Granulocyte colony-stimulating factor administration to HIV-infected subjects augments reduced leukotriene synthesis and anticryptococcal activity in neutrophils

J Clin Invest. 1998 Aug 15;102(4):663-70. doi: 10.1172/JCI2117.


Neutrophil (PMN) dysfunction occurs in HIV infection. Leukotrienes (LT) are mediators derived from the 5-lipoxygenase (5-LO) pathway that play a role in host defense and are synthesized by PMN. We investigated the synthesis of LT by PMN from HIV-infected subjects. There was a reduction (4.0+/-1.3% of control) in LT synthesis in PMN from HIV-infected compared with normal subjects. This was associated with reduced expression of 5-LO-activating protein (31.2+/-9.6% of normal), but not of 5-LO itself. Since HIV does not directly infect PMN, we considered that these effects were due to reduced release of cytokines, such as granulocyte colony-stimulating factor (G-CSF). We examined the effect of G-CSF treatment (300 microgram daily for 5 d) on eight HIV-infected subjects. PMN were studied in vitro before therapy (day 1) and on days 4 and 7. LTB4 synthesis was increased on day 4 of G-CSF treatment, and returned toward day 1 levels on day 7. 5-LO and 5-LO-activating protein expression were increased in parallel. As a functional correlate to this increase in PMN LT synthesis by G-CSF, we examined the effects on killing of Cryptococcus neoformans. Anticryptococcal activity of PMN from HIV-infected subjects was less than that of PMN from normal subjects. G-CSF treatment improved fungistatic activity of PMN. This increase in antifungal activity was attenuated by in vitro treatment with the LT synthesis inhibitor, MK-886. In conclusion, PMN from HIV-infected subjects demonstrate reduced 5-LO metabolism and antifungal activity in vitro, which was reversed by in vivo G-CSF therapy.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 5-Lipoxygenase-Activating Proteins
  • AIDS-Related Opportunistic Infections / prevention & control
  • Arachidonate 5-Lipoxygenase / biosynthesis
  • Arachidonic Acid / metabolism
  • Carrier Proteins
  • Cryptococcus neoformans / immunology*
  • Granulocyte Colony-Stimulating Factor / therapeutic use*
  • HIV Infections / drug therapy*
  • Humans
  • Immunity, Cellular / drug effects
  • Leukotriene B4 / biosynthesis
  • Leukotrienes / biosynthesis*
  • Membrane Proteins
  • Neutrophils / drug effects*
  • Neutrophils / immunology
  • Prospective Studies


  • 5-Lipoxygenase-Activating Proteins
  • ALOX5AP protein, human
  • Carrier Proteins
  • Leukotrienes
  • Membrane Proteins
  • Granulocyte Colony-Stimulating Factor
  • Leukotriene B4
  • Arachidonic Acid
  • Arachidonate 5-Lipoxygenase