the

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cell's genetic information.

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And what that means is that the cell is,

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the viruses will always be there as long as that cell lives.

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Now, in HIV for reasons that we still don't,

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don't understand very well, a small fraction of a large,

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the large majority of cells

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that get infected in this way die.

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So they, so that they're, they're gone.

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And that's, that's why the disease goes away when you treat,

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because the cells that have were infected will die.

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The the, and no new cells will be infected.

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But a very small residue of cells, remains

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in which the virus, for some reason

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and reason we don't really understand very well,

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has effectively been shut off.

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So it can no longer express itself, can no longer make

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a new virus to spread to other cells,

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and the cell,

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and no longer kill the cell that it's in, so

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that cell can survive indefinitely.

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And it was observed by other groups, quite a,

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quite a long time before that the,

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we started working on this, that,

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these cells are very often a cell,

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called a CD four positive T cell.

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Uh, CD four T cells are cells of the immune system

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that are essential for,

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generating a correct immune response

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and protecting us, from, infection with bacteria,

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parasites, and other viruses.

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And the damage done to these cells is what causes aids.

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The loss. The loss of these cells, of this particular type

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of T-cell, is what leads to the symptoms of aids

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and inevitable, almost inevitable death if the virus

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is not treated.

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Um, but if the virus is treated,

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those cells no longer die.

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But a few of them, as I said, will, can carry these,

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carry the, the provirus, the DNA form of the virus,

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as one of their genes.

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Basically, these pro viruses can be, in many,

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many different sites, in the cell genome,

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which is, both a hindrance to trying to,

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to figure out what's going on,

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but also can very help very much, in identifying,

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cells that, that

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that specific cells and, and,

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and identifying which cells have actually were actually

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originally infected to give rise to the, the cells

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that you see carrying the virus.

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And we, we,

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and other groups have been using a very, very nice,

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sensitive, assays to identify

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the, the DNA form.

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It's called the pro viruses of cells, of, in, in,

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these CD four T cells, that,

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have the potential to give rise to more virus

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even many years after they're, they're infected.

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Uh, when you stop therapy, they can give rise to virus.

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All they can give rise to a little

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bit of virus all the time.

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Um, mo in most of the cells of virus, for reasons we don't,

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still don't completely understand,

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it's suppressed in its ability

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to be expressed to give virus.

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But it e every now

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and then, some small fraction of these cells will start

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to make a little bit of virus.

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And so there's always a little bit of virus around,

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even in individuals where,

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where the virus can no longer get from one cell to another

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because its ability to do so is being stopped

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by antiviral drugs.

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Um, when you stop those drugs, that little bit of virus

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can rekindle the infection, like the embers basically in a,

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in a long dead fi, otherwise long dead fire.

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Um, and you, you throw new fuel on it by,

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by, by, by stopping the, the therapy

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and the, that can then rekindle the infection

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and the, the virus.

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In fact, the process of infection will take off

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and resume really right back, right

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where it was before you started.

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And the striking thing that, my colleagues

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and I observed, now 10 years ago, was

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that we used an in, we used an assay that allowed us

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to detect not only the presence

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of these pro viruses in these, in these cells,

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and a very rare cell,

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less than one in a thousand cells usually carries

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one in these pro viruses.

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Um, and, we could,

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but we could detect that

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and we could also identify exact, we could

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also identify exactly where it was integrated by the assay

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that we were using, which I won't go into detail,

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but it allowed us to see the virus, see where in the genome,

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which, in which of the about 3 billion base pairs

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of our genome, this, this integration had occurred.

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And we could detect one more thing.

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And that is,

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how many cells contain this provirus at exactly this site.

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Now, because integration is, there are very many sites,

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possible sites for integration of the provirus in,

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in the cell that the vi

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that the virus can actually be inserted at.

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And it's more, it's not random where they go.

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Um, but we, we estimated there are more over well over

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10 million sites for integration of, so, so the probability

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that that happens twice, in the same cell,

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in the same site in two different cells is extremely rare.

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You never see it pro essentially at one in 10 million

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or much, much less than probably one in 10 million.

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So, but we, we, we, the assay that we used,

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which had been devised by a, a very clever fellow

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in England, named Charles Ham,

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was allowed us to, not only,

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find the provirus, not only tell exactly where it was,

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but to estimate how many cells

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actually had the provirus at exactly that site.

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And from that, we could infer, given the rarity

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of integration it's at, at any given site,

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that these cells must have been the descendants

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of one originally infected cell.

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Now, CD four T cells are a, a component

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of the immune system and the job of it.

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One of the jobs of immune, cells is to react to,

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invading bacteria and, and,

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and pathogens other pathogens.

