Reversal of abnormalities of neutrophil adhesion molecule expression in HIV infection following protease inhibitor therapy

Moore, D A.J.1; Henderson, D1; Gotch, F1; Gazzard, B1

Author Information

1Kobler Clinic and Academic Department of Immunology, Chelsea and Westminster Hospital, 369 Fulham Road, London SW10 9NH, UK.

Sponsorship: D. M. was a Research Fellow supported by a Special Trustees Research Fellowship Grant from the Special Trustees of Charing Cross Hospital, London, UK when this work was carried out.

Note: This study was presented in part at 37th Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, September 1997.

Date of receipt: 2 June 1998; accepted: 12 June 1998.

Article Outline

Neutrophil dysfunction is well described in HIV infection [1] and may contribute significantly to the increased susceptibility to bacterial infection observed amongst HIV-infected subjects [2]. The precise nature of this dysfunction is contentious, although chemotactic responses (which rely on the appropriate sequential expression of cell surface adhesion molecules) appear to be consistently impaired, particularly in late-stage disease [3]. A recent cross-sectional study of polymorphonuclear neutrophil (PMN) cell surface molecules in a group of HIV-positive patients demonstrated reduced expression of the adhesion molecules CD11a and L-selectin (CD62L), particularly in those with CD4 cell counts below 100 × 106/l, with suboptimal shedding of CD62L in response to N-formyl-methionylleucyl-phenylalanine (FMLP) stimulation [4]. During longitudinal follow-up, several patients commenced highly active antiretroviral therapy (HAART) including a protease inhibitor. We re-investigated eight individuals (mean, 42 weeks later; range, 11–71 weeks) who have shown significant CD4 cell count responses, to assess the impact of therapy on previously abnormal PMN adhesion molecule expression. Median rise in CD4 cell count was 147 × 106/l, with mean CD4 cell count rising from 40 × 106/l (range, 0–92 × 106/l) 222 × 106/l (range, 96–481 × 106/l). Six patients received triple therapy (two nucleoside analogues and one protease inhibitor) and two patients received quadruple therapy (including two protease inhibitors).

All adhesion molecule studies were performed using a whole blood flow cytometric method with mouse anti-human IgG1 fluorescein isothiocyanate and phycoerythrin-conjugated monoclonal antibodies. Artefactual distortion of expression due to PMN stimulation was minimized by limiting centrifugation to a single brief spin at 4°C following erythrocyte lysis and (except when stimulating with FMLP at 37°C) keeping samples on ice at all other times. Care was taken to ensure that subjects were not suffering from any intercurrent or occult infection, or receiving prescribed or non-prescribed non-steroidal anti-inflammatory drugs or opiates, which may have affected the results [5,6].

The expression of CD62L and CD11a on the surface of circulating PMN was significantly reduced in nearly all subjects prior to HAART. Expression of these adhesion molecules increased to normal (within HIV-negative reference range) in all eight subjects following the commencement of HAART (Table 1).

Shedding of CD62L (which is important to enable PMN extravasation to proceed) in response to in vitro FMLP stimulation was impaired prior to HAART [mean post-stimulation CD62L mean cell fluorescence (MCF) 57.4 versus 44.0 in HIV-negative controls], consistent with previous reports [7]. In all eight subjects, protease inhibitor therapy increased shedding of CD62L with all residual values in the normal range (average MCF, 41.7).

The mean proportion of neutrophils expressing CD18 increased from below the reference range (93.9 versus 97.3–99.7%) to normal (97.8%). CD18 MCF was normal pre-HAART and unchanged on treatment. However, CD18 is linked to several other cell surface molecules and therefore many more factors have a confounding influence on this particular adhesion molecule.

There is currently great interest in qualitative as well as quantitative immune reconstitution associated with antiretroviral therapy. These preliminary results suggest that abnormalities of neutrophil adhesion molecule expression, which we have previously shown to be associated with CD4 cell counts below 100 × 106/l, may be reversed when a favourable CD4 cell count response to protease inhibitor therapy occurs.

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© 1998 Lippincott Williams & Wilkins, Inc.