Day17: Yet another hypothesis for chronic immune activation

One major field of study in HIV is the difference in pathogenicity between SIV and HIV, since many species of monkeys which acquire SIV do not develop immunodeficiency. One of the observed differences is that monkeys which do not develop immunodeficiency do not show chronic immune activation upon SIV infection, while chronic immune activation is one of the hallmarks of HIV infection. Recently, Rawson and colleagues report in Nature Medicine that the chronic immune activation observed in HIV infection may be related to antigen processing during cell death.

 

Apotosis (pronounced apo-toe-sis) is the process of programmed cell death. When a cell suffers certain types of insults or is signaled in certain specific manners, the cell starts a chain reaction that leads to an orderly death of the cell. The cellular DNA is cleaved, the membrane “blebs” (breaks into smaller particles, similar to budding) and changes composition, and the cell is taken in by antigen presenting cells (APCs) for orderly disposal. This process is important during development and is also a pivotal process in the proper maintenance of the immune system. One key class of proteins in this process is the caspases. These proteins are the initial effectors of the chain reaction leading to apoptosis. They are proteases, similar to HIV protease in function, but they have different specificities.

 

According to the recent Nature Medicine paper, active apoptosis leads to an alteration of normal antigen processing. The authors took non-apoptotic and apoptotoc cells and used proteomics to determine differences in protein abundance for the two conditions. Using mass spectrometry, the authors observed that several of the proteins that had reduced abundance during apoptosis are proteins known to be targets in autoimmunity. The authors then tested the immunogenicity of the identified peptides for HIV-positive and HIV-negative subjects. Effector CD8 cells for the HIV-positive subjects showed greater responses to the peptide pool than HIV-negative subjects. After several rounds of in vitro stimulation, CD8 cells from HIV-negative subjects also reacted to the peptide pool, suggesting that CD8 cells specific for these epitopes are present in uninfected subjects, but are ignorant of their target.

 

The authors further confirmed the existence of self-reactive CD8 cells in HIV-positive subjects by tagging these cells with pentamers and analyzing the frequency using flow cytometry. In HIV-negative subjects, these reactive cells numbered less then 0.02% of CD8 cells. The number of positive CD8 cells for HIV-positive subjects was much higher. The number of self-reactive CD8 cells in HIV-positive subjects directly correlated with the percentage of apoptotic CD4 cells. The strength of self-reactive response inversely correlated with the number of live non-apoptotic CD4 cells in each HIV-positive subject.

 

The data also show that APCs presented with lysed apoptotic cells are better at stimulating CD8 responses against the self-reactive peptides than APCs presented with lysed non-apoptotic cells. When the apoptotic cells were cultured with caspase inhibitors, APC activation of CD8 effectors was decreased.  I am not entirely sure how they managed to generate apoptotic cells in the presence of a caspase inhibitor (particularly caspase 8 when they used a fas-method of apoptosis induction) and the methods do not clearly define this. Or maybe I am too dense to understand what they actually did here, but it seems problematic to me.

 

The study suggests that the autoreactive CD8 cells may contribute to CD4 loss during HIV infection. In the context of chronic immune activation, these CD8 cells, which would normally not be activated, undergo clonal expansion and are primed by cross-presenting APCs. This cross-presentation was blocked by caspase inhibitors, suggesting that the peptide fragments necessary for this self-reactivity are dependent upon caspases and may be directly cleaved by the caspases. It is easy to imagine a feedback cycle where HIV-associated apoptosis results in the priming of self-reactive CD8 cells, which in turn cause more apoptosis and a resulting chronic immune activation. As usual, more research will need to be done to determine if this hypothesis is correct, but if it is it may be possible to break the cycle of chronic immune activation in HIV-infected individuals and, hopefully, decrease HIV pathogenesis.

Day 14: CDC releases health disparities report

The Centers for Disease Control and Prevention released a report on health disparities in HIV/AIDS, viral hepatitis, TB and STDs this month. The report follows data from 2001 through 2004 in the US.

 

As we have been hearing for years, HIV rates among blacks and Hispanics are considerably higher than rates for other ethnicities. According to the report, HIV rates were 8.5 times higher for blacks than for whites (69.3 cases/100,000 vs. 8.2 cases/100,000). Notably, blacks accounted for 50% of new HIV cases.

 

The good news is that rates declined over this period for blacks, Hispanics, and in the Northeast. Levels were stable for other ethnicities and US regions. By region, the Northeast had the highest rate of infection (despite the decline), with 30.1 cases/100,000; comparatively, the South had rates of 23.5 cases/100,000. I have always heard that the rates of infection were increasing most rapidly in the South, but these data show that new cases were stable in this region for this period.

 

The report also broke down the new cases by age group. The highest rate of infection was among persons aged 35-39. I can only assume that this has to do with the latency period of HIV and that this age group reflects people who are getting infected in their 20s.

New infections were observed primarily in men, who accounted for 73% of new cases in 2004. Of these men, men who have sex with men accounted for 65% of cases.

 

The mode of transmission among males was predominantly reported as male-to-male sexual contact, with a slight upward tick in 2004. Infection due to injection drug use had a slight steady decrease over this period. For females, heterosexual contact was the main reported cause of infection, although this category decreased over the course of the study.

 

So, what does this study tell us? For many years, I have read and heard that the incidence of HIV was increasing the most among black and Hispanic women and in the South. It is important to note that the data in the CDC report are the number of new cases, which may differ slightly from the actual incidence. So, the face of HIV in the US may be changing compared to the early epidemic, but what we see in this study is a slightly different story. New cases of HIV are still dominated by men who have sex with men and the Northeast US appears to be the epicenter. Clearly, there is an issue when blacks have a considerably higher rate of new infections compared with whites. The reason for this difference is not clear, it could be due to prevention efforts, HIV education, access to treatment or care, or it could also be biological. Certainly, all of these issues need to be examined so we can reduce the incidence of HIV among all demographic groups.

