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Cell Marker Linked to Poor Immune Recovery on Antiretroviral Therapy

A cell surface protein known as PD-1 (a marker of cell apoptosis, or programmed death) is expressed at higher levels in HIV positive individuals who experience slow CD4 T-cell recovery after starting antiretroviral therapy, according to an Austrian study described in the February 1, 2011, Journal of Acquired Immune Deficiency Syndromes. This increase in PD-1 expression appeared distinct from overall T-cell activation or immune system exhaustion due to age.

Combination antiretroviral therapy (ART) typically lowers HIV viral load to an undetectable level within a few months of starting treatment. Then -- with little or no new replicating virus to infect them -- CD4 cells begin to recover, often reaching near-normal levels.

But some individuals -- especially those who start treatment later with more advanced disease -- experience full viral suppression without significant CD4 cell recovery, a phenomenon known as discordant response.

HIV experts do not yet full understand why discordant response occurs or what are its clinical consequences. But researchers in Austria recently identified a marker that may help predict which patients will experience poor immune recovery despite viral load suppression.

Katharina Grabmeier-Pfistershammer from Medical University Vienna and colleagues analyzed PD-1 expression on CD4 and CD8 T-cells of HIV patients with poor immune recovery despite virologically successful ART.

PD-1 expression on T-cells correlates with cell exhaustion and disease progression in people with HIV, the study authors noted as background. Previous research has shown that viral suppression on ART usually results in immune restoration and reduced PD-1 expression, but this does not always occur.

In this laboratory analysis, investigators looked at expression of surface markers on T-cells from patients experiencing discordant virological/immunological response.

Results

• T-cells from people with discordant response expressed significantly higher levels of PD-1 than those from people with normal CD4 cell recovery after starting ART.
• PD-1 expression was inversely correlated with CD4 cell count.
• Poor immune recovery was not, however, associated with increased expression of markers of T-cell activation in general.
• T-cells expressing PD-1 were more prone to inhibition of cell proliferation mediated by programmed death ligand.

The finding that discordant responders showed increased PD-1 expression but not increased T-cell activation overall suggests that "PD-1 is a unique marker for failing immune reconstitution despite viral suppression," the researchers wrote.

Furthermore, they found that T-cells from HIV patients with poor immune recovery differed from those of elderly people, again showing that stepped-up PD-1 expression is distinct from the overall immune system exhaustion that comes with age, known as immunosenescence.

In conclusion, the study authors wrote, these findings indicate that "PD-1-mediated T-cell suppression may have a role in impaired immune reconstitution in HIV patients."

Investigator affiliations: Department of Dermatology, Division of Immunology, Allergy and Infectious Diseases, Medical University Vienna, Vienna, Austria; Institute of Immunology, Center of Physiology, Pathophysiology and Immunology, Medical University Vienna, Vienna, Austria; aDepartment of Dermatology, Wilhelminenspital, Vienna, Austria.

1/21/11

Reference

K Grabmeier-Pfistershammer, P Steinberger, A Rieger, and others. Identification of PD-1 as a Unique Marker for Failing Immune Reconstitution in HIV-1-Infected Patients on Treatment. Journal of Acquired Immune Deficiency Syndromes 56(2): 118-124 (Abstract). February 1, 2011.