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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 patient’s 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."

— Abigail Zuger, MD

Published in Journal Watch HIV/AIDS Clinical Care June 1, 2009

Citation(s):

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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• The Puzzle of CD4-Cell Depletion Despite Good Viral Suppression
  MURUGAN SANKARANANTHAN, Tirunelveli, Tamilnadu- INDIA, 2 Jun 2009 9:14 PM EST
  Few other possibilities may be thought off in these lines: People who had been infected with both HIV 1&2 (we... [more]
• Abberent CD4 responses
  OLAYINKA . A. OLASODE, OBAFEMI AWOLOWO UNIVERSITY, NIGERIA, 2 Jun 2009 9:14 PM EST
  This might actually support early commencement of HAART at higher CD4 levels before active lymph nodes are replaced by collagen.In... [more]
• Lower CD4 Counts
  DD C, 4 Jun 2009 2:15 PM EST
  I've been on HAART since I was infected (acute phase) almost six years ago. At first, my CD4 count was... [more]
• CD4 depletion in the face of good viral load suppression
  Balarabe Sani-Garko, ABU Teaching Hospital, Zaria, 5 Jun 2009 12:29 PM EST
  HIV/AIDS management also includes proper and appropriate management of opportunistic infections, these infections if untreated/undertreated may alter outcomes in HIV... [more]
• CD4-Cell Depletion Despite Good Viral Suppression - Let's look at the thymus
  AP Oppenheimer, 12 Jun 2009 2:27 PM EST
  I think that this issue could be more of a central cause than a peripheral one or better yet a... [more]

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