AIDS Treatment Update, Issue 64, April 1998
Edward King

We last reported on immune reconstitution (rebuilding the immune system) in AIDS Treatment Update issue 48/49, published in January 1997. At that time many experts were gloomy, arguing that much of HIV's damage to the immune system - such as the loss of immune cells `programmed' to recognise specific foreign organisms, or destruction of the physical structure of the lymph nodes - might be irreversible. However, at the Fifth Conference on Retroviruses and Opportunistic Infections held in Chicago in February, much more optimistic findings were presented.

DIFFERENT TYPES OF CD4 CELLS

There is more than one type of CD4 cell, but the standard CD4 count test performed in clinics is a relatively crude measurement that simply tells you how many CD4 cells of all types are present in a blood sample. In research studies, scientists have been looking more closely at which types of CD4 cells are returning, and where they are coming from.

CD4 cells can be divided into na ve cells (also known as CD45RA+ cells) and memory cells (CD45RO+ cells). Na ve CD4 cells are `blank' cells that have not yet been programmed to recognise a specific foreign substance (called an antigen). When a na ve cell encounters a `foreign' antigen it becomes activated and produces many copies of itself which stimulate immune responses against the antigen. Afterwards, some of these CD4 cells are converted into inactive, `resting' memory CD4 cells, ready to respond rapidly if they encounter their particular antigen again in the future.

When the CD4 count falls in someone with untreated HIV infection, both na ve and memory cells are being lost. The loss of na ve cells reduces the body's ability to respond to new antigens, while the loss of memory cells leaves `gaps' in the immune system where it can no longer respond to antigens it has encountered in the past.

HIV can enter both na ve and memory CD4 cells. However, new evidence suggests that when HIV enters a resting memory CD4 cell, it cannot merge its genetic material into the cell's DNA and thus cannot reproduce itself. It is only when the cell later encounters its antigen, and becomes activated again, that HIV can start to reproduce in the cell - and only then is the virus susceptible to anti-HIV drugs. Thus, resting memory cells may provide HIV with an important hiding place within the body, where it can lurk for months or years unaffected by even the most potent of today's therapies.

WHERE DO CD4 CELLS COME FROM?

The conventional view is that new CD4 cells can come from two different sources.

First, existing CD4 cells can produce copies of themselves through a process known as `clonal expansion'; na ve cells reproducing in this way produce new na ve cells, and memory cells produce new memory cells.

Secondly, in a process thought to occur primarily in children, entirely new cells may be generated in the bone marrow and travel to an organ in the upper chest called the thymus, from which they emerge as mature, na ve CD4 cells. They then circulate in the body until they encounter an antigen, at which point they orchestrate immune responses and become memory CD4 cells.

THE EFFECTS OF ANTI-HIV TREATMENT

Studies presented in Chicago looked in detail at the CD4 count increases seen among people taking HAART. The most common pattern is for people to experience dramatic increases in their CD4 count in the first few months of treatment, followed by a more gradual increase during the following months.

The current consensus is that the initial rapid increase contains very few newly produced CD4 cells. Instead, the majority of the `new' CD4 cells in the blood are thought to be ones that were previously in the lymph nodes, where most of the HIV in the body is found. Once HAART therapy is started, the CD4 cells regain their ability to travel from the lymph nodes and into the bloodstream. Most of these cells appear to be memory CD4 cells.

The later, more gradual increase in the CD4 count, on the other hand, is believed to contain new CD4 cells. Some seem to come from the cloning of pre-existing na ve and memory CD4 cells. People with low CD4 counts often have extremely few na ve cells left, so it is likely to take them a long time to rebuild their stocks of na ve cells in this way.

Nevertheless, the latest studies suggest that even among people who have no measurable na ve cells when they start treatment, na ve cells may start to appear after several months of HAART. One possibility is that these people did have a very small number of na ve cells - too low to be detected - that are now being cloned. Alternatively, these cells may be newly produced ones, manufactured in the bone marrow and matured either in the thymus or, it is now thought, perhaps in a different unidentified tissue. The thymus gradually shrinks after adolescence and can also be damaged by HIV, which in the past led many experts to be pessimistic about the prospects for good immune reconstitution in adults. However, researchers have detected new CD4 cells in response to HAART even among HIV-infected people whose thymuses have been surgically removed for unrelated reasons, proving that the thymus is not essential for CD4 replenishment.

When we last reported on this issue, some scientists were concerned that immune recovery may only be possible among people whose immune damage had not reached a `point of no return' - although no-one was clear precisely where that point might lie. However, there are now many studies showing that even people with extremely low CD4 counts can experience very substantial increases in their CD4 counts during HAART therapy. The most recent studies also suggest that not only the quantity but also the quality of the CD4 cells improves - they do appear to be properly functioning cells.

There was also positive news from the lymph nodes. In a healthy person, the lymph nodes are thought to play a key role in the interaction between various immune cells - they contain immune cells (called follicular dendritic cells) that trap foreign organisms and `present' them to CD4 cells, which then kick-start other immune responses. Among people with untreated HIV infection, the structure of the lymph nodes is often damaged, and it had been unclear whether they could recover even if HIV is suppressed. But studies presented in Chicago did indeed show clear signs that the lymph nodes were regaining their normal structure among people receiving HAART.

Finally, there is new evidence of immune reconstitution occurring even among people who do not achieve `undetectable' viral load. In a recent report in The Lancet, Swiss doctors reported on a group of extensively antiretroviral-experienced people with moderate to advanced HIV infection (average CD4 count 162 before starting HAART) who took HAART continuously but never achieved `undetectable' viral load. Nevertheless, after 48 weeks of treatment they had experienced an average CD4 count increase of 105.

Similar results were reported in Chicago. Doctors from San Francisco found that people who failed to achieve or maintain 'undetect-able' viral load with HAART still experienced CD4 count increases and were at very low risk of developing opportunistic infections (abstract 419). These results indicate that while 'undetectable' viral load may be optimal to avoid drug resistance, it is still possible to achieve substantial immunological benefits with a lesser degree of viral suppression.

These studies are grounds for considerable optimism. They suggest that even people who start treatment relatively late may enjoy real and substantial improvements in their immune functions - questioning the need for `hitting early' with anti-HIV drugs. Even if immune damage caused by HIV has left `gaps' in their immune repertoire, there is now hope that these may eventually be `plugged' by newly-formed na ve CD4 cells.

GENERATING HIV-SPECIFIC RESPONSES

Many studies have shown that the immune system's ability to recognise and respond to common antigens improves after effective anti-HIV therapy is started. But paradoxically, the one exception to this rule may be immune responses against HIV itself.

Several studies presented in Chicago found that anti-HIV immune responses do not usually improve during treatment, and they may in fact decline. Untreated people have relatively high levels of HIV antigens in their bodies, prompting the immune system to produce antibodies and other immune responses against them (although these are insufficient to eradicate or suppress the virus, for reasons discussed below). HAART regimens can suppress HIV replication to very low levels, so there are no longer many HIV antigens for the immune system to recognise; from the immune system's perspective it looks as though the virus has mostly gone away, so it starts to shut down its anti-HIV immune responses.

It is unclear whether or not this is a bad thing. The immune system may simply be reducing its anti-HIV activity because the need for it is no longer so great. HIV-specific memory cells do exist, so if viral replication increases again the immune system should quickly be able to scale up its responses again. Nevertheless, some researchers are looking at ways of maintaining strong anti-HIV responses during HAART, such as giving people a vaccine consisting of HIV proteins, alongside their anti-HIV therapy. The idea is that the vaccine will trick the immune system into believing that high levels of HIV remain in the body, so anti-HIV immune responses will be sustained.

TREATING PRIMARY INFECTION

Debate continues about the pros and cons of starting anti-HIV treatment during the first days and weeks after exposure to HIV (primary infection).

Some researchers believe that very early treatment could be harmful. Pointing to the research summarised above, they argue that suppressing HIV during primary infection may result in less vigorous HIV-specific immune responses.

Others agree that strong HIV-specific immune responses are important, but think that the latest research actually strengthens the case for treating primary infection. Dr Bruce Walker, an immunologist in Massachusetts, presented his theory about why the immune system usually fails to mount an effective response to HIV. His studies suggest that soon after infection, long-term non-progressors (HIV-infected people who maintain high CD4 counts and good health for many years without requiring anti-HIV treatments) develop high levels of CD8 cells that specifically target HIV. For the body to produce these cells, CD4 cells must first detect HIV and become activated. But activated CD4 cells are HIV's preferred target cells - so the virus infects and kills the very cells that could stimulate an effective immune response.

Dr Walker argued that if newly infected people are treated with HAART regimens within six months of exposure to HIV, it may be possible to prevent activated CD4 cells from being infected and destroyed, allowing strong CD8 responses to develop. He reported eleven cases of people who started treatment during seroconversion and now have undetectable viral load and very strong immune responses against HIV, similar to those seen in long-term non-progressors.

In these cases, treatment during primary infection does not seem to have hampered the development of HIV-specific immune responses. However, this field of research is still very young, and the only way to find out for certain whether very early treatment is beneficial or harmful would be to conduct controlled trials comparing treatment versus no treatment.

BOX 1: OPPORTUNISTIC INFECTIONS FIND NEW FORMS

A proportion of people who have recently started on a HAART regimen are developing unusual manifestations of opportunistic infections during the first few months of treatment. Researchers believe that these reactions are often caused by excessive responses by the recovering immune system.

For example, people with low CD4 counts may have low levels of MAI infection that is not yet causing any symptoms. If they start HAART they may develop swollen lymph nodes or, sometimes, skin abscesses within a few weeks of starting therapy, apparently caused by the immune system's reactions against the MAI organisms.

People with low CD4 counts are also at risk of CMV infection at the back of the eye (retinitis). CMV retinitis lesions are thought to be caused by the immune system killing retinal cells that have been infected with CMV. With treatment and maintenance therapy with anti-CMV drugs, the lesions may become inactive. However, in some cases the lesions have reactivated and begun to spread at their edges when people start HAART. This is presumably because the recovering immune system becomes more efficient at killing CMV-infected retinal cells. There have also been reports of new types of CMV-related eye problems, such as inflammation within the back part of the eye (vitritis), among people who had previously been treated for CMV retinitis. This condition, which can affect the sight, is thought to be caused by the immune system's high CD4 counts.

In one study presented in Chicago, only two out of 20 people experienced recurrences of oral candidiasis (thrush) after they stopped prophylaxis with anti-fungal drugs. These twenty people had all had good responses to HAART regimens, with an average 134 cell increase in their CD4 counts and 14 had undetectable viral load (abstract 489). (Prophylaxis against oral thrush is not usually given in the UK.)

If you do decide to stop prophylaxis because you have responded well to HAART, but your anti-HIV regimen subsequently fails, it may be necessary to restart prophylaxis promptly even if your CD4 count is still relatively high.

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