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And, and then,

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but another job is to, once it's, once it's dealt

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with a pathogen, to sit quietly, go into a quiet state,

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and, but remember that had had seen that pathogen,

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so when it shows up again, it can react very quickly

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and, and be be ready to,

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to take on the same pathogen again.

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And it does that by going

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through a process called clonal expansion.

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It's what these cells do.

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They, the, the,

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the cells all have the potential before you,

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before they start when they're made, to react

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to one particular organism

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or another, one particular sequence

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that might be found protein sequence

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that might be found in one organism

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or another, that be it a bacteria or cell

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or cell infected with a virus or, or a parasite.

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Uh, and very quickly increase its numbers so

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that it can attack the invading, as quickly

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as possible and get, and get rid of it.

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And then, and then once it's done,

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that go back into a quiet resting state, which most

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of which, most of the cells die off, but a few survive

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and ready to, ready to come back again.

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And you can get these, so you can get these,

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these cells have the property.

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They go through these, these cycles of this expansion,

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and we call it clonal expansion

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because it starts with a single cell.

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A clone is a group of cells that have been, that are derived

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by cell division from one, one original cell.

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And, and so the, the virus has

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the persistence of this virus.

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We discovered, actually hijacked has hijacked this

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clonal expansion process.

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Uh, and that is, what allows the virus

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to persist in such large numbers.

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Uh, although it looks very small,

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one in a one in a thousand cells, sounds small,

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but there are about,

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that would be about a billion cells altogether that would

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have a provirus in them and over your whole body.

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So it's really quite a large number

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distributed all over your body

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and just waiting for, to,

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find an antigen to react to.

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Um, other groups have, have shown,

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or another group has, has shown that one

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of the main antigens that these cells, react to

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is HIV itself.

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Of course, HIV is invader.

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There is an immune response against HIV.

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Um, HIV has many, adaptations.

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So even though there is this immune response, it's,

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it's not enough to eliminate the virus.

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Unlike most other viruses, which are eliminated

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by these kinds of immune responses, HIV can evade that.

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It's for reasons we're not gonna be able to get into here.

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And so we, we found that the, that the ability

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of these, the virus to form this, these to,

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to grow virus infected cells

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to grow into these large clones, is really

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what makes the HIV persist be able to persist

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for, for decades Now, we, we know examples

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of people infected 30 years

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or more, who've been, successfully treated

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and have stopped the treatment.

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Um, and the virus has come right back again.

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And it's not only did the cell, not only the virus can sit,

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the, the cells containing the, the provirus can sit,

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but they expand.

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They can expand. And so that there's always more there.

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Um, and, and so you really, it really is

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what makes the virus right now impossible to eradicate.

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Although people are trying to come up

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with very clever strategies to do so,

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nobody has come very close to even, being able

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to even make a dent, dent in that,

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resident persistent virus infected cell population.

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We have to keep on trying what, what people are.

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One of the things people are trying to do, is to,

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is to activate these cells.

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These cells are, at the time you find them,

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although these cells have been, have, have gone

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through phases where they have been dividing like crazy,

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at the, and, and it is possible to come up with therapies

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to, to and at, well, the dividing, dividing cells,

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once they start to divide the, the,

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the theory is they'll make virus.

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Although that's, that's certainly not, generally

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that can't be true,

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because they don't, the cells are able to have been able

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to expand without dying so that the, with,

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with the virus in them

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and with, with a perfectly good virus in them.

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And, so that,

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although some of them no doubt have died as a consequence

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of, of, of the virus becoming reactivated

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and being able to kill them, many

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of them have, many of them have not.

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And we don't know quite why that is either.

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Um, but people have been one, one of the strategies

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that people have been trying for some time now is

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to find ways of activating the expression

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of the virus in these cells

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or activating the, the, the cells to, to divide specifically

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to divide somehow, which might then activate the virus.

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And so, but one has to be a little careful about doing that.

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You can get many kinds of,

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autoimmune conditions would co could come from just

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activating, ran, sort

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of randomly activating cell division of these cells.

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Um, but there are some agents, people have been trying that

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to, reactivate virus expression

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to reactivate the cell in some way, to get virus expression

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and then to, to, to, to then use that fact to be able

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to kill the, to kill the cells,

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either having the virus kill the cells

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or by having, some agent,

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an induced immune response of some kind

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that recognizes the virus and so on.

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Um, so far, a lot have time and money

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and effort's been in, invested in these areas.

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And, and so far, the virus has proven

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to be smarter than we are in these regards.

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A lot of the work has been done, for example, by,

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the Silicon Lab, Bob

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and Janet Silicon, at Johns Hopkins University.

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Uh, they, they, they made a lot of the

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initial observations on which our work

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and that of many others is built.

14:29.305 --> 14:32.265
And they've continued to contribute in a very,

14:32.265 --> 14:33.425
deep way to this area.

