Design of HIV Coreceptor Derived Peptides That Inhibit Viral Entry at Submicromolar Concentrations

Abstract

HIV/AIDS continues to pose an enormous burden on global health. Current HIV therapeutics include inhibitors that target the enzymes HIV protease, reverse transcriptase, and integrase, along with viral entry inhibitors that block the initial steps of HIV infection by preventing membrane fusion or virus-coreceptor interactions. With regard to the latter, peptides derived from the HIV coreceptor CCR5 were previously shown to modestly inhibit entry of CCR5-tropic HIV strains, with a peptide containing residues 178-191 of the second extracellular loop (peptide 2C) showing the strongest inhibition. Here we use an iterative approach of amino acid scanning at positions shown to be important for binding the HIV envelope, and recombining favorable substitutions to greatly improve the potency of 2C. The most potent candidate peptides gain neutralization breadth and inhibit CXCR4 and CXCR4/CCR5-using viruses, rather than CCR5-tropic strains only. We found that gains in potency in the absence of toxicity were highly dependent on amino acid position and residue type. Using virion capture assays we show that 2C and the new peptides inhibit capture of CD4-bound HIV-1 particles by antibodies whose epitopes are located in or around variable loop 3 (V3) on gp120. Analysis of antibody binding data indicates that interactions between CCR5 ECL2-derived peptides and gp120 are localized around the base and stem of V3 more than the tip. In the absence of a high-resolution structure of gp120 bound to coreceptor CCR5, these findings may facilitate structural studies of CCR5 surrogates, design of peptidomimetics with increased potency, or use as functional probes for further study of HIV-1 gp120-coreceptor interactions.

The CCR5-∆32 Mutation: Impact on Disease Outcome in Individuals with Hepatitis B Infection in the Southern Khorasan Population (East of Iran)

“…As was proved, this mutation has a protective role against chronic HBV infection and HIV, and also leads to a non-functional receptor that could modify disease in Rheumatoid arthritis patients, so it is concluded that the population of Birjand has greater hereditary susceptibility to chronic HBV infections, HIV, and Rheumatoid arthritis, compared to Europeans in terms of the CCR5 ∆32 mutation (13,14,18).…”

“…The CCR5 plays a role in T cell proliferation and activation by binding to its ligand RANTES (CCL5) and additionally works as the principal co-receptor for macrophage (M)-tropic strains of Human Immunodeficiency Virus type 1 (HIV-1) (14,15). The latest studies have demonstrated the protective role of homozygous for the CCR5 ∆32 genotype against HIV infection, yet in relation to heterozygous CCR5 ∆32 (∆32/wt), the results have been practically controversial (16,17).…”

Peptides to combat viral infectious diseases

“…An example is peptide 2C which is derived from the C-terminal portion of the extracellular loop of CCR5. C2 competes with CCR5 for binding to gp120 [ 54 ] and inhibits HIV-1 entry at a double-digit micromolar concentration in vitro [ 52 , 18 ].…”

The Role of Natural Antibodies to CC Chemokine Receptor 5 in HIV Infection

“…As HIV entry process requires expression of both CCR5 and CD4 on cell membrane, receptor- and co-receptor-mimetic peptides ( 143 , 144 ) have been proposed as an alternative strategy to block HIV entry but, as for chemokines, no one has been already tested in human clinical trial.…”