Inhibition of HIV infectivity by a natural human isolate of Lactobacillus jensenii engineered to express functional two-domain CD4.
The predominant mode of HIV transmission worldwide is via heterosexual contact, with the cervico-vaginal mucosa being the main portal of entry in women. The cervico-vaginal mucosa is naturally colonized with commensal bacteria, primarily lactobacilli. To address the urgent need for female-controlled approaches to block the heterosexual transmission of HIV, we have engineered natural human vaginal isolates of Lactobacillus jensenii to secrete two-domain CD4 (2D CD4) proteins. The secreted 2D CD4 recognized a conformation-dependent anti-CD4 antibody and bound HIV type 1 (HIV-1) gp120, suggesting that the expressed proteins adopted a native conformation. Single-cycle infection assays using HIV-1HxB2 carrying a luciferase reporter gene demonstrated that Lactobacillus-derived 2D CD4 inhibited HIV-1 entry into target cells in a dose-dependent manner. Importantly, coincubation of the engineered bacteria with recombinant HIV-1HxB2 reporter virus led to a significant decrease in virus infectivity of HeLa cells expressing CD4-CXCR4-CCR5. Engineered lactobacilli also caused a modest, but statistically significant, decrease in infectivity of a primary isolate, HIV-1JR-FL. This represents an important first step toward the development of engineered commensal bacteria within the vaginal microflora to inhibit heterosexual transmission of HIV.
Chang
Theresa L-Y
TL
Osel, Inc., 1800 Wyatt Drive, Suite 14, Santa Clara, CA 95054, USA.
Chang
Chia-Hwa
CH
Simpson
David A
DA
Xu
Qiang
Q
Martin
Patrick K
PK
Lagenaur
Laurel A
LA
Schoolnik
Gary K
GK
Ho
David D
DD
Hillier
Sharon L
SL
Holodniy
Mark
M
Lewicki
John A
JA
Lee
Peter P
PP
D000998:Antiviral Agents; D001483:Base Sequence; D015704:CD4 Antigens / Q000235:genetics*; D017931:DNA Primers; D004797:Enzyme-Linked Immunosorbent Assay; D004926:Escherichia coli / Q000235:genetics; D005260:Female; D015658:HIV Infections / Q000635:transmission; D015497:HIV-1 / Q000472:pathogenicity*; D006801:Humans; D007778:Lactobacillus / Q000235:genetics* / Q000302:isolation & purification; D008561:Membrane Fusion; D014621:Vagina / Q000382:microbiology
D000998:Antiviral Agents; D015704:CD4 Antigens; D017931:DNA Primers