SEGMENT 3: Dr. Freiberg discusses inflammation in relation to HIV and cardiovascular disease.

Dr. Matthew Freiberg, University of Pittsburgh:  When we think about atherosclerosis now, when we think of mechanisms, we think of oxidized LDL and alterations in the innate and the adaptive immune system. HIV is a very interesting model for a lot of reasons. One of the biggest reasons is that its target as a virus is right after the adaptive immune system. 

The reason that is important is when you think about how we think of atherosclerosis now and what has been studied mostly, it’s more on the innate side with things like CRP [C-reactive protein], which most people are familiar with. We have plenty of data, I think at this point, among the HIV community that we see that HIV-infected people have increased levels of biomarkers that we classically associate with innate immunity, including like IL-6 or CRP and altered coagulation like D-dimer. 

HIV is interesting that just because it is a virus and the immune response to a virus may stimulate the innate side, you also have this adaptive immunity and microbial translocation, and we will get into both of those. On the adaptive side, our group and others have suggested, though not proven, that as you reduce your CD4 cell count, there seems to be an increased risk of myocardial infarctions, at least in the veteran’s cohort. The question is: What does that mean? How does the adaptive immune system translate into increased risk? 

We know in mouse models that the balance between T-helper 1 and T-helper 2 cells seems to be associated with increased vascular risk. We know that if we alter T regulatory function, which may help suppress atherosclerosis development, at least in animal models, that if you have lower amounts of those or you block that function, then atherosclerosis continues to increase. 

If you have a virus that is specifically going after these very things, the T-cell system, which may be helping regulate not only the adaptive, but the innate immune system as well, and it’s targeting these cells, you can imagine that HIV may be mediating its affects directly through alterations in the adaptive immune system. 

In addition to that, we also know that if CD4 cells are depleted in the gut mucosa, the gut becomes leaky. What I mean by that is that bacterial products that are inside there can leak across the gastrointestinal membrane and into the portal circulation. Now this is not unique pathophysiology. We have known for quite some time that alcohol can do the same thing via a separate mechanism. 

The point is that when those bacterial products get into your portal circulation and into your blood stream, they shouldn’t be there. They can stimulate the immune system rather substantially. If you think about the fact that HIV may be attacking the adaptive immune system, it in itself is immunogenic because the body is trying to respond to the virus as a foreign antigen, if you will, and that the virus by virtue of wiping out the CD4 cell counts can deplete or cause gaps in the gastrointestinal membrane that can cause this bacteria to leak across and stimulate the immune system, you can imagine that HIV is a pretty pro-inflammatory process. 

With all of those levels and mechanism and potentially inflammation, it may be, although we don’t know, that that is exactly how HIV is mediating its affect. One of the interesting things that people have looked at is this idea of naïve versus memory cell ratio. You produce all these naïve cells out of your thymus and they’re floating around trying to protect your body and then you get these effector cells, and this is oversimplified, of course, but these effector cells that have been programmed now to target certain antigens. 

If you have a thymus that’s being involuted early by HIV, because it attacks that, and you don’t have an ability also to replenish these naïve T-cells that you need to fight other infections, you may also “burn” through your adaptive immune system in a way that, again independent of just destroying the T-cells, if you don’t have this naïve T-cell population, you may become pro-inflammatory, if you will. 

This virus is teaching us a lot. It’s a human model, if you will, for how inflammation, and I will put it in quotes, but how the immune system may contribute to cardiovascular risk. While we have all these studies in mice, particularly with the adaptive immune system, HIV is now suggesting or promoting to us a way to look at this. 

Interestingly enough, I just had a conversation with an immunologist who does transplant disease in children, on the way back from a flight from Atlanta. What’s interesting to them is that they say that these transplants, when they take a good heart – when I say a good heart, it is transplantable and not in horrible shape – and let’s say you put it in a child who does not have any comorbid diseases like smoking, diabetes, and hypertension for decades. They still find that these hearts don’t last as long as you might expect them to. The question is, why is that? 

Well, when we were talking – and it’s interesting science – imagine, if you will, that you have an innate and an adaptive immune system. In HIV, we clear out the adaptive immune system, it’s untreated, so you are left with this innate side. Let’s say the innate, now, it doesn’t have the control that it likes or maybe it becomes overactive and causes damage. For transplantation, we are trying to block down the adaptive immune system so that the organ doesn’t reject. 

One of the things we talked about is what we ‘e doing in transplant cardiology really the story of HIV where instead of you’re biologically eliminating the CD4 cells, we’re chemically eliminating them with antirejection medications? And I’m not suggesting that you shouldn’t give people these medicines to prevent rejection. But we wondered, is it possible that by eliminating or chemically controlling this adaptive immune system in transplant, is the innate side now doing something different that’s causing these coronary atherosclerosis to occur earlier in these transplant people, similar to what we might be seeing in people who are infected with HIV, and consistent with what we might see in a mouse model?

What I think is really exciting about HIV is that not only are we looking into trying to find ways to minimize the risk of cardiovascular disease now that HIV really has changed from this terminal fatal condition to more of a chronic disease, but we are helping them with what we believe is going to be a big problem for these people because of HIV, because of the ART, because of their comorbid disease. But, we are also, through studying people with HIV, we may be able to gain keen insights in how the inflammatory system may contribute to cardiovascular risk and to improve health for other people via studying people with HIV infection. 

If some of the hypotheses I have mentioned today with transplant, if it really is a similar process, we may indirectly, by studying HIV, help the whole transplant system as well, or vice versa. For me, that’s really neat. That’s a lot of different people from basic science to clinical that might be able to work together with the human model transplant HIV to really understand how heart disease may work, or at least coronary atherosclerosis, ischemic stroke, and maybe even, by extension, heart failure.