UC San Francisco researchers are reporting results that suggest the immune system of HIV patients mounts a robust response to at least one opportunistic infection following aggressive HIV drug therapy.
The finding, reported in the August issue of Nature Medicine, focused specifically on cytomegalovirus (CMV), the leading cause of blindness in people with AIDS.
However, said the researchers, the study may help to clarify an ongoing question in HIV treatment: Do the CD4+ T cells that are replenished by the immune system after highly active antiretroviral therapy (HAART) create the pathogen-specific responses needed to combat the opportunistic infections that afflict people with AIDS, including pneumocystis pneumonia? Each pathogen requires an individualized type of response by CD4+ T cells, which are key cells of the immune system. They are also the cells ravaged by HIV.
"CD4+ T-cell counts go up after therapy, but there is conflicting evidence as to whether the quality of the immune response is sufficient to enable patients to withstand opportunistic infections," said Joseph M. McCune, MD, PhD, an associate professor of medicine at UCSF and associate investigator at the Gladstone Institute of Virology and Immunology, which is affiliated with UCSF. "This study suggests that immune reconstitution may occur, at least in the case of responses against CMV."
The improved survival rates of people treated with aggressive HIV therapy have been attributed in part to the fact that patients are now started on therapy while their CD4+ counts are still high, and they are therefore able to mount a strong immune response, and in part to the fact that physicians are more adept at treating them.
Whether HAART plays a role in reducing opportunistic infections has been a puzzle. In February, another group of UCSF researchers reported a dramatic decline in several common opportunistic infections in HIV+ patients at San Francisco General Hospital. While they suspected the critical factor might be a reconstituted immune system after therapy, they said further studies need to be done to tease out the explanation.
In the current study, the UCSF researchers examined three groups of HIV patients. One group had an average CD4+ T cell count of 28 cells per microliter, putting them well below the level at which patients are diagnosed as having AIDS (less than 200 cells per microliter) and had active CMV disease.
This group had previously received ganciclovir, which is used to combat CMV. Another group had CD4+ T cell counts ranging from 10 to 1,000 cells per microliter after treatment with HAART, and had never had CMV disease. A third group had previously had CMV disease, but after treatment with HAART and ganciclovir these people had CD4+ T cell counts averaging 225 cells per microliter and quiescent CMV disease.
Using a relatively new technique that detects CMV-specific CD4+ T cells, the researchers determined that the patients with active CMV had low levels of these special CD4+ T cells, while patients who had never had the disease or had dormant disease had high levels of them.
"We've found a correlation between the absence of disease and the presence of CD4+ T cells that specifically respond to CMV," said McCune.
To prove the correlation, he said, would require tracing the progress of a single group of HIV+ patients with low CD4+ T cell counts and active CMV through HAART therapy to see whether they then developed CMV-antigen-specific CD4+ T cell responses and dormant CMV.
"Statistically, our data look pretty good," said McCune, "but the prospective study needs to be done."
The UCSF team plans to analyze immune responses against other pathogens that cause opportunistic infections in people with AIDS, said McCune.
The UCSF research was supported in part by grants from the University of California-wide AIDS research program and the National Institutes of Health.