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Early Immune System Changes and Level of HIV in Cells Predict Later Disease Progression

Subtle changes in CD4 and CD8 cell levels and immune activation can indicate likelihood of progression later in the course of HIV disease, according to a study described in the January 15, 2010 Journal of Infectious Diseases. Researchers also found that the amount of integrated virus in CD4 cells is a predictive factor, and said their findings support early initiation of antiretroviral therapy (ART).

Anuradha Ganesan from the National Naval Medical Center and colleagues designed a study to test the hypothesis that quantifying central memory T-cells during early HIV infection might provide prognostic information, given that variability in disease progression cannot be fully predicted based on CD4 cell count or plasma viral load alone.

T-cells can be identified by the specific cell surface markers they carry. Naive T-cells are "uncommitted" and able to respond to new pathogens, while memory cells remain after an immune response and are "primed" to respond to a future attack from the same invader.

The investigators looked at stored blood samples from 466 HIV positive individuals receiving care through the U.S. military health system, obtained a median 225 days after the estimated date of seroconversion. Most patients (94%) were men, half were white, about 40% were black, the median age was 26 years, and the median CD4 count was 552 cells/mm³.

The researchers measured expression of the cell surface markers CD45RO, CCR5, CCR7, CD27, and CD28 in order to quantify naive and memory cell subsets in blood samples from these recently infected patients. They also assessed cell proliferation, CD127 expression, and cell-associated HIV (cells carrying integrated HIV genetic material).

Results

• Over a median 4 years of follow-up, 135 individuals progressed to an AIDS-defining illness or death.
• Neither the proportion nor absolute number of CD4 or CD8 memory T-cells correlated with disease progression, defined as time to AIDS or death.
• However, there were significant associations between progression and CD4 and CD8 T-cell proliferation, as well as loss of naive CD8 cells or CD127 memory CD8 cells.
• Higher levels of markers for immune activation on CD4 and CD8 cells predicted faster disease progression.
• There was also a significant link between a higher amount of cell-associated virus in CD4 cells and faster progression.

Based on these findings, the researchers concluded, "Our results demonstrate that the extent of the immunopathogenesis established early in HIV infection predicts the course of future disease."

Early immunological disturbances "are observed even among subjects with relatively preserved CD4 cell counts," they continued. "Early levels of immune activation may set the stage for future disease."

Finally, they added, "Because antiretroviral drug treatment reverses such defects in part, our study provides mechanistic clues to why early use of antiretrovirals may prove beneficial."

National Naval Medical Center, Infectious Disease Clinical Research Program, Uniformed Services University; Vaccine Research Center and Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases, Bethesda, MD; Biostatistics Research Branch, Scientific Application International Corporation–Frederick, Frederick, MD; United States Military HIV Research Program, Walter Reed Army Institute of Research, Rockville, MD.

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Reference

A. Ganesan, PK Chattopadhyay, TM Brodie, and others. Immunologic and virologic events in early infection predict subsequent rate of progression. Journal of Infectious Diseases 201(2): 272-284 (Abstract). January 15, 2010.