 

M. Linde

Day 9: Some good news

The UN revised its estimate on the number of HIV-infected persons, reducing the estimate from almost 40 million to just under 33 million. While this is still an astounding number, at least it means that the epidemic is not as advanced as was feared. Granted, 33 million infected people and growing means HIV is still the #1 threat to humanity–in my book at least. I hope the correction in the estimate doesn’t cause others out there to believe that HIV is not as important a cause as it was yesterday.

Day 8: What we have here is a failure to communicate

Apparently many people don’t think AIDS is fatal. How one could think this with the estimated 20 million people dead from the disease is beyond me. I can only conclude that education efforts are (as usual) failing.

 

The data come from a survey of over 4,500 respondents conducted by the MAC AIDS Fund in the US, UK, India, Russia, France, China, Mexico, Brazil, and South Africa. Reuters reported that close to 60% of respondents in India believe a cure is available and that about 42% overall did not understand that HIV is fatal. Almost half of all polled believe that most people living with HIV are being treated. While I don’t expect most people to know the scope of the disease or even specific about the treatment, I do expect that we at least have education initiatives explaining that AIDS is fatal.

 

This brings me to what I believe is the saddest aspect of the epidemic: AIDS is an entirely preventable disease. We know how to reasonably protect ourselves from acquiring HIV. However, obviously we are doing a terrible job at this, as evidenced by the estimated 40 million people infected with the virus. Why is this not a top priority? Education and prevention measures are loaded issues, as they deal with sex and drugs, but why can’t we put aside our moral judgments and try to curb the spread of HIV? It’s a complete tragedy, because the epidemic never had to reach this level and I am sure it is destined to get worse.

 

M. Linde

Day 5: What happened with the Merck vaccine?

While the prospect of a therapeutic vaccine might be looking up, there still isn’t much good news on the prospect for a preventative vaccine. Merck announced last week that their new vaccine candidate may have actually increased subjects’ risk for HIV infection. How they didn’t see this until the large scale clinical trial is amazing, but I am guessing that they were as surprised by this as everyone else was.

 

But should they have been so surprised? We know that HIV infects activated CD4 cells. Some in the field have wondered whether providing a source of activated T cells by traditional vaccination would actually increase the risk of infection. So maybe that’s the answer to the question. Add to this that it has been shown that HIV preferentially infects HIV-specific CD4 cells and you can see a pattern where an immediate immune reaction might give HIV a greater chance of establishing infection. It’s hard to prove that this is what happened, but I certainly think it is a possibility.

 

The other possibility of that the vector had some synergistic effect with HIV. The vaccine was a modified adenovirus, designed to express parts of HIV. There are several examples of two viruses working synergistically. There’s even some evidence that mutants from the same virus can work together to increase pathogenesis (Vignuzzi Nature 2006—really interesting article). Maybe a viral vector isn’t the proper vehicle for the vaccine. I suppose we can’t say until Merck sorts out what happened. Either way, in spite of the vaccine failure, we are going to learn something about immunology and HIV. So I guess the trial wasn’t a total loss.

 

M. Linde

Day 3: The first good therapeutic vaccine idea in a long time

There was an interesting paper that came out of Doug Nixon’s lab at UCSF. The paper, reported in PLoS Pathogens (open access), looks at the relationship between HIV and human endogenous retroviruses (HERVs). HERVs are retroviruses that are already in your genome. Presumably, they entered into the human genome in ancient times and now are stably integrated. They are held in check by host proteins that presumably evolved in response to these retroviruses.

 

As HIV is a retrovirus, some of these proteins can also hold HIV in check. It would be nice if they did (I would happily be out of a job), but HIV has found a way to negate the action of these proteins. Further, some HIV proteins that help HIV replicate also help HERVs replicate. So HIV also activates the dormant HERVs in the cells it infects. Lots of work in this field has been done by Brad Jones (who is second author on the paper), a grad student at University of Toronto who seems poised to be a real player in HIV research. Let’s hope he stays in the field.

 

Now, when the immune system is presented with cells producing proteins that are abnormal, it generates a response. This usually results in suppression of whatever it is that causes the abnormal proteins. HIV, however, mutates rapidly and can escape from the immune system. HERVs are encoded in the genome, though, so they don’t mutate like HIV. Therefore, the immune system can generate a response against HERVs and kill the cells that express them. As these would also be HIV infected cells, this would likely be a good thing.

 

First, Garrison and colleagues show that HIV-positive subjects have significantly greater HERV expression than HIV-negative subjects. They also found that the HIV-positive subjects generated an immune response to HERV-specific sequences, while the HIV-negative subjects did not. These responses looked normal for what one would expect in a controlled response against an infection. One of the patients who showed good response against HERV sequences was also able to control HIV infection without the use of antiviral therapy and, overall, patients who showed good response to HERV sequences also had lower amounts of virus in the blood. It’s easy to visualize how HERV responses might also help control HIV spread in the body.

 

So, the authors suggest that maybe by vaccinating infected patients against HERV sequences could help HIV-positive patients control their infection without anti-HIV therapy. It would be cheap and easy—more than I can say for most therapeutic vaccine ideas out there. Seems like a good idea, don’t it? I hope it pans out.

 

M. Linde

Day 1: Welcome to The HIV Blog

Hello all,

Welcome to day 1 of “The HIV Blog”. Herein you will find information on recent events in the HIV/AIDS world: basic science, clinical science, epidemiology, and policy. More importantly, you will find my opinions on all things HIV/AIDS. I hope you enjoy it.

M. Linde