I’m summarising this information because I believe it’s a substantial challenge to our understanding of HIV pathogenesis – disease-causing process – and has particular implications for the period of seroconversion and early primary infection.
Some of this research comes from a presentation given by Dr Daniel Douek from the Vaccine Research Centre of the National Institute of Allergy and Infectious Diseases at the US National Institutes of Health. It also included related research which appeared in a September 2004 issue of the Journal of Experimental Medicine, on article by Dr Douek, and another from the prominent HIV researcher Martin Markovitz and his colleagues.
Markovitz and Douek’s articles covered quite similar territory, and arrived at the same conclusion: it seems that the very first days following HIV infection may be much more important to the course of HIV disease than has hitherto been thought.
HIV and its monkey equivalent, the simian immunodeficiency virus (SIV) are classified, in the prevailing view, as “lentiviruses” or “slow viruses”, meaning that they do not appear to induce immunodeficiency (here defined as the loss of sufficient CD4 cells to cause disease) for several months to up to ten years after infection.
However, Markovitz and Douek’s groups have now done some studies in monkeys and in human primary infection which suggest that in the first few days of infection with HIV, specific and quite rapid damage to the immune system may be occurring.
The main area of focus is the gut, including the intestinal track and the rectum. It’s long been known that there are a lot of specific cells at the surface of the lining of the gut and rectum which can be infected with HIV, and that’s why anal sex in particular seems to be such an efficient form of HIV transmission. It’s also well-known that during the first few days of infection, there are extremely high levels of virus, and the HIV is replicating during this period with a speed and ferocity which is unparalleled at any other point in chronic infection. So seroconversion is therefore a time at which HIV is also exceptionally transmissible.
What has not been well understood is what is happening at this time to the immune system.
Douek and his group decided to study this question by looking at the effects of HIV on the activation and depletion of specific kinds of CD4 cells and CD8 cells in the blood, the gastrointestinal tract, and the lymph nodes.
HIV can actually infect different kinds of cells, but it has a “preference” for a sub-set of T-lymphocytes, a class of cells in the immune system which are activated when infections, viruses etc. enter the body, to help fight them off. To successfully enter a T-cell, HIV has to interact with two specific parts of the cell: it binds to a marker on the cell’s surface called CD4 (that’s why they’re called CD4+ (positive) T-cells or CD4 cells), and then it binds to a protein on the surface of the cell called a chemokine receptor. The two chemokine receptors which HIV uses to enter cells are called CCR5 and CXCR4. People can be infected with HIV which uses one or both of these chemokine receptors. HIV seems to prefer CCR5 positive cells earlier in infection, and can often switch to use the CXCR4 receptor later in infection.
The experimental group of drugs called CCR5 inhibitors are designed to prevent HIV from attaching to CCR5 and so stop it from infecting the cell.
When a virus like HIV enters the body, the body responds by sending various sorts of immune cells to deal with it. The cells have different functions. Most T-cells live in the tissues of the body’s lymph system – and the intestines, gut, rectum etc constitute the body’s largest lymph organ, and also, contain very high levels of immune cells, including the very cells which HIV likes to preferentially infect: CD4 T-cells which also express or show the CCR5 receptor to which HIV can bind. In fact, the gastrointestinal tract harbours most of the body’s T-cells, much higher numbers than circulate in the bloodstream. Ordinarily, when a person gets a CD4 cell count done, what is being counted are the numbers of CD4 cells present and circulating around in the bloodstream. But this doesn’t account for the CD4 cells which at any time are present in the gastrointestinal tract or other lymph organs.
A second important factor about the gastrointestinal tract and gut is that because it is pretty close to the external environment, and because it is constantly exposed to microbes etc. through food, it’s also a site of pretty high and constant immunological activity. This means that there are often various types of immune cells, including all sorts of T-cells, present and active in the gut at any time. Finally, the mucosal surface of the gut and GI tract is therefore also often in a state of low-grade inflammation (for the same reasons).
So to summarise the picture:
- the gastrointestinal tract has abundant number of the kinds of cells which HIV likes to preferentially infect (i.e. CCR5 positive CD4 cells), in which it can quickly multiply; and
- there are other physiological reasons, including the presence of other cells which can get infected with HIV, which explain why the tissues of the gut and rectum are very susceptible to the entry of HIV.
The question is, what happens when HIV enters and infects the cells in the gut? The main point about the research done by the two groups above is that they reached a very similar conclusion: that during primary HIV infection (in particular seroconversion and the first days of infection), there is a significant and preferential depletion of the mucosal CCR5 positive CD4 cells within the gut and gastrointestinal tract. There is also a marked reduction in the numbers of other kinds of mucosal immune cells.
Many of the CD4 cells which are “activated” in the gastrointestinal tract are actually what is referred to as memory cells. “Memory cells” are cells which have receptors allowing the cell to attack specific foreign bodies to which it has previously been exposed. So the cells which HIV infects and kills so apparently rapidly in the gut after exposure to HIV are also those cells which contain “memory” against other pathogens and infections.
When Douek and his colleagues compared the kinds of things happening in the gut of someone recently exposed to HIV, they found profound differences in the numbers of CD4 positive CCR5 positive cells. There were many less such cells in the person with HIV. However, when they compared the amount of these same cells in circulating blood, there wasn’t any difference between HIV positive and HIV negative individuals, suggesting that all the damage and cell depletion in HIV was happening very early on, in the gut – but not at that point in the bloodstream.
But what does all this really mean?
Both Daniel Douek’s and Marty Markowitz’s research seem to show the same thing: that there is substantial loss of memory CD4 cells in the gut very early on following HIV infection, and that without treatment to prevent viral replication, over time, this may be what triggers the serious flow-on consequence: the inability of the body to maintain an adequate pool of memory CD4 cells. Markovitz’s paper notes, “The loss of specific clones of CD4 T-cells in the [gastrointestinal] mucosa may predispose to accelerated immune senescence [deterioration]”.
If this is the case, then my reading of the implications is:
- We need to strongly encourage research into interventions with post-exposure prophylaxis, as well as potentially pre-exposure prophylaxis.
- Treatment of people identified very early in infection (e.g. at seroconversion etc.) probably matters – to prevent HIV replication as quickly as possible; and
- new classes of drugs which specifically interfere with the capacity of HIV to enter cells are probably going to be absolutely vital. In particular, if it’s CCR5 CD4 cells which are being preferentially infected, it would be my view that the optimal place for these drugs is very likely to be as early on in infection as possible, and that we should also be considering them seriously as candidate PEP and PREP drugs, maybe in conjunction with other anti-HIV agents already used. Research into this area may help establish the full meaning of what is going on immunologically at this time.
A footnote, from my point of view is that this provides more evidence about the particular transmissibility of HIV around seroconversion, and the mechanisms for infection in the gut. I take this to suggest that perhaps at this time, due to high levels of virus and increased activity of cells in the gut, that possibly, things which would not ordinarily result in the transmission of HIV may actually be less safe at this time, which may be really important information for people who know they are seroconverting, or during the first days/weeks of infection.