[Show abstract][Hide abstract] ABSTRACT: Most human immunodeficiency virus (HIV)-infected individuals experience increases in peripheral CD4(+) T cell counts with suppressive antiretroviral therapy (ART) that achieves plasma HIV RNA levels that are less than the limit of detection. However, some individuals experience decreasing CD4(+) T cell counts despite suppression of plasma viremia. We evaluated 4 patients with a history of CD4(+) T cell decline despite successfully suppressive ART, from a median of 719 cells/mm(3) (range, 360-1141 cells/mm(3)) to 227 cells/mm(3) (range, 174-311 cells/mm(3)) over a period of 18-24 months; 3 of the patients were receiving tenofovir and didanosine, which may have contributed to this decrease. There was no evidence of HIV replication, nor of antiretroviral drug resistance in the blood or lymphoid tissue, or increased proliferation or decreased thymic production of naive CD4(+) T cells. All 4 patients had significant fibrosis of the T cell zone of lymphoid tissue, which appeared to be an important factor in the failure to reconstitute T cells.
The Journal of Infectious Diseases 07/2009; 199(11):1648-56. · 5.85 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective: To compare the architecture and HIV-1 RNA and Gag p24 protein expression in lymph nodes (LN) excised from individuals during chronic highly active antiretroviral therapy (HAART) with LN removed from the same patient after plasma virus rebound following the interruption of HAART.
Materials and methods: Six HIV-1-infected patients on HAART, with CD4 cell counts greater than 350 cells/μl, and plasma HIV-1 RNA less than 50 copies/ml, underwent inguinal LN excision upon discontinuation of HAART, and again after rebound of plasma virus. Lymph nodes were evaluated by immunohistochemical staining for Gag p24 antigen and Ki67, in-situ hybridization for HIV-1 RNA and H3-histone, and transmission electron microscopy (TEM).
Results: LN at baseline were quiescent to mildly hyperplastic and generally contained more primary than secondary follicles. Only one LN had detectable follicular dendritic cell (FDC)-associated p24 antigen, none had HIV RNA. Few mononuclear cells (MNC) expressed RNA or p24 antigen. Plasma virus at the second biopsy ranged from 329 to 3.2 × 106 copies/ml. CD4 cell count decline ranged from 5 to 51% during drug hiatus, and was greatest in patients with highest viral rebound. Four of six of the second LN were more hyperplastic than the initial LN, two showed paracortical hyperplasia. MNC expression of HIV RNA in the second LN paralleled the level of plasma viremia. Increased Ki67 and H3-histone signal occurred in the second LN.
Conclusion: Quiescent LN from individuals on HAART rapidly become hyperplastic and activated within 1-2 months after treatment interruption. As in acute HIV infection, virus expression by LN MNC parallels the rebound in plasma viremia and fall in CD4 cell count.
AIDS 08/2000; 14(12):1709-1715. · 6.41 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objectives: To evaluate changes in architecture, viral RNA, and viral protein over 6 months in lymph nodes from retroviral-naïve HIV-infected persons before and after commencing highly active antiretroviral therapy (HAART).
Methods: Nine antiretroviral-naïve HIV-infected persons had lymph nodes excised at baseline and at 2 and 6-8 months after beginning a four-drug combination regimen containing zidovudine, lamivudine, nevirapine, and indinavir. Two patients had AIDS. Lymph nodes were examined by immunohistochemical staining for Gag p24 HIV, CD3, CD21, CD20, HAM 56, and Ki67 antigens and by in-situ hybridization (ISH) for HIV RNA and H3-histone RNA.
Results: Eight of nine baseline lymph nodes showed follicular hyperplasia and germinal center and paracortical mononuclear cell activation. At 2 months, the lymph nodes from seven patients, including the AIDS patients, showed more follicular hyperplasia and activation than their baseline specimens but with decreased mononuclear cell activation. By 6 months, seven lymph nodes were less hyperplastic and activated than their corresponding 2 month specimens. Combined ISH/immunohistochemical staining of baseline lymph nodes revealed productively infected T (CD3) and B (CD20) cells and macrophages (HAM56+). HIV RNA-positive mononuclear cells were infrequent at 2 months, and rare at 6 months. HIV RNA was still associated with follicular dendritic cells (FDC) at 2 months, but not at 6 months. HIV p24-positive antigen in germinal centers persisted through all 6, and the one 8 month specimens. The baseline lymph nodes from one of the AIDS patients was involuted and T cell depleted, whereas the follow-up lymph nodes were hyperplastic with normal T cell levels.
Conclusion: Follicular hyperplasia and cell activation, possibly caused by persistent viral protein in germinal centers, may help explain why HIV viremia rebounds so rapidly after the interruption of HAART. Restoration of architecture may follow the treatment of patients with AIDS who initially had involuted and CD4 cell-depleted lymph nodes.
AIDS 11/1999; 13(16):2219-2229. · 6.41 Impact Factor