14:34.065 --> 14:37.825
A particularly nice study came out of, one of, one

14:37.825 --> 14:40.505
of their people, this was actually relatively recent,

14:40.905 --> 14:45.535
a few years ago, in which they were able,

14:45.915 --> 14:48.575
to identify, this came from a, a fellow

14:48.595 --> 14:51.135
who had actually worked with us on, on our original study,

14:51.865 --> 14:54.805
and then is, but it had had been work, had been working

14:54.805 --> 14:59.205
with them more recently, named Francesco Ti who, who did

14:59.765 --> 15:04.195
a very smart fellow who, devised a way

15:04.195 --> 15:08.235
to identify, the specific antigen

15:08.615 --> 15:12.555
to which some of these cells that contain HIV pro viruses,

15:12.775 --> 15:16.235
to to which they belonged,

15:18.255 --> 15:21.915
and then correlate directly the response

15:21.935 --> 15:24.955
to these antigen, to these specific antigens, one

15:24.955 --> 15:27.675
of which was HIV and other, which was,

15:27.675 --> 15:32.045
another virus called CMV,

15:32.545 --> 15:35.565
and was able to then correlate that with, with what's,

15:35.565 --> 15:38.245
what was going on with the pro viruses and where they,

15:38.305 --> 15:39.525
and where they were integrated.

15:40.485 --> 15:43.185
Um, I'll mention one interesting, thing

15:43.185 --> 15:46.225
that we observed originally that has been, I think, somewhat

15:47.575 --> 15:49.275
misinterpreted by other people,

15:50.295 --> 15:51.595
and that is that in some

15:51.595 --> 15:53.435
of these very highly expanded clones

15:53.435 --> 15:55.955
and some of these clones end up being very highly expanded

15:56.015 --> 15:57.075
so that there would be a million

15:57.095 --> 15:58.875
or more cells over the body that had,

15:59.025 --> 16:01.035
that was all descendant from a single cell

16:01.035 --> 16:04.475
that had been infected sometime during the, sometime

16:04.475 --> 16:06.115
before the virus,

16:06.135 --> 16:08.875
before the patient was treated with antiretroviral therapy.

16:11.715 --> 16:15.935
And, we were able to show

16:15.935 --> 16:18.975
that in some of these large, in some of these large clones,

16:19.185 --> 16:21.215
there were some very specific regions

16:21.215 --> 16:22.455
of just a couple of genes.

16:22.455 --> 16:27.305
We, we identified seven genes altogether in which,

16:27.925 --> 16:32.065
a, there was a, a, a real abundance

16:32.125 --> 16:34.145
of pro viruses within a very small portion

16:34.145 --> 16:35.265
region of that gene.

16:36.585 --> 16:39.805
And if you looked, if you just took cells in cell culture

16:39.945 --> 16:41.965
and infected them, you didn't see anything special about

16:41.965 --> 16:43.165
what was going on in that gene.

16:44.325 --> 16:47.665
So it wasn't, it wasn't as though the, there, the virus,

16:47.805 --> 16:49.625
the pro virus really liked to go into

16:49.625 --> 16:52.825
that specific spot in the region of the, of the genome.

16:54.805 --> 16:58.785
Um, what it had to be was that, cells

16:58.785 --> 17:02.025
that had the pro viruses in these particular regions,

17:02.035 --> 17:07.025
these particular very small regions, were somehow,

17:07.565 --> 17:11.745
very selectively, expanded in some way.

17:11.855 --> 17:14.985
Many retroviruses that had been studied a long time ago

17:15.125 --> 17:19.145
by many people, were shown that this is,

17:19.145 --> 17:20.865
this is a way in which they could cause cancer

17:21.285 --> 17:23.665
and by go, by integrating into,

17:24.705 --> 17:27.855
these are non non HIV retroviruses ones,

17:27.855 --> 17:30.815
particularly ones in experimental animals like,

17:31.575 --> 17:36.315
chickens, originally mice, that retroviruses in,

17:36.375 --> 17:40.875
in, in integrated in a, a couple of, well, a couple of,

17:41.155 --> 17:43.555
actually a few hundred genes that are known this way now,

17:44.365 --> 17:48.065
could alter the expression of that gene,

17:48.225 --> 17:51.485
particularly turn on its expression in a way

17:51.485 --> 17:53.165
that was inappropriate for that cell

17:53.185 --> 17:57.925
and caused that cell to, to, in, so if these were genes

17:57.925 --> 18:01.885
that were involved somehow in regulating the cell cell

18:02.085 --> 18:05.005
division process, okay, and integration in them

18:05.025 --> 18:07.685
and turning them, turning on the expression in the simplest

18:07.685 --> 18:09.965
case is turning on the expression of these genes

18:10.495 --> 18:14.285
could cause inappropriate activation of cell division,

18:14.345 --> 18:16.765
so a cell would start dividing when it wasn't supposed to.

