Immune correlates of protection against nonprimary congenital cytomegalovirus transmission in an HIV-infected mother-infant cohort

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Immune correlates of protection against nonprimary congenital cytomegalovirus transmission in an HIV-infected mother-infant cohort ABSTRACT Vertical transmission of cytomegalovirus (CMV) is the most common congenital infection worldwide, resulting in deafness and neurodevelopmental delay for affected children. Natural maternal immunity to CMV only partially protects against mother-to-child in utero transmission, and indeed, the majority of congenital CMV (cCMV) transmissions worldwide occur in the setting of preexisting maternal immunity. A vaccine to prevent pregnant women from acquiring CMV or subsequently transmitting the virus to their child in utero has been a top priority for the U.S. National Academy of Medicine for nearly twenty years. However, vaccine development remains impeded by a gap in knowledge of the immune responses that protect again cCMV transmission, particularly in CMV-seropositive women. Chronically CMV-infected, HIV-uninfected mothers transmit CMV in utero at a rate of ~1%, yet CMV/HIV- coinfected mothers transmit CMV at a rate 5- to 10-fold higher. The mechanisms underlying this high incidence of cCMV in HIV-infected women remain underexplored but suggest that impaired CMV-specific maternal immunity may contribute to cCMV transmission. Thus, the high incidence of cCMV among HIV-exposed, uninfected infants provides a unique opportunity to define the maternal immune correlates of protection against cCMV transmission in CMV-seropositive populations. In this study, I propose to study samples from 9 historical cohorts spanning 12 countries of HIV-infected mothers and their HIV-exposed infants to define the maternal CMV-specific humoral and cellular responses associated with protection against cCMV. I hypothesize that the high rate of cCMV transmission in chronically HIV/CMV-infected women is due to reduced maternal immune responses against diverse CMV strains compared to HIV-uninfected women. In this study, I aim to (1) Identify the maternal antibody immune correlates of protection against cCMV in HIV/CMV-coinfected mothers, (2) Identify the maternal cellular immune correlates of protection against cCMV in HIV/CMV-coinfected mothers, (3) Compare the diversity of placentally transmitted CMV variants in HIV-exposed and unexposed infants. By identifying maternal immune correlates of protection against cCMV transmission in CMV-seropositive mothers, this work will provide valuable insight into rational vaccine design for CMV-seropositive populations to reduce the global burden of cCMV.