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Abstract
Evaluation of the Pathogenesis of Declining CD4+T Cell Counts in HIV-1 Infected Patients Receiving Successfully Suppressive Antiretroviral Therapy
Dybul M.1, Nies-Kraske E.1, Condoluci D.2, Schacker T.3, Orenstein J.4, Brenchley J.1, Fox C.5, Daucher M.1, Dewar R.6, Maldarelli F.7, Hallahan C.1, Planta M.1, Douek D.1, Coffin J.7, Fauci A.1
Introduction: Some HIV-infected patients experience declining CD4+T cell counts while receiving successfully suppressive ART. We examined whether HIV replication in occult sites, e.g. lymphoid tissue (LT), increased proliferation and decreased production of CD4+T cells, or pathologic changes to LT that support T cell homeostasis were causative.
Methods: We evaluated 4 patients receiving ART with a history of CD4+T cell decline from a median of 719 (range 360-1141) to 227 cells/mm3 (range 174-311) over 18 to 24 months despite suppressing plasma viremia. LT and peripheral HIV burden were evaluated with bDNA, HIV DNA PCR, in situ hybridization (ISH), and immunohistochemistry (IHC). Proliferation and production of peripheral CD4+T cells were assessed by Ki67 FACS analysis and TREC PCR. LT architecture was examined by IHC and quantitative image analysis (QIA).
Results: Cell-associated HIV RNA was <50 c/106 PBMC or LNMC. A median of 65 copies HIV DNA/106 PBMC (range 6 –292) was found in all patients; there were 60 and 800 copies HIV DNA/106 LNMC in 2 patients in whom proviral DNA was detectable. IHC detected p24 antigen in the LT of 3 patients. Low-level HIV replication (determined by ISH) was seen in 1 patient. Median levels of 1090 TREC/ml blood (range 51-6495) were comparable to a group of 12 age-matched controls (median 744; range 303-3347 TREC/ml). The T cell zone (TZ) of the paracortex contained extensive fibrosis with vascular proliferation. IHC revealed significant depletion of CD4+T cells in the TZ.
Conclusions: Observed levels of HIV RNA, DNA, and p24 were commensurate with those reported for patients receiving suppressive ART without CD4+T cell decline. There was no evidence that CD4+T cell decline was a result of HIV replication in LT, or altered thymic output. Fibrosis of the TZ is the likely mechanism of failure to reconstitute normal turnover of peripheral CD4+T cells due to damaged homeostatic mechanisms in LT.
The 3rd IAS Conference on HIV Pathogenesis and Treatment
Abstract no.
WePe8.1B01
Suggested Citation
"DybulM., et al.
Evaluation of the Pathogenesis of Declining CD4+T Cell Counts in HIV-1 Infected Patients Receiving Successfully Suppressive Antiretroviral Therapy.
Poster Exhibition:
The 3rd IAS Conference on HIV Pathogenesis and Treatment:
Abstract no.
WePe8.1B01"
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