Presented at the Neonatal Society 2005 Spring Meeting.
Gaiha GD, Clark HW
MRC Immunochemistry Unit, Department of Biochemistry, University of Oxford, Oxford OX1 3QU
Perinatal transmission of human immunodeficiency virus (HIV) has been shown to be markedly higher in infants born prematurely (< 30 weeks) (1). The innate immune collectins surfactant protein A and D (SP-A, SP-D) are known to be deficient in premature infants. The recent discovery that SP-D is expressed in the female genital tract (2) and the identification of SP-A as an important hormonal signal for parturition (3) further supports the need to understand the possible role of these proteins in foetal immune defense (3). We hypothesized that these innate immune molecules may interact with HIV and potentially have a role in helping prevent perinatal HIV transmission. To test this we investigated biochemical interactions between SP-A and SP-D with the gp120 protein of HIV, using surface plasmon resonance (BIACORE). Our data reveals a novel interaction between SP-A and SP-D and gp120 from both X4 and R5 HIV strains. The binding of SP-A and SP-D to gp120 was Ca2+-dependent and inhibitable by EDTA. Surface plasmon resonance analyses and competition of the SP-A and SP-D interaction with gp120 by various hexoses suggested that binding occurs via the C-type lectin activity of the carbohydrate recognition domains. Consistent with this, we observed decreased SP-A and SP-D binding to endoglycosidase H treated gp120 which suggests that high mannose structures are the major collectin binding sites on gp120. To assess the possible functional significance of these interactions, we investigated the effect of binding by collectin on the interaction between HIV gp120 and CD4, the principal target for HIV infection on lymphocytes. Competition of gp120-CD4 interactions by SP-A and SP-D revealed that SP-A inhibits CD4 binding to gp120 by 80% at physiological concentrations, whereas SP-D had no effect. In addition, SP-A inhibits free gp120 binding to CD4 by > 50% whereas SP-D enhanced binding of gp120 to CD4. Collectively, these results suggest that release of SP-A during parturition may support a powerful innate immune defense mechanism to HIV that is relatively deficient in prematurely born infants. Low levels of SP-A in the prematurely delivered infant may contribute to the higher perinatal HIV transmission rates seen in this population.
References
1. European Collaborative Study. Lancet 1992; 339: 1007-12.
2. Leth-Larsen R . et al Mol Hum Reprod. 2004 Mar;10(3):149-54.
3. Condon JC, P Jayasuria, JM Faust, and CR Mendelson, Proc Natl Acad Sci USA 2004; 101: 4978-83.