18:17.425 --> 18:19.045
And that's basically what starts the cell

18:19.305 --> 18:20.445
to being a cancer cell.

18:21.275 --> 18:22.695
Is this in a cancer disease

18:22.715 --> 18:24.575
of cells inappropriately dividing.

18:27.015 --> 18:31.395
So, but these, the integration, some of,

18:31.395 --> 18:33.515
and some of the genes that we're seeing this way actually

18:33.515 --> 18:35.035
are genes that had been associated

18:35.035 --> 18:36.275
with cancer in some cases.

18:38.905 --> 18:42.195
However, we could find no evidence that these, these,

18:42.365 --> 18:45.515
these, these cells that had these particular integrations

18:45.515 --> 18:46.875
were in fact cancer cells.

18:47.775 --> 18:52.595
Um, and, some analyses, actually lead us to think

18:52.595 --> 18:55.115
that have led us let that see me to think.

18:55.255 --> 18:59.035
And, and, and I think Steve, my, my co-author, Steve Hughes,

18:59.655 --> 19:01.345
to think,

19:01.785 --> 19:04.705
although we haven't been able to test this unfortunately

19:04.705 --> 19:08.385
very, very well yet, that what was going on with,

19:08.385 --> 19:13.135
with these cells, with these integration sites, is it,

19:13.195 --> 19:16.735
which many people still cite as activating these cells

19:16.795 --> 19:20.495
to divide inappropriately, as Dr as being drivers

19:20.835 --> 19:22.255
of this clonal expansion.

19:22.995 --> 19:25.735
We think instead of being drivers of clonal expansion,

19:26.165 --> 19:27.495
what they are is inhibitors

19:28.075 --> 19:29.615
of the other half of the process.

19:30.665 --> 19:34.885
And that is, remember that I said this, that T cells,

19:35.715 --> 19:38.525
have the property that they expand like crazy

19:39.035 --> 19:41.685
when there's an antigen present that they have to respond to

19:42.285 --> 19:46.005
a, a pathogen, a bacterium or parasite or something.

19:46.665 --> 19:48.445
And then when that is gone,

19:48.555 --> 19:52.285
they also die off like me leaving just a few behind.

19:53.435 --> 19:55.885
Well, we think it, we, we hypothesize,

19:55.915 --> 19:58.965
this is still hypothesis, that integration in these,

19:59.155 --> 20:02.685
what, what the mis expression that must of these genes

20:02.685 --> 20:05.045
that these, that we, where we see these clusters

20:05.045 --> 20:06.925
of integration sites, what

20:06.925 --> 20:09.645
that does is it doesn't drive the expansion, but it dri

20:09.665 --> 20:13.775
but it suppresses the, it suppresses the die off.

20:14.535 --> 20:16.875
And so if it does that, if you, if you think about it

20:18.225 --> 20:22.995
with e successive cycles of this, of, of, of this,

20:23.095 --> 20:28.075
die off these, in,

20:28.135 --> 20:31.755
the clones that clones that are expanding will be

20:32.275 --> 20:37.085
progressively taken over by, by pro viruses

20:37.085 --> 20:38.405
that are integrated in these sites

20:38.525 --> 20:40.405
because they'll die less than everybody else.

20:41.385 --> 20:45.945
And so if, if, if, if they die, say T twice

20:45.965 --> 20:49.445
as poorly, if you like, they survive twice as well,

20:50.115 --> 20:54.165
then at after 10 cycles, they're, they'll, they'll be,

20:54.235 --> 20:55.685
they'll, they'll really have taken over

20:55.685 --> 20:57.525
with the almost the entire population.

20:57.915 --> 21:00.685
They won't change the size of that population necessarily.

21:00.685 --> 21:03.685
They'll just, they'll just, determine which which

21:04.365 --> 21:07.205
survivors end up growing each time and which ones,

21:07.745 --> 21:08.965
and so that's what we, that's

21:08.965 --> 21:10.445
what we postulate is happening.

21:10.475 --> 21:11.765
It's a very dramatic effect,

21:11.785 --> 21:13.925
but it's one, it probably doesn't have much

21:13.925 --> 21:15.445
of an effect on anything.

21:16.235 --> 21:20.685
Um, however, we have,

21:20.785 --> 21:23.645
we have found integration in, in, in one gene,

21:23.705 --> 21:27.525
my in cell culture, that this is another paper

21:27.525 --> 21:30.965
that we published, that,

21:31.325 --> 21:34.725
a actually can drive, survival of cells.

