The Puzzle of CD4-Cell Depletion Despite Good Viral Suppression
In some patients, CD4-cell counts fail to rise as expected. Could extensive lymph node fibrosis be responsible?
We expect that when combination antiretroviral therapy (ART) suppresses a patients HIV viremia, a steady increase in CD4-cell count will ensue. In some patients, however, such increases are minimal or fail to occur, and in others, CD4-cell counts plummet after an initial rise, even though viral load remains undetectable. The combination of ddI and tenofovir has been associated with these aberrant CD4-cell responses, but the underlying mechanism is unclear, and the phenomenon is also seen in patients taking other drugs.
In a recent study, NIH researchers sought evidence to support any of several hypothetical explanations for the aberrant CD4-cell responses seen in four patients on combination ART whose CD4 counts had fallen from a median of 719 cells/mm3 to a median of 227 cells/mm3 despite persistently undetectable plasma viral loads. Three of the four patients were receiving a regimen containing tenofovir and ddI.
Residual replicating HIV did not seem to be the problem: Results of ultrasensitive PCR and assays for peripheral blood mononuclear cell–associated HIV RNA and proviral HIV DNA — and of assays for cell-associated HIV RNA and proviral DNA in mononuclear cells from inguinal lymph nodes — were similar to those obtained in other, successfully treated patients. Thymic production of naive CD4 cells was similar to that seen in successfully treated age-matched controls. No evidence of occult drug resistance sabotaging treatment was found. Changing ART regimens to avoid the tenofovir/ddI combination had little effect on CD4-cell counts during the follow-up period (median duration, 10 months).
The single unusual finding was a striking abnormality in inguinal lymph node architecture in the four patients: From 24% to 34% of the T-cell zone was replaced by collagen. In contrast, collagen levels in six successfully treated patients have been reported to range from 2% to 12% (J Clin Invest 2002; 110:1133).
Comment: We do not know the exact pathogenesis of CD4-cell depletion in untreated HIV infection, so creating logical hypotheses to explain aberrant CD4 responses is especially challenging. These authors offer the intriguing suggestion that the unusual lymph node architecture documented in all four patients in this study may be related to (or even responsible for) the inadequate CD4-cell response — i.e., that CD4-cell depletion is independent of specific components of an antiretroviral regimen and is instead caused by lymph node fibrosis. They note that such architectural damage may well be "clinically irreversible with currently available interventions."
Published in Journal Watch HIV/AIDS Clinical Care June 1, 2009
Nies-Kraske E et al. Evaluation of the pathogenesis of decreasing CD4+ T cell counts in human immunodeficiency virus type 1–infected patients receiving successfully suppressive antiretroviral therapy. J Infect Dis 2009 Jun 1; 199:1648.
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