Print this page    •   Back to Web version of article

TheBodyPRO.com
High-Dose Intravenous Immunoglobulin May Reduce Latent HIV Reservoir in Resting CD4+ Cells, Study Suggests
A Discussion With Magnus Gisslén, M.D., Ph.D.

February 10, 2009

There's nothing like hearing the results of studies directly from those who actually conducted the research. In this interview, you'll meet one of these impressive HIV researchers and read his explanation of a study he presented at CROI 2009. After his explanation, he then answers questions from the audience.

Magnus Gisslén: The viral reservoir in latent, HIV-infected CD4+ cells is very stable and has a very long half-life. As yet, no approach to decrease this reservoir has proven effective.

We looked at intravenous immunoglobulin [IVIG] given in high dosage together with effective antiretroviral therapy [ART] to see how it interacts with this reservoir.1 The idea was raised from one patient of mine that has Guillain-Barré syndrome [GBS], which is treated with intravenous immunoglobulin. He had treatment with ART and immunoglobulin at the same time. Subsequently, he decided to stop his ART due to different reasons; mainly, that he wanted to do so. His viral load stayed below 50 copies/mL for several months, which is rather uncommon, although it can happen sometimes. That led us to the hypothesis that the immunoglobulin might have had some effect.

Magnus Gisslen, M.D., Ph.D.
Magnus Gisslén, M.D., Ph.D.
We tried to test this hypothesis with a small pilot study where we included nine subjects, all with effective treatment with an HIV RNA less than 50 copies for at least 1.5 years. They took their antiretrovirals with immunoglobulin for five consecutive days -- 30 grams of immunoglobulin each day.

We looked at the HIV-infected units per million resting cells before and after the treatment with immunoglobulin. That was replication-competent virus [RCV]. We found that there was a decrease of RCV in the majority of patients.

In seven patients, we had the possibility to evaluate because we could detect virus in the reservoir. Of those, five decreased [in RCV]. They decreased by 68% or more in this reservoir, until we couldn't find any change from baseline to follow-up.

Also, we found that during or shortly after they got their immunoglobulin therapy, they had a small viral load increase in plasma -- up to 10, 15, 20 copies/mL of blood. The magnitude of this increase was closely related to the amount of virus in the reservoir at baseline. Also, there was a relationship found when we sequenced virus from plasma and the reservoir. It looks like the virus in plasma came from the reservoir.

Together, it looks like somehow the HIV reservoir is affected by intravenous immunoglobulin. Intravenous immunoglobulin has several effects on the immune system: It acts on the cellular level, on the Fc receptor and on cytokines. So it has a lot of different, complex modes of action. And actually, we don't know the mechanism. We found that IL-7 [interleukin-7] increased in all cases from baseline to day eight, but we don't know why this looks like it works.

But this was a small study, of course; it has to be replicated and extended in larger studies.

Audience Member #1: I wanted to clarify one thing about the history. In the history, you had a patient who went off treatment and was still on IVIG. It would seem to me that that person would have non-reservoir virus -- regular old virus -- replicating and that the IVIG was keeping that. What made you think it was reservoir?

Magnus Gisslén: He wasn't on IVIG. IVIG treatment was just to five days. He stopped his antiretroviral therapy, let's say, five, six months later on.

We went back and looked at the period when he was treated with the immunoglobulin and found during that period, he had a viral blip. The virus was below detection limit before immunoglobulin treatment and then it increased slightly after the immunoglobulin was given. ... It was a wild hypothesis.

Audience Member #1: But it was the blip that made you think that it was the reservoir.

Magnus Gisslén: Yes.

Audience Member #1: The other question I have has to do with the mechanism. If this strategy is indeed working, what do you think the mechanism is that would lead to the depletion of the reservoir?

Magnus Gisslén: That's a very good question. Actually, I don't know how intravenous immunoglobulin acts on the virus in the reservoir. IL-7 can, in some cases -- at least, it's been shown in vitro -- activate the virus without a broad cell activation of latent virus. It might have been through that mechanism, but it can be whatever. We don't know. We are looking at that.

Audience Member #2: I would like you to comment briefly on the practicality of IVIG. In some articles it seems like it's a wonder substance. We don't understand the mechanism, but we don't know how aspirin works either. But the cost is prohibitive and the supply is small and dwindling. Could you comment briefly on that?

Magnus Gisslén: I totally agree. This is not a drug to be used in a lot of patients. It's just giving some clues to what can happen, but you are right: It's quite safe to use it, not very many side effects, but it's expensive and it must be given intravenously.

Audience Member #2: Is there any alternative?

Magnus Gisslén: We don't know the mechanism, so probably there are alternatives, but we have to find them.

Audience Member #3: Of the seven patients who showed what you think are declines in the reservoir, did they go off treatment? Have they remained off treatment?

Magnus Gisslén: No, they did not. They are still on treatment. To design such a study you have to be very careful what subjects to select. For example, they can't be on an NNRTI [non-nucleoside reverse transcriptase inhibitor]-based treatment, since to stop that would create a risk of resistance. Also, after the intravenous immunoglobulin, the viral load didn't go down to zero. We still had virus, so if we stopped treatment, maybe it'd take a longer time, but it would come back. So we didn't [stop treatment].

Audience Member #4: Just to clarify: Your conclusion that the increase in plasma virus actually came from the resting pool was based on comparable magnitudes of decrease and increase in the resting CD4 cells -- and also on similar sequencing?

Magnus Gisslén: Not exactly. The level of virus in the reservoir at baseline correlated very closely to the increase of the plasma virus -- the magnitude of increase. It was [inaudible] 0.8, something like that, so it's closely related. Also, when we looked at the single genome sequencing of the gag region of the virus, we found that virus in plasma and in the reservoir were closely related -- but that was only two subjects, because we need to have sufficient virus in the plasma to do this sequencing. We could do the one with the highest viral load, about 20 copies/mL.

Also, what we found -- I didn't mention it -- was that the virus in the plasma, this residual viremia, it was positive. It was about 2 copies/mL in six, or in five, of the seven subjects at baseline, but only one at follow-up. That is another sort of indication that the reservoir is decreasing.

This transcript has been edited for clarity.


Reference

  1. Gisslén M, Lindkvist A, Edén A, et al. Reduction of the latent HIV-1 reservoir in resting CD4+ T lymphocytes by high-dosage intravenous immunoglobulin treatment added to ART. In: Program and abstracts of the 16th Conference on Retroviruses and Opportunistic Infections; February 8-11, 2009; Montréal, Canada. Abstract 88.




This article was provided by TheBodyPRO.com. Copyright Body Health Resources Corporation. All rights reserved.

You can find this article online by typing the following address into your Web browser:
http://www.thebody.com/content/art51696.html

Please Note: Knowledge about HIV changes rapidly. Note the date of this article's publication, and before treating patients or employing any therapies described in these materials, verify all information independently. If you are a patient, please consult a doctor or other medical professional before acting on any of the information presented in this article.

General Disclaimer: The Body is designed for educational purposes only and is not engaged in rendering medical advice or professional services. The information provided through The Body should not be used for diagnosing or treating a health problem or a disease. It is not a substitute for professional care. If you have or suspect you may have a health problem, consult your healthcare provider.