21:34.825 --> 21:36.725
And this we found in the cell culture system,

21:36.745 --> 21:40.085
but it's also been seen, by my colleague Steve Hughes

21:40.185 --> 21:44.765
and, and John Miller's, who's a, was a,

21:44.915 --> 21:47.485
another colleague at an, at the University of Pittsburgh,

21:49.115 --> 21:52.975
and they found that in t-cell cancers rare T,

21:53.475 --> 21:58.055
so h one of the consequences of HIV infection,

21:58.235 --> 22:02.295
is cancer, increased incidence of cancer,

22:02.295 --> 22:04.375
particularly cancers that are known to be caused

22:04.435 --> 22:08.235
by other viruses, such as Epstein-Barr virus,

22:08.495 --> 22:10.475
for example, or,

22:12.635 --> 22:15.375
or some others.

22:16.975 --> 22:19.635
And however, there is one cancer that,

22:21.025 --> 22:25.365
is one type of cancer that is does not associated

22:25.365 --> 22:27.405
with another virus, and that's, that's,

22:27.605 --> 22:31.995
a lymphoma cancer of lymphocytes, like,

22:32.315 --> 22:34.195
t like T cells or like D cells.

22:34.375 --> 22:37.195
We found that in cell culture that you could get integration

22:37.255 --> 22:39.635
of the provirus into one specific gene,

22:39.875 --> 22:43.115
a gene called stat three, which is a very well known gene

22:43.115 --> 22:46.155
to immunologist because it regulates a lot of, a lot

22:46.155 --> 22:49.955
of the immune response in a cell is regulated,

22:49.955 --> 22:52.275
through, by, by this, by this gene.

22:52.305 --> 22:54.915
It's a master regulator of, of quite a,

22:55.075 --> 22:57.155
a quite important aspects of the immune response.

22:57.215 --> 22:58.315
But it, but it,

22:58.535 --> 23:00.875
but what it does is it's an,

23:00.935 --> 23:02.395
an important step in the pathway

23:02.695 --> 23:04.875
by which cells are activated to divide.

23:05.825 --> 23:08.885
And the pro virus of apparent in,

23:08.985 --> 23:11.325
in provirus in these genes in,

23:11.345 --> 23:14.125
in our cell culture model seems to help derive expression

23:14.125 --> 23:16.005
of the, of this, of this gene.

23:16.705 --> 23:17.725
And then,

23:18.105 --> 23:22.485
and that, in, in ways we're still studying, can,

23:22.905 --> 23:26.405
allow increased both increased survival

23:26.425 --> 23:29.565
and I think increased division rate of the cell that

23:29.675 --> 23:33.565
that has it and are Hughes and,

23:33.625 --> 23:36.205
and Millers found that in

23:37.685 --> 23:42.405
a rare t-cell lymphomas, lymphomas of, of,

23:42.665 --> 23:44.885
cancer of the, of the same kinds

23:44.885 --> 23:47.925
Of cells that HIV is, targets.

23:48.585 --> 23:51.725
Um, in some cases we'll have integrations in exactly the

23:51.725 --> 23:53.325
same place that we identified in,

23:53.545 --> 23:57.105
in these cell culture models in, in the, in,

23:57.165 --> 23:59.665
in Georgia to drive expression of the STAT three genome

24:00.125 --> 24:03.785
and another group in, in B cell lymphomas in associated

24:03.785 --> 24:07.585
with HIV, which are also, many of which are, are not the,

24:07.685 --> 24:11.185
the, the origin is not known,

24:11.275 --> 24:14.065
found in at least one just a single case report.

24:14.125 --> 24:19.025
But they found in at least one that there was a,

24:19.325 --> 24:20.985
an integration in the same place,

24:21.145 --> 24:24.265
a provirus in the same place, in stat three,

24:24.325 --> 24:25.905
in in this b-cell lymphoma.

24:26.935 --> 24:30.155
So we think HIV can cause cancer in this way,

24:30.155 --> 24:31.795
but it's, it's, it's quite rare.

24:31.795 --> 24:33.835
There is some concern though, about HIV

24:34.755 --> 24:38.825
directed gene therapy, HIV vectors used for gene therapy

24:39.045 --> 24:41.385
as being able to perhaps do the same thing.

24:41.385 --> 24:44.315
There's, there, there's that, that's an issue

24:44.315 --> 24:46.715
that's under some active investigation now.

