AIDS and malaria: Coinfection in a primate model and chemokine receptor binding
Description
The interaction between the acquired immune deficiency syndrome (AIDS) and malaria is understudied. The surface glycoprotein (gp120) of the human immunodeficiency virus (HIV) must bind to a chemokine receptor, CCR5 or CXCR4, to invade CD4+ cells. Plasmodium vivax uses the Duffy Binding Protein (DBP) to bind the Duffy Antigen Receptor for Chemokines (DARC) and invade reticulocytes. RANTES and its analogs can inhibit HIV infection. We demonstrated that RANTES and an analog inhibit DBP binding to DARC. RANTES levels in the sera of human malaria patients were significantly elevated compared to controls. Chemokines or compounds directed against chemokine receptor binding may be beneficial to both AIDS and vivax malaria A peptide sequence similarity was discovered between the V3 loop of gp120 and the DBP. We found that the site of similarity was necessary but not sufficient for DARC binding and contained a consensus heparin binding site (hbs) essential for DARC binding. A hbs peptide had similar affinity for heparin as V3 loop peptides from heparin-inhibited HIV strains, but different specificity. Polyanion inhibition of the hbs peptide binding to heparin recapitulated the inhibition of these polyanions for DBP binding to DARC in whole cell assays. Heparan sulfate binding was not necessary for DBP binding to DARC, and the hbs was necessary for members of the erythrocyte binding protein family with different receptors. The hbs may form part of a conserved erythrocyte receptor binding pocket whose specificity is determined by downstream residues, and is inhibited by polyanions when its specificity is for chemokine receptors A pilot trial tested the feasibility of a primate model of HIV and Plasmodium coinfection by using simian immunodeficiency virus (SIV) and P. knowlesi in the rhesus macaque (Macaca mulatta ). Of seven macaques infected with SIV, one was coinfected with P. knowlesi early in SIV disease, another was coinfected late in SIV disesase, and one was infected with P. knowlesi alone. The courses of the two diseases suggested that SIV and P. knowlesi may not exacerbate each other in the macaque, and that coinfection with these agents is promising as a model for coincident AIDS and malaria in humans