The overall goal of this proposal is to determine whether neutralizing antibody plays a significant role in limiting the establishment of infection in perinatal transmission of HIV. This is an important question, because if such a correlation can be established, novel strategies for augmenting humoral responses during pregnancy can be attempted. Clinical studies have established the importance of plasma virus load in the pregnant mother at the time of birth, but virus load levels alone are not sufficient to explain all transmission. The establishment of a relevant animal model for transmission would complement clinical studies by allowing variables to be controlled and tested individually. To address this question, we plan to establish a maternal-infant transmission model in M. nemestrina using the pathogenic chimeric virus SHIVSF162P. SHIVSF162P utilizes the chemokine receptor CCR5 and was developed by serial passage in M. mulatta. Infection results in high primary viremia, high persistent virus load and gradual CD4+ cell decline within the first year of infection.
In Aim 1, they will determine the transmission rate of pathogenic SHIV from dams to infants born by vaginal delivery and allowed to suckle for three weeks. Viral load as a cofactor in transmission will be scored by measuring maternal and infant plasma viral loads in transmitter and non-transmitter mother-infant pairs. Naturally arising antiviral antibody produced in the mother and passively transferred to the fetus and infant will be measured to determine if this is a cofactor in transmission. The hypothesis formulated is that high titer neutralizing antibody (Ab) present prior to and during parturition and during the first two weeks after birth will effectively prevent the establishment of infection in HIV-exposed infants. The mAb IgG1-b12 has broadly neutralizing activity against many HIV-1 primary isolates as well as SHIVSF162P and will be used in all the studies proposed.
In Aim 2, this mAb will be administered to uninfected dams near term to establish half-life and in vivo concentrations of passively transferred Ab and levels of transplacental Ab in their newborns.
In Aim 3, we will define the effective dose and regimen for mAb IgG1-b12 in preventing the establishment of oral infection with pathogenic SHIV in newborn M. nemestrina.
In Aim 4, pregnant dams will be infected during the third trimester and dosed twice prior to birth; newborns will be given two additional doses. These experiments, if successful, will help establish a perinatal transmission model in primates.