Quick Answers

Persistence of HIV: Understanding the Role of CD4 T Cells and Proviruses in Infection Dynamics**

00:00:00 - And another group, first observed, something unexpected. I, we should have expected it actually, but we didn't. and that is that, I have to back up a little bit. HHIV infection, I'm sure, as your audience knows, can be very, very successfully treated, with drugs that block the replication of the virus, in the body. It's, it's its ability to be transferred from one cell to the next, to the next, to the next. And we can do that very, very effectively, with modern antiretroviral therapy. one pill a day in many cases. but, as as soon
00:00:44 - the virus starts to come back again. And the reason it comes back again, is that HIV is a retrovirus. And retroviruses have the unique property that as part of their normal replication pro pathway in a cell, they have to integrate their genetic information into the cell's genetic information. And what that means is that the cell is, the viruses will always be there as long as that cell lives. Now, in HIV for reasons that we still don't, don't understand very well, a small fraction of a large, the large majority of cells that get infected in this way die. So they, so that they're, they're gone.
00:01:28 - because the cells that have were infected will die. The the, and no new cells will be infected. But a very small residue of cells, remains in which the virus, for some reason and reason we don't really understand very well, has effectively been shut off. So it can no longer express itself, can no longer make a new virus to spread to other cells, and the cell, and no longer kill the cell that it's in, so that cell can survive indefinitely. And it was observed by other groups, quite a,
00:02:09 - we started working on this, that, these cells are very often a cell, called a CD four positive T cell. CD four T cells are cells of the immune system that are essential for, generating a correct immune response and protecting us, from, infection with bacteria, parasites, and other viruses. And the damage done to these cells is what causes aids. The loss. The loss of these cells, of this particular type of T-cell, is what leads to the symptoms of aids
00:02:49 - is not treated. but if the virus is treated, those cells no longer die. But a few of them, as I said, will, can carry these, carry the, the provirus, the DNA form of the virus, as one of their genes. Basically, these pro viruses can be, in many, many different sites, in the cell genome, which is, both a hindrance to trying to, to figure out what's going on, but also can very help very much, in identifying,
00:03:32 - that specific cells and, and, and identifying which cells have actually were actually originally infected to give rise to the, the cells that you see carrying the virus. And we, we, and other groups have been using a very, very nice, sensitive, assays to identify the, the DNA form. It's called the pro viruses of cells, of, in, in, these CD four T cells, that,

"Understanding the Persistence of HIV: The Role of Proviruses and Immune Cell Dynamics"

00:04:14 - even many years after they're, they're infected. when you stop therapy, they can give rise to virus. All they can give rise to a little bit of virus all the time. mo in most of the cells of virus, for reasons we don't, still don't completely understand, it's suppressed in its ability to be expressed to give virus. But it e every now and then, some small fraction of these cells will start to make a little bit of virus. And so there's always a little bit of virus around, even in individuals where, where the virus can no longer get from one cell to another because its ability to do so is being stopped by antiviral drugs.
00:04:54 - can rekindle the infection, like the embers basically in a, in a long dead fi, otherwise long dead fire. and you, you throw new fuel on it by, by, by, by stopping the, the therapy and the, that can then rekindle the infection and the, the virus. In fact, the process of infection will take off and resume really right back, right where it was before you started. And the striking thing that, my colleagues and I observed, now 10 years ago, was
00:05:35 - to detect not only the presence of these pro viruses in these, in these cells, and a very rare cell, less than one in a thousand cells usually carries one in these pro viruses. and, we could, but we could detect that and we could also identify exact, we could also identify exactly where it was integrated by the assay that we were using, which I won't go into detail, but it allowed us to see the virus, see where in the genome, which, in which of the about 3 billion base pairs of our genome, this, this integration had occurred. And we could detect one more thing. And that is,
00:06:21 - Now, because integration is, there are very many sites, possible sites for integration of the provirus in, in the cell that the vi that the virus can actually be inserted at. And it's more, it's not random where they go. but we, we estimated there are more over well over 10 million sites for integration of, so, so the probability that that happens twice, in the same cell, in the same site in two different cells is extremely rare. You never see it pro essentially at one in 10 million or much, much less than probably one in 10 million.
00:07:01 - which had been devised by a, a very clever fellow in England, named Charles Ham, was allowed us to, not only, find the provirus, not only tell exactly where it was, but to estimate how many cells actually had the provirus at exactly that site. And from that, we could infer, given the rarity of integration it's at, at any given site, that these cells must have been the descendants of one originally infected cell.
00:07:44 - of the immune system and the job of it. One of the jobs of immune, cells is to react to, invading bacteria and, and, and pathogens other pathogens. And, and then, but another job is to, once it's, once it's dealt with a pathogen, to sit quietly, go into a quiet state, and, but remember that had had seen that pathogen, so when it shows up again, it can react very quickly and, and be be ready to,

"Clonal Expansion: The Mechanism Behind HIV Persistence in the Immune Response"**

