Abstract
Mother-to-child transmission of HIV-1 remains a major global health challenge. Currently, HIV-1-infected infants require strict lifelong adherence to antiretroviral therapy to prevent replication of virus from reservoirs of infected cells, and to halt progression of disease. There is a critical need for immune interventions that can be deployed shortly after infection to eliminate HIV-1-infected cells in order to promote long-term remission of viremia, or to potentially cure pediatric HIV-1-infection. Bispecific HIV × CD3 DART® molecules able to co-engage the HIV-1 envelope protein on the surface of infected cells and CD3 on cytolytic T cells have been previously shown to eliminate HIV-1 infected cells in vitro and are candidates for passive immunotherapy to reduce the virus reservoir. However, their potential utility as therapy for infant HIV-1 infection is unclear as the ability of these novel antibody-based molecules to work in concert with cells of the infant immune system had not been assessed. Here, we use human umbilical cord blood as a model of the naïve neonatal immune system to evaluate the ability of HIV x CD3 DART molecules to recruit and redirect neonatal effector cells for elimination of autologous CD4+ T cells infected with HIV-1 encoding an envelope gene sequenced from a mother-to-child transmission event. We found that HIV × CD3 DART molecules can redirect T cells present in cord blood for elimination of HIV-infected CD4+ T cells. However, we observed reduced killing by T cells isolated from cord blood when compared to cells isolated from adult peripheral blood—likely due to the absence of the memory and effector CD8+ T cells that are most cytolytic when redirected by bispecific DART molecules. We also found that newly developed HIV × CD16 DART molecules were able to recruit CD16-expressing natural killer cells from cord blood to eliminate HIV-infected cells, and the activity of cord blood natural killer cells could be substantially increased by priming with IL-15. Our results support continued development of HIV-specific DART molecules using relevant preclinical animal models to optimize strategies for effective use of this immune therapy to reduce HIV-1 infection in pediatric populations.
Highlights
Despite the effectiveness of perinatal and postnatal antiretroviral prophylaxis, and the relatively low transmission rates of HIV1 in utero, intrapartum, and during breast-feeding, there remain over 160,000 new pediatric HIV-1 infections annually worldwide [1,2,3,4]
We found that HIV × CD16 DART molecules can recruit and redirect natural killer (NK) cells from cord blood to eliminate autologous HIV-infected CD4+ T cells; and we determined that the redirected activity of cord blood NK cells can be substantially increased by priming with IL-15
We and others have demonstrated that bispecific DART molecules able to co-engage HIV-1 Env on infected cells, and CD3 antigen on cytolytic T cells, can be used to eradicate acutely infected and reactivated latently-infected cells in vitro [17, 18]
Summary
Despite the effectiveness of perinatal and postnatal antiretroviral prophylaxis, and the relatively low transmission rates of HIV1 in utero, intrapartum, and during breast-feeding, there remain over 160,000 new pediatric HIV-1 infections annually worldwide [1,2,3,4]. To provide long-term control or cure of pediatric HIV infection and abrogate the need for lifelong viral suppression, early initiation of ART will need to be combined with additional strategies to eliminate HIV-1-infected cells responsible for persistence of the virus reservoir. Bispecific HIV × CD3 DART molecules use a monovalent HIVtargeting arm comprised of the antigen-binding region of mAbs specific for highly conserved regions of the HIV envelope protein (Env) to recognize HIV-1-infected target cells, and a monovalent CD3 binding arm for recruitment of cytolytic T cells. Passive immunization with HIV × CD3 DART molecules could form the basis of a strategy for cure of HIV by combining early initiation of ART to control viral load and reduce the size of the reservoir with concurrent initiation of HIV × CD3 DART molecule immunotherapy to eliminate infected cells. Our data indicate that strategies to optimize and enhance the cytotoxic potential of neonatal effector cells, or allowing additional time after birth for the immune system to develop, will likely be needed to maximize the therapeutic potential of HIV-specific DART molecules for use in pediatric populations
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