Modulation of the effector function of human macrophages for Histoplasma capsulatum by HIV-1. Role of the envelope glycoprotein gp120.

Abstract

We have demonstrated that monocyte-derived macrophages (M ) from HIV ϩ individuals are deficient in their capacity to phagocytose Histoplasma capsulatum (Hc) yeasts, and are more permissive for the intracellular growth of Hc. To determine whether these defects in M function were caused by HIV infection of the M and/or by pathological events associated with HIV infection, cultured normal human M were infected with the HIV-1 BaL strain. Virus production, quantified by reverse transcriptase activity and p24 antigen, was evident on day 8 after infection and peaked on day 16. On days 12, 16, and 20 after infection, HIV-1-infected M were deficient in their capacity to recognize and bind Hc yeasts compared with control M , and also were more permissive for the intracellular growth of Hc. Culture of normal M with the envelope glycoprotein gp120 inhibited phagocytosis of Hc yeasts by M in a concentration-dependent manner, but did not cause more rapid intracellular growth of Hc. Normal M cultured in the serum of HIV ϩ individuals with impaired M function subsequently were deficient in their capacity to phagocytose Hc yeasts, and were more permissive for the intracellular growth of yeasts compared with M cultured in normal serum. Conversely, culture of normal M in the serum of HIV ϩ patients with normal M function did not affect the interaction of Hc yeasts with M . Moreover, when M from HIV ϩ individuals that were initially defective in host defense against Hc were cultured in normal HIV Ϫ serum, normal M function was demonstrated. Adsorption of gp120 from the serum of two HIV ϩ patients removed the capacity of the serum to cause a M defect in phagocytosis of Hc, but had no effect on the capacity of the serum to cause accelerated intracellular growth. These data demonstrate that observed defects in M interaction with Hc yeasts may be caused by gp120 and other, as yet unknown serum component(s) probably released into serum by HIV-infected cells. (

Depletion of circulating natural type 1 interferon-producing cells in HIV-infected AIDS patients

“…The effector functions of monocytes and macrophages, including phagocytosis and intracellular oxidative responses, can be found decreased in HIV-infected subjects 8,9 and in cultured cells in the presence of HIV. [10][11][12][13] Superoxide production by neutrophils 14 as well as natural killer cell function as measured by the lymphokineactivated killer activity and responsiveness to interferon-␣ (IFN-␣) 15,16 have been shown to be defective in HIV-infected subjects.…”

Phagocytic Activity in Human Immunodeficiency Virus Type 1 Infection

“…In vitro tests confirm these data and demonstrate that only infective virions can affect both phagocytic activity and intracellular killing of macrophages; instead, treatment with gp120 alone may reduce only the phagocytosis of the yeast (16).…”

“…Monocyte-derived macrophages from HIV-infected subjects also present impaired phagocytic functions against Histoplasma capsulatum yeast and are more permissive for their intracellular replication (16). In vitro tests confirm these data and demonstrate that only infective virions can affect both phagocytic activity and intracellular killing of macrophages; instead, treatment with gp120 alone may reduce only the phagocytosis of the yeast (16).…”

The Innate and Adaptive Immune Response to Pulmonary Histoplasma capsulatum Infection

“…Phagocytosis is not altered, but rather binding is. Another finding of note in these studies is that the generation time of H. capsulatum in MΦ form HIV-infected subjects is more accelerated as compared to controls (Chaturvedi and Newman, 1997). Although a doubling time has not been reported, incorporation of 3 H-leucine by yeasts in MΦ from HIV-infected subjects substantially exceeds that in HIV seronegative subjects.…”

“…HIV infects not only T cells but also MΦ and can perturb the function of the latter population. MΦ from HIV-infected individuals phagocytize fewer yeast than cells from those who are HIV seronegative, and the explanation is that fewer unopsonized yeast bind to the surface of MΦ from HIVinfected individuals (Chaturvedi et al, 1995;Chaturvedi and Newman, 1997). Phagocytosis is not altered, but rather binding is.…”