00:08:23 - And it does that by going through a process called clonal expansion. It's what these cells do. They, the, the, the cells all have the potential before you, before they start when they're made, to react to one particular organism or another, one particular sequence that might be found protein sequence that might be found in one organism or another, that be it a bacteria or cell or cell infected with a virus or, or a parasite. and very quickly increase its numbers so that it can attack the invading, as quickly
00:09:05 - And then, and then once it's done, that go back into a quiet resting state, which most of which, most of the cells die off, but a few survive and ready to, ready to come back again. And you can get these, so you can get these, these cells have the property. They go through these, these cycles of this expansion, and we call it clonal expansion because it starts with a single cell. A clone is a group of cells that have been, that are derived by cell division from one, one original cell. And, and so the, the virus has the persistence of this virus. We discovered, actually hijacked has hijacked this
00:09:44 - and that is, what allows the virus to persist in such large numbers. although it looks very small, one in a one in a thousand cells, sounds small, but there are about, that would be about a billion cells altogether that would have a provirus in them and over your whole body. So it's really quite a large number distributed all over your body and just waiting for, to, find an antigen to react to. other groups have, have shown, or another group has, has shown that one of the main antigens that these cells, react to
00:10:26 - Of course, HIV is invader. There is an immune response against HIV. HIV has many, adaptations. So even though there is this immune response, it's, it's not enough to eliminate the virus. Unlike most other viruses, which are eliminated by these kinds of immune responses, HIV can evade that. It's for reasons we're not gonna be able to get into here. And so we, we found that the, that the ability of these, the virus to form this, these to, to grow virus infected cells to grow into these large clones, is really what makes the HIV persist be able to persist
00:11:11 - of people infected 30 years or more, who've been, successfully treated and have stopped the treatment. and the virus has come right back again. And it's not only did the cell, not only the virus can sit, the, the cells containing the, the provirus can sit, but they expand. They can expand. And so that there's always more there. and, and so you really, it really is what makes the virus right now impossible to eradicate. Although people are trying to come up with very clever strategies to do so, nobody has come very close to even, being able
00:11:54 - resident persistent virus infected cell population. We have to keep on trying what, what people are. One of the things people are trying to do, is to, is to activate these cells. These cells are, at the time you find them, although these cells have been, have, have gone through phases where they have been dividing like crazy, at the, and, and it is possible to come up with therapies to, to and at, well, the dividing, dividing cells, once they start to divide the, the, the theory is they'll make virus. Although that's, that's certainly not, generally

"Strategies for Reactivating HIV Expression and Implications for Treatment"

00:12:33 - because they don't, the cells are able to have been able to expand without dying so that the, with, with the virus in them and with, with a perfectly good virus in them. And, so that, although some of them no doubt have died as a consequence of, of, of the virus becoming reactivated and being able to kill them, many of them have, many of them have not. And we don't know quite why that is either. but people have been one, one of the strategies that people have been trying for some time now is to find ways of activating the expression of the virus in these cells
00:13:16 - to divide somehow, which might then activate the virus. And so, but one has to be a little careful about doing that. You can get many kinds of, autoimmune conditions would co could come from just activating, ran, sort of randomly activating cell division of these cells. but there are some agents, people have been trying that to, reactivate virus expression to reactivate the cell in some way, to get virus expression and then to, to, to, to then use that fact to be able to kill the, to kill the cells, either having the virus kill the cells
00:13:56 - an induced immune response of some kind that recognizes the virus and so on. so far, a lot have time and money and effort's been in, invested in these areas. And, and so far, the virus has proven to be smarter than we are in these regards. A lot of the work has been done, for example, by, the Silicon Lab, Bob and Janet Silicon, at Johns Hopkins University. they, they, they made a lot of the initial observations on which our work and that of many others is built. And they've continued to contribute in a very, deep way to this area.
00:14:37 - of their people, this was actually relatively recent, a few years ago, in which they were able, to identify, this came from a, a fellow who had actually worked with us on, on our original study, and then is, but it had had been work, had been working with them more recently, named Francesco Ti who, who did a very smart fellow who, devised a way to identify, the specific antigen to which some of these cells that contain HIV pro viruses, to to which they belonged,
00:15:21 - to these antigen, to these specific antigens, one of which was HIV and other, which was, another virus called CMV, and was able to then correlate that with, with what's, what was going on with the pro viruses and where they, and where they were integrated. I'll mention one interesting, thing that we observed originally that has been, I think, somewhat misinterpreted by other people, and that is that in some of these very highly expanded clones and some of these clones end up being very highly expanded so that there would be a million or more cells over the body that had,
00:16:01 - that had been infected sometime during the, sometime before the virus, before the patient was treated with antiretroviral therapy. And, we were able to show that in some of these large, in some of these large clones, there were some very specific regions of just a couple of genes. We, we identified seven genes altogether in which, a, there was a, a, a real abundance of pro viruses within a very small portion region of that gene. And if you looked, if you just took cells in cell culture

"The Role of Proviral Integration in T Cell Expansion and Potential Cancer Development"**

