Antibody dependent cellular cytotoxicity and HIV-1 mother to child transmission

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PROJECT