Clade C strains predominant in developing African countries, where maternal HIV transmission cannot be prevented with AZT. We seek to develop passive + active immunization strains intrapartum HIV clade C transmission. In Project 2, we will focus an passive immunization. Using a combination of 3 neutralizing human IgG monoclonal antibodies (mAbs), we have achieved solid protection of neonatal macaques against mucosal (oral) SHIV-vpu+ challenge and partial protection against pathogenic against pathogenic SHIV89.6P challenge. While these results are encouraging, they were generated with chimeric viruses encoding clade B env genes. Project 2 will develop passive immunization with synergistic human C infection as test virus in primates.
The Specific Aims are to: 1. Find synergistic human mAbs combinations against primary clade C strains isolated from 2- to 4- month old infants. 2. Determine whether human mAbs that neutralize primary pediatric clade C isolates can inhibit SHIVenvC1 synergistically when used in combination. SHIVenvC1, the test virus encoding env of a primary pediatric HIV clade C isolate, will be constructed by ore B. Its neutralization profile will be compared to a panel of primary pediatric HIV isolates. 3. Test whether prophylaxis with the most potent combination of 3 or more neutralizing human mAbs can protect neonatal macaques against mucosal SHIVenvC1 challenge. 4. Evaluate the most potent combination of human neutralizing mAbs for its ability to protect neonatal macaques against systemic infection after mucosal challenge with SHIVenvC1. With this post-exposure mAb prophylaxis study, we mimic the real life situation of intrapartum virus exposure. 5. Test whether passive immunization with the most potent combination of human neutralizing mAbs+ active vaccination with a DNA prime/protein boost strategy (developed by Project 3) can protect macaque infants challenged orally at birth with SHIVenvC1. Active + passive immunization will be started post challenge. It protection is seen, a second virus challenge will be given a few months later to model late mother-infant HIV transmission through breast feeding. The proposed experiments are highly significant because they seek to develop immunoprophylaxis against maternal HIV transmission in a region of the world where the AIDS epidemic rages out of control.
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