00:16:41 - what was going on in that gene. So it wasn't, it wasn't as though the, there, the virus, the pro virus really liked to go into that specific spot in the region of the, of the genome. what it had to be was that, cells that had the pro viruses in these particular regions, these particular very small regions, were somehow, very selectively, expanded in some way. Many retroviruses that had been studied a long time ago by many people, were shown that this is, this is a way in which they could cause cancer
00:17:24 - these are non non HIV retroviruses ones, particularly ones in experimental animals like, chickens, originally mice, that retroviruses in, in, in integrated in a, a couple of, well, a couple of, actually a few hundred genes that are known this way now, could alter the expression of that gene, particularly turn on its expression in a way that was inappropriate for that cell and caused that cell to, to, in, so if these were genes that were involved somehow in regulating the cell cell
00:18:05 - and turning them, turning on the expression in the simplest case is turning on the expression of these genes could cause inappropriate activation of cell division, so a cell would start dividing when it wasn't supposed to. And that's basically what starts the cell to being a cancer cell. Is this in a cancer disease of cells inappropriately dividing. So, but these, the integration, some of, and some of the genes that we're seeing this way actually are genes that had been associated with cancer in some cases. However, we could find no evidence that these, these,
00:18:45 - were in fact cancer cells. and, some analyses, actually lead us to think that have led us let that see me to think. And, and, and I think Steve, my, my co-author, Steve Hughes, to think, although we haven't been able to test this unfortunately very, very well yet, that what was going on with, with these cells, with these integration sites, is it, which many people still cite as activating these cells to divide inappropriately, as Dr as being drivers of this clonal expansion.
00:19:26 - what they are is inhibitors of the other half of the process. And that is, remember that I said this, that T cells, have the property that they expand like crazy when there's an antigen present that they have to respond to a, a pathogen, a bacterium or parasite or something. And then when that is gone, they also die off like me leaving just a few behind. Well, we think it, we, we hypothesize, this is still hypothesis, that integration in these, what, what the mis expression that must of these genes that these, that we, where we see these clusters
00:20:06 - that does is it doesn't drive the expansion, but it dri but it suppresses the, it suppresses the die off. And so if it does that, if you, if you think about it with e successive cycles of this, of, of, of this, die off these, in, the clones that clones that are expanding will be progressively taken over by, by pro viruses that are integrated in these sites because they'll die less than everybody else. And so if, if, if, if they die, say T twice

"Integration of HIV Provirus: Implications for T-Cell Survival and Cancer Development"

00:20:50 - then at after 10 cycles, they're, they'll, they'll be, they'll, they'll really have taken over with the almost the entire population. They won't change the size of that population necessarily. They'll just, they'll just, determine which which survivors end up growing each time and which ones, and so that's what we, that's what we postulate is happening. It's a very dramatic effect, but it's one, it probably doesn't have much of an effect on anything. however, we have, we have found integration in, in, in one gene, my in cell culture, that this is another paper
00:21:31 - a actually can drive, survival of cells. And this we found in the cell culture system, but it's also been seen, by my colleague Steve Hughes and, and John Miller's, who's a, was a, another colleague at an, at the University of Pittsburgh, and they found that in t-cell cancers rare T, so h one of the consequences of HIV infection, is cancer, increased incidence of cancer, particularly cancers that are known to be caused by other viruses, such as Epstein-Barr virus,
00:22:12 - or some others. And however, there is one cancer that, is one type of cancer that is does not associated with another virus, and that's, that's, a lymphoma cancer of lymphocytes, like, t like T cells or like D cells. We found that in cell culture that you could get integration of the provirus into one specific gene, a gene called stat three, which is a very well known gene to immunologist because it regulates a lot of, a lot of the immune response in a cell is regulated,
00:22:52 - It's a master regulator of, of quite a, a quite important aspects of the immune response. But it, but it, but what it does is it's an, an important step in the pathway by which cells are activated to divide. And the pro virus of apparent in, in provirus in these genes in, in our cell culture model seems to help derive expression of the, of this, of this gene. And then, and that, in, in ways we're still studying, can, allow increased both increased survival and I think increased division rate of the cell that that has it and are Hughes and,
00:23:37 - a rare t-cell lymphomas, lymphomas of, of, cancer of the, of the same kinds Of cells that HIV is, targets. in some cases we'll have integrations in exactly the same place that we identified in, in these cell culture models in, in the, in, in Georgia to drive expression of the STAT three genome and another group in, in B cell lymphomas in associated with HIV, which are also, many of which are, are not the, the, the origin is not known, found in at least one just a single case report.
00:24:44 - an integration in the same place, a provirus in the same place, in stat three, in in this b-cell lymphoma. So we think HIV can cause cancer in this way, but it's, it's, it's quite rare. There is some concern though, about HIV directed gene therapy, HIV vectors used for gene therapy as being able to perhaps do the same thing. There's, there, there's that, that's an issue that's under some active investigation now.

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Clonal Expansion of Infected CD4+ T Cells in People Living with HIV

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