Evaluation of the antiretroviral effects of a PEG-conjugated peptide derived from human CD38.
OBJECTIVE
Cell infection by HIV-1 is inhibited by both the expression of CD38 and a soluble peptide (sCD38p) corresponding to its extracellular membrane-proximal amino acid sequence (amino acids 51 - 74). We show here the effects of PEG conjugation to sCD38p and provide new insights into the mechanisms behind the anti-HIV-1 effects of CD38 and derived peptides.


METHODS
In-vitro and in-silico study.


RESULTS
PEGylation of sCD38p increased its ability to inhibit replication of HIV-1 in MT-4 cells and syncytia formation in cocultures of MT-2 and persistently HIV-1(IIIB)-infected H9(IIIB) cells. In silico modeling suggests that sCD38p and CD4 form stable heterodimers involving, among others, an interaction between lysine 57 (K57) of CD38 and a groove in the CD4 receptor, which, in CD4/gp120 complexes, is partially occupied by a lysine residue of the HIV-1 envelope glycoprotein. K57 substitution with a glycine in sCD38p impaired its ability to inhibit syncytia formation in MT-2/H9(IIIB) cell cocultures and gp120 binding to CD4 in a mouse T cell line expressing human but not mouse CD4.


CONCLUSIONS
PEGylation significantly improves the anti-HIV-1 activity of sCD38p, whose effect is probably due to competition with gp120 for a common binding site on CD4 although other mechanisms cannot be excluded so far. The inhibitory concentrations of the sCD38p-PEG as well as its poor toxicity, merit further consideration in anti-HIV-1 strategies.
Bensi
Thea
T
1'A Avogadro' University of Eastern Piedmont, Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), Department of Medical Science, Novara, Italy.
Mele
Federico
F
Ferretti
Massimo
M
Norelli
Sandro
S
El Daker
Sary
S
Chiocchetti
Annalisa
A
Maria Rojo
Josè
J
Cauda
Roberto
R
Dianzani
Umberto
U
Savarino
Andrea
A
D051997:ADP-ribosyl Cyclase 1 / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology*; D001665:Binding Sites; D015704:CD4 Antigens / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D015726:Giant Cells / Q000187:drug effects / Q000821:virology; D015699:HIV Envelope Protein gp120 / Q000378:metabolism; D015658:HIV Infections / Q000188:drug therapy; D015497:HIV-1 / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D051379:Mice; D011092:Polyethylene Glycols / Q000737:chemistry*; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects
D019380:Anti-HIV Agents; D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120; D011092:Polyethylene Glycols; D051997:ADP-ribosyl Cyclase 1