The ability of Highly Active AntiRetroviral Therapy (HAART) to suppress HIV replication, increase CD4 cell counts in the blood, and prevent or delay opportunistic infections is now well documented. Individual responses can vary, toxicities remain a problem and the best time to start HAART continues to be debated, but the overall trend of restored immunity and prevention of illness has come as a welcome surprise. Many researchers feared that the damage to the immune system caused by HIV would be irreversible, but HAART studies have contradicted this assumption. These studies paint a picture of immune restoration occurring in multiple phases -- some fast and others slow and variable -- ultimately leading to near-normal immune system function in many individuals. Research into immune restoration also provides a new opportunity to understand the mechanisms by which HIV damages the immune system, a necessary step for designing therapies that might speed immune recovery or help people whose immunity remains impaired despite HAART.
One marker for this process is the CD4 cell count. This routine test gives you the number of CD4 cells in a milliliter of blood. Declining counts are linked to an increasing threat of illness -- especially when specific thresholds are crossed. Studies have found that a drop below 200 CD4 cells is the most significant risk factor for the development of OIs.
Along with the fall in numbers, there are profound changes in CD4 cell function, first revealed in the late 1980s by immunologist Gene Shearer and colleagues at the National Institutes of Health. Shearer demonstrated what can best be described as a spreading dysfunction among CD4 cells over the course of HIV infection. First to be impacted are memory CD4 cell responses to specific common antigens (pieces of infectious agent, from infections like influenza virus), which decline to below-normal levels early on. But eventually the CD4 cell population as a whole is affected. Due to the central coordinating role played by CD4 cells, this loss of function is almost inevitably accompanied by defects in B-cell and CD8 cell responses.
The pace of immune system impairment is known to be linked to the level of HIV replication (the viral load) and the degree of abnormal immune activation. One of the great mysteries of HIV infection is that it both suppresses immune function and also hyper-activates some immune system cells. The late Janis Giorgi from the University of California at Los Angeles pioneered this area of research, showing that certain markers of T-cell activation (particularly surface molecules called HLA-DR and CD38) actually increase as HIV infection progresses.
The second phase of immune restoration described by Autran comprised a much slower but steady increase in naïve T-cells (both CD4 and CD8) that became detectable about four months after HAART was initiated. This increase continued during a year of follow-up. Longer-term studies have since shown that this slow gain of naïve T-cells can continue for a period of years, until normal or near-normal levels are attained. The source of these naïve T-cells has since been shown to be the thymus, an organ that was once thought to be inactive in adulthood. A young English researcher based in Texas, Danny Douek, overturned this assumption using a test that can identify naïve T-cells that have recently left the thymus. The test looks for TREC (T-cell Receptor Excision Circles), which are small pieces of DNA present almost exclusively in newly-made naïve T-cells.
In a search for factors that influence naïve T-cell increases, immunologist Mike Lederman from Case Western University in Cleveland, Ohio discovered that the pace of naïve T-cell recovery correlated with age, with younger people gaining naïve cells fastest. In children, the effect is most dramatic -- the rate of naïve T-cell recovery is 10-40 times faster than that of adults. This finding is consistent with Douek's recent TREC research showing that the thymus is most active in childhood, but then decreases production of naïve T-cells to a steady (but gradually slowing) daily output that continues into old age.Measuring Memory T-Cell Responses"). Before therapy, when the average CD4 cell count was 176, study participants showed no response to either antigen. Within three months of starting HAART, significant responses to both TB and CMV became detectable. Since this initial study in 1997, many other reports have confirmed improvements in antigen-specific T-cell responses, some using newer testing technologies. Additional antigens that have been studied include influenza, candida (the fungus that causes thrush) and tetanus. The one exception to this rule appears to be HIV. Responses to HIV antigens can sometimes be detected before starting HAART, but do not improve after beginning therapy. In fact, the reduction in HIV levels caused by HAART seems to cause a decline in HIV-specific T-cells.
Improvements in immune function after HAART can also be assessed more indirectly. Large, widely-publicized cohort studies involving thousands of people have demonstrated that HAART dramatically reduces the occurrence of OIs. Evidence that is even more persuasive comes from studies in which preventive treatments (prophylaxis) for OIs were successfully stopped if HAART boosted CD4 cell counts above certain thresholds. Even treatments for active OIs can sometimes be discontinued without recurrence of disease, a situation unimaginable just a few years ago.*
Studies have also documented so-called "paradoxical" effects of HAART. Around 10% of people taking HAART experience ongoing CD4 cell count increases despite only temporary reductions in viral load. A number of theories have been put forward to explain this phenomenon, such as drug-resistant HIV potentially being less harmful to T-cells and/or the thymus. Another possibility is that a brief reduction in viral load can be sufficient to cause a major redistribution of T-cells from the lymphoid organs. Some researchers have found that this type of paradoxical response is associated with a decrease in immune activation markers that persists after viral load has risen. At the other extreme, perhaps 5% of people on HAART experience sustained reductions in viral load but only minor increases in CD4 cells. Recent studies utilizing the TREC test have found that this problem may relate to a lack of production of naïve T-cells by the thymus.
* The new United States Public Health Service (USPHS) guidelines on preventing OIs, updated in November, include specific criteria for stopping prophylaxis for PCP, MAC and toxoplasmosis. The USPHS guidelines also describe circumstances under which treatment for active MAC, toxoplasmosis, cryptococcal meningitis and CMV might safely be stopped. The guidelines are available on the Internet at http://www.thebody.com/cdc/pdfs/oi_1101.pdf (PDF).
Immune Restoration Disease
|In some uncommon cases, an increase in CD4 cell count from very low levels (less than 100) can be associated with unusual flare-ups of infections. This phenomenon has been called "immune restoration disease" and appears to relate to the development of new immune responses against the particular pathogen (reported examples include mycobacterium avium complex [MAC], CMV, hepatitis B and C, tuberculosis and herpes zoster). A detailed report on immune restoration diseases by Australian doctor Martyn French is on the internet -- a link is contained in the Web version of this article at: www.acria.org.|