One of the most active areas of HIV cure research focuses on the cell reservoirs where latent virus is believed to be hiding, out of the reach of existing antiretroviral therapy. Despite considerable research in this area over the past several years, there is still a great deal we don't know about how these reservoirs form -- or even where they are all located. Without deepening this knowledge, taking the next steps toward eradicating those reservoirs may not be possible.
In a poster presentation at ICAAC 2014, Henry Mwandumba, Ph.D., the Wellcome Intermediate Clinical Fellow and a clinical senior lecturer with the Malawi-Liverpool-Wellcome Trust Clinical Research Programme, revealed research findings that appear to clearly indicate the presence of HIV reservoirs in alveolar macrophages within the lung tissue of patients on antiretroviral therapy.
Mwandumba et al's study involved 54 volunteers recruited at the Queen Elizabeth Central Hospital in Blantyre, Malawi. Five of the volunteers were HIV negative, 12 were HIV positive but had never received treatment, and 37 were receiving antiretroviral therapy (all but 10 had an undetectable viral load). Bronchoalveolar lavages were conducted, and HIV-infected alveolar macrophages were found to be present in small but significant percentages of all three subsets of volunteers.
I spoke with Dr. Mwandumba at ICAAC 2014 about the study's findings. (You can also read about additional study data in NATAP's poster summary.)
Is this the first evidence we've seen that HIV reservoirs actually exist in the lungs?
For some time, people have known that alveolar macrophages can get infected with HIV. But this is really the first time that we're showing that HIV does persist in these cells, even when patients go into antiretroviral therapy.
Did the treatment an HIV-positive person was on have any effect on the extent to which you could still see HIV in the macrophages?
Not very much. The decrease in the frequency of HIV-infected alveolar macrophages was only minimal if you compare those who had been on antiretrovirals for, say, more than four years, compared to antiretroviral-naive individuals.
Actually, this is very consistent with what has been observed in the peripheral blood. If you look at reservoir cells in peripheral blood in individuals who are on antiretroviral therapy, that doesn't seem to change very much with treatment.
It reaches a very low level.
That's right. Once they've reached the plateau, it doesn't move too much after that. That's what probably we're observing in the lung, as well: You get a decrease to begin with, but then it kind of flattens off -- but doesn't go away completely.
What does this mean in terms of our approach toward ultimately trying to develop a means for eradication or a cure?
My take is that this is a large body of cells that have a virus that really hasn't been characterized properly. And in any efforts to find strategies to eradicate viral reservoirs in other sites, the lungs should be considered, because alveolar macrophages are a huge part of [the cell population]; you're talking of millions of cells in this compartment. If you have about 2% of them infected with HIV, then you're talking about large numbers of cells that can potentially seed virus into the peripheral circulation if somebody, say, stops treatment, or if their treatment fails.
So whatever strategies are being considered for eradicating virus in other reservoirs, the lungs should really be considered as an important site.
Can you speculate whether there's likely to be any difference in the manner in which one attempts to activate latent HIV here, as opposed to in other reservoirs?
Really, I can't. But the worry with this is that, as you know, the lung is in continuous communication with the cell environment; a lot of things are going to excite the alveolar macrophages. The beauty about alveolar macrophages is that they are very, very quiet cells, so it takes a lot to excite them. But you can imagine that if these cells were activated easily, then -- if this was a replication-competent virus -- it would be churning [HIV] out of the lung at frequent intervals.
Are you planning any further research along this front?
We know that since we published our first reports of this, there are a number of groups that are really interested in looking at cells in the lung -- cellular alveolar macrophages -- as reservoirs of HIV. And I know of a number of groups that are trying to focus on this now.
In terms of where we're taking this work forward, first of all we have to define whether this infection is actually productive, whether the alveolar macrophage infection is productive. And we are currently doing experiments to try to define that.
I'm impressed by the number of people you had volunteer for this study, because this is not the most comfortable research to take part in. How did you get so many people engaged?
I think the advantage we have is that we have been doing research bronchoscopy in Malawi for over 14 years now. A lot of that has been directed at trying to define the causes of so-called smear-negative TB [tuberculosis], which is very common in HIV-infected individuals. But some of the studies have also been looking at basic science -- and in order to do that, we have had a lot of consultations with the communities, explaining why these studies are important, but making sure that people understand that this is really largely for research purposes if they're coming in as healthy, asymptomatic volunteers.
I think the success has really come from individuals understanding what we're doing, and not really hiding information from them.
So just openness, honesty?
Yeah. But to some extent we look after them from the medical point of view as well, because if they fall ill, they have open access to health services. They probably see that as an incentive, because even after the study is gone, if they're unwell, or they need medical attention, they can come to the study clinic and they'll still be helped by the study team. That's been going on for years now. In a way, that keeps the community engaged.
It's a draw that we underestimate in the U.S., that the access to guaranteed treatment is a real plus.
To get a little bit specific about some of the details: Did the drugs that a person was on -- for the people who are living with HIV -- have any effect, as far as you could tell, on the extent to which you could still see HIV in the macrophages?
Not very much. As you can see from this, the decrease in the frequency of HIV-infected alveolar macrophages was only minimal if you compare those who had been on antiretrovirals for, say, more than four years, compared to antiretroviral-naïve individuals. Actually, this is very consistent with what has been observed in the peripheral blood. If you look at reservoir cells in peripheral blood in individuals who are on antiretroviral therapy, that doesn't seem to change very much with treatment.
Myles Helfand is the editorial director of TheBody.com and TheBodyPRO.com.
Follow Myles on Twitter: @MylesatTheBody.