Ongoing T-cell activation is associated with smaller gains in CD4 cell count in patients on HAART with effective suppression of HIV viral load, according to a US study published in the May 15th edition of The Journal of Infectious Diseases. The investigators believe that T-cell activation may explain why some patients have only modest gains in CD4 cell count despite receiving anti-HIV therapy and achieving an undetectable viral load.
T-cell activation is associated with the progression of HIV disease in untreated patients, and investigators in San Francisco postulated that ongoing T-cell activation might be limiting the extent of immune recovery in patients with only small improvements in their CD4 cell count despite both short and long-term suppression of HIV viral load by HAART.
Accordingly, 99 patients from the Study of the Consequences of the Protease Inhibitor Era (SCOPE) who had maintained a viral load under 1,000 copies/mL for at least three months, were investigated to see if there was a relationship between T-cell activation and overall CD4 cell gains. The study also included 13 untreated HIV patients and six HIV-negative volunteers as controls.
The majority of patients were men in their 40s, and were receiving a HAART regimen based on protease inhibitors. At baseline, average CD4 cell count was 210 cells/mm3 (range 84 - 382 cells/mm3), median duration of HIV suppression was 21 months (range eleven to 36 months), but 20% of patients had had a viral load measurement between 50 copies/mL and 1,000 copies/mL. Hepatitis C co-infection was present in 28% of patients.
The HAART treated patients had lower levels of activated CD4 +cells than the untreated controls (4% versus 8%), but higher than the HIV-negative controls (1%). Similarly, activated CD8+ cell percentage was lower in HAART treated patients than untreated patients (11% versus 46%), but substantially higher than uninfected controls (1%). These results remained unchanged when patients with hepatitis C virus were excluded and analysis was restricted to patients who had maintained an undetectable viral load in the previous three months.
Investigators found a relationship between T-cell activation and impaired CD4 recovery in both the three months after starting HAART and the longer term. On average, every 5% increase in the proportion of activated CD4+ T cells resulted in 45 fewer CD4 cells/mm3 during the first three months of HAART, and every 5% increase in activated CD8+ cells 35 fewer CD4 cells/mm3 in the longer term.
Factors associated with ongoing T-cell activation included hepatitis C coinfection; frequent low-level detectable HIV viral load (50 - 1,000 copies/mL); and, nadir CD4 cell count, with each 100 cell increase in the nadir count resulting in 1% fewer activated CD4+ cells and 1.5% fewer activated CD8+ cells.
Ongoing T-cell activation could be, the investigators speculate, the result of the inflammatory effect of HIV infection, draining the pool of both resting and memory CD4 cells. Immune modulators may offer means of combating T cell activation.
The investigators conclude: “abnormal levels of T-cell activation exist in most patients experiencing long-term HAART-mediated viral suppression and that extent of activation is associated with treatment-associated CD4+ T-cell gains. Improving our understanding of how HIV activates the immune system may lead to the development of more specific adjuvants to HAART that reverse the immunologic perturbations caused by HIV infection.”
The authors point to a recently published Italian study which showed that people with early HIV infection treated with HAART plus eight weeks of the immunosuppressive drug cyclosporin achieved significantly higher CD4 cell counts than people treated with HAART alone, as well as displaying significantly stronger HIV-specific immune responses.
Further information on this website
Cyclosporin - overview
The immune system and HIV - menu of comprehensive information
CD4 and viral load - booklet (Spanish version available) in the information for HIV-positive people series
Hunt PW et al. T cell activation is associated with lower CD4+ T cell gains in human immunodeficiecny virus-infected patients with sustained viral suppression during antiretroviral therapy. Journal Infectious Diseases, 187: 1534 - 1543, 2003.