Leukemia inhibitory factor inhibits HIV-1 replication and is upregulated in placentae from nontransmitting women

Abstract

The placenta may play a critical role in inhibiting vertical transmission of HIV-1. Here we demonstrate that leukemia inhibitory factor (LIF) is a potent endogenous HIV-1-suppressive factor produced locally in placentae. In vitro, LIF exerted a potent, gp130-LIFRβ-dependent, HIV coreceptor-independent inhibition of HIV-1 replication with IC 50 values between 0.1 pg/ml and 0.7 pg/ml, depending on the HIV-1 isolate. LIF also inhibited HIV-1 in placenta and thymus tissues grown in ex vivo organ culture. The level of LIF mRNA and the incidence of LIF protein-expressing cells were significantly greater in placentae from HIV-1-infected women who did not transmit HIV-1 to their fetuses compared with women who transmitted the infection, but they were not significantly different from placentae of uninfected mothers. These findings demonstrate a novel pathway for endogenous HIV suppression that may prove to be an effective immune therapy for HIV infection.

Expresión diferencial en placenta de beta-defensinas humanas y detección de variantes alélicas en el gen DEFB1 de madres positivas para VIH-1

“…These results agree with previous studies that have reported no association between the presence of the ∆32 allele and reduced risk of perinatally acquired HIV-1 infection (22,26,27). Other mechanisms proposed for the natural resistance to HIV-1 have included soluble factors with antiviral properties for preventing vertical transmission (28)(29)(30)32,33,54,55).…”

“…In addition, the ∆32 mutation has not been found to confer protection against HIV-1 vertical transmission (22,26,27 response, have strong antiviral activity as a primary function or as a "collateral" effect. At least 5 factors have been identified in the maternal-fetus interface: stromal α-chemokine derived factor-1 (SDF-1) (28), leukemia inhibitory factor (LIF) (29), alloantigenstimulated factor (ASF) (30), RNases associated with human chorionic gonadotropin (hCG) (31)(32)(33) and, most recently, the β and α-defensins (34)(35)(36). Defensins are small cysteine-rich cationic peptides that exhibit antimicrobial activity against a broad spectrum of microorganisms (37).…”

Macrophages and HIV-1: dangerous liaisons

“…Nevertheless, the inhibitory activity of MDC is still controversial, and the mechanism through which MDC inhibits both R5 and X4 isolates also remains elusive Perez-Bercoff et al, 2003). Finally, LIF, a factor that can be released by CD4 + T cells, CD8 + T cells (Metcalf et al, 1990) and monocytes/macrophages (Anegon et al, 1991), inhibits HIV-1 in a tropismindependent manner and is produced at higher concentrations in placentae from nontransmitting HIV-infected women than in placentae from transmitting women (Patterson et al, 2001). Nevertheless, others factors undoubtedly constitute another important component of -MAF‖ activity.…”

Vers une compréhension du mécanisme de transmission du VIH in utero

“…Inversement, les femmes qui, infectées par le VIH, n'ont pas transmis le virus à leur nouveau-né, ont une concentration plus éle-vée de LIF [4]. En conséquence, il semble que les cytokines ou les facteurs de croissance, présents dans l'environnement placentaire et dont l'expression est modulée dans le temps, pourraient jouer un rôle important dans la régulation du cycle de réplication du VIH et la susceptibilité des trophoblastes au VIH.…”

“…Par ailleurs, le risque de transmission augmente de 10% à 15% en cas d'allaitement [1]. Différents facteurs, d'origine maternelle ou virale, peuvent favoriser la transmission mère-enfant du VIH: la charge virale plasmatique, le nombre de lymphocytes T CD4 + , le stade plus ou moins avancé de l'infection par le VIH-1, la présence de maladies concomitantes, l'absence d'anticorps neutralisant le VIH, la malnutrition, ainsi que des facteurs génétiques tels que des mutations dans le corécepteur cellulaire du VIH, une faible production du facteur d'inhibition de la leucémie (LIF) et un polymorphisme HLA mère-enfant réduit [2][3][4]. Le phénotype viral est aussi à prendre en compte dans la transmission [5].…”