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Smoldering Embers of HIV’s ‘Raging Fire,’ Partly Doused, Threaten to Rekindle the Blaze

A Thymus Trickles

While we had the ear of Dr. David Ho, we thought we’d take advantage of the opportunity to sharpen our own picture of what he thinks is going on immunologically during the course of chronic HIV infection and, given that as a backdrop, what we can realistically expect from the new antiretroviral combinations over time. David’s answers were both candid and alluring.

Q: Is there actual viral replication in the brain? Or is the virus just there, latently?

DH: No, there is active replication of virus in the brain. Ninety-nine percent of the virus we find in the central nervous system is found in what are called microglial cells, which are essentially macrophages — and should burn out.

Q: And what about the bone marrow?

DH: There’s virus in the bone marrow as well. You can take it out and culture it. There is. If you say “What cells is it in?” It’s clearly in lymphocytes and macrophages — some. But the question is, “Are bone marrow precursor stem cells infectable?” And there the literature is unclear. There are some papers I could quote you that would say that they are infectable, and I could quote you others that say they are not. The bulk of the in vivo [experiments that were performed by] taking bone marrow from infected individuals and examining them using in situ techniques, the bulk of those studies show “no.” In vitro, however, if you take CD34+ cells and add HIV, you can definitely demonstrate infectability.

Q: Looking at all this from an immunological perspective, one would observe that if certain cells are not activated they may stay naive and be re-recruited for another purpose. Also, an unchallenged memory cell could theoretically stick around forever.

DH: In my opening remarks, I failed to mention a couple of things which relate to this comment. I told you that the two compartments which contain HIV that seem to be burning out more slowly are the macrophages and the latently infected lymphocytes. Let’s says that, once all this is defined in greater detail, [we determine that we] need to treat for three years before these compartments will burn out. We shouldn’t just sit around and accept that. There are maneuvers we can make that will activate cells.

Certain antigenic stimulation with interleukins will drive the [latently infected] T-cell pool. There are large polysaccharides, sugars, we can give that will make macrophages gobble them up and then go into what is called “oxidative burst” and die faster and therefore turn over faster. We could also use M-CSF or GM-CSF to do the same. So there are maneuvers that could possibly shorten that period and increase the [cell] turnover and shorten the life span of those cell populations.

Q: Do you have any plans to do that?

DH: Yes, actually, in the four-drug [AZT+3TC+1592+141W94] studies [in both acute and chronically infected individuals] we are beginning to incorporate some of those thoughts.

Q: And what about the immunological “holes” in one’s immune repertoire? Once you’ve lost a memory cell, you may not be able to replace it. Many HIV-infected people feel that they’ve got to get on this triple therapy quickly before there are too many holes punched into their immune repertoire.

DH: This is an important area. I think it is another important consideration for early intervention. You know, we can actually get CD4 cell counts to go up with this triple combination, on average 100 to 150 over the short haul, over the first 4-6 weeks. And that rise is pretty prominent in some people.

We still don’t understand why one person, with the same level of antiviral effect would have a 300 cell increase and another person would have only a 50 cell increase. We don’t understand that. We also don’t understand why, as a cohort, the maximum-on average now, if you take cohort data, not individual data-CD4 cell rise is plateauing in the first few weeks at a maximum of 150 cells. So what has been damaged in the replenishment process of lymphocytes. That’s not very clear.

Q: Are their thymuses all the same?

DH: Well, see, we are dealing mostly with adults, and there is very good literature from the cancer field that tells us that the thymus is not working very well beyond age 25 – -probably age 20. And so if it’s going to make new naive [T] cells, they’re going to just trickle out, they’re not going to pour out. The encouraging thing is with the combination chemotherapy you not only see the rapid rise [in CD4 cells], but you also see some gradual increase [over the longer haul]. And now the important thing is to go in and understand the phenotype of those cells and also the function of those cells — in the first few weeks and also over the long haul. But there are not enough studies going on in this critical area.

Q: Say that in your triple therapy studies, some months from now, the lymph nodes come back “clean,” and several study participants volunteer to go off therapy. How would you characterize the probability of their infection truly being eradicated?

DH: I would say there is a chance — and that we need to determine that feasibility.

Q: Could you put a number on it? Fifty percent? Eighty percent? Ten?

DH: It’s difficult to assign a number. I would say that the probability is low.

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