Pneumocystis jiroveci pneumonia prophylaxis is not required with a CD4+ T-cell count < 200 cells/microl when viral replication is suppressed.

OBJECTIVE: To determine the safety of discontinuing Pneumocystis jiroveci pneumonia (PCP) prophylaxis, in patients on effective antiretroviral therapy with CD4+ T-cell counts that have plateaued at < 200 cells/microl. METHODS: We prospectively evaluated a cohort of HIV infected patients at a multidisciplinary HIV clinic with sustained HIV RNA levels < 50 copies/ml and CD4+ T-cell counts that have plateaued at < 200 cells/microl and who have discontinued PCP prophylaxis. RESULTS: Nineteen patients fulfilled the above criteria. Eleven had been taking daily trimethoprim-sulfamethoxazole, seven were receiving monthly aerosolized pentamidine, and one patient never received any prophylaxis. The median CD4+ T-cell count at the time of discontinuation and at the most recent determination were 120 (range, 34-184) and 138 (range, 6-201) cells/microl, respectively. To date, patients have been off PCP prophylaxis for a mean of 13.7 +/- 10.6 months and a median of 9.0 (range 3-39) months for a total of 261 patient-months. To date, no patient has developed PCP. This is significantly different from the risk of developing PCP with a CD4+ T-cell count of < 200 cells/microl in untreated HIV infection (rate difference 9.2%; 95% confidence interval, 5.7 to 12.8%; P < 0.05). CONCLUSION: With sustained suppression of viral replication, PCP prophylaxis may not be necessary, regardless of CD4+ T-cell count. This illustrates a degree of immune recovery that occurs with virologic suppression that is not reflected in absolute CD4+ T-cell count or percentage and suggests that guidelines for P. jiroveci pneumonia prophylaxis may need to be re-evaluated.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) and inflammatory stimuli up-regulate secretion of the soluble GM-CSF receptor in human monocytes: evidence for ectodomain shedding of the cell surface GM-CSF receptor alpha subunit.

Soluble GM-CSF receptor alpha subunit (sGMRalpha) is a soluble isoform of the GMRalpha that is believed to arise exclusively through alternative splicing of the GMRalpha gene product. The sGMRalpha mRNA is expressed in a variety of tissues, but it is not clear which cells are capable of secreting the protein. We show here that normal human monocytes, but not lymphocytes, constitutively secrete sGMRalpha. Stimulation of monocytes with GM-CSF, LPS, PMA, or A23187 rapidly up-regulates the secretion of sGMRalpha in a dose-dependent manner, demonstrating that secretion is also regulated. To determine whether sGMRalpha arose exclusively through alternative splicing of the GMRalpha gene product, or whether it could also be generated through ectodomain shedding of GMRalpha, we engineered a murine pro-B cell line (Ba/F3) to express exclusively the cDNA for cell surface GMRalpha (Ba/F3.GMRalpha). The Ba/F3.GMRalpha cell line, but not the parental Ba/F3 cell line, constitutively shed a sGMRalpha-like protein that bound specifically to GM-CSF, was equivalent in size to recombinant alternatively spliced sGMRalpha (60 kDa), and was recognized specifically by a mAb raised against the ectodomain of GMRalpha. Furthermore, a broad-spectrum metalloprotease inhibitor (BB94) reduced constitutive and PMA-, A23187-, and LPS-induced secretion of sGMRalpha by monocytes, suggesting that shedding of GMRalpha by monocytes may be mediated in part through the activity of metalloproteases. Taken together, these observations demonstrate that sGMRalpha is constitutively secreted by monocytes, that GM-CSF and inflammatory mediators up-regulate sGMRalpha secretion, and that sGMRalpha arises not only through alternative splicing but also through ectodomain shedding of cell surface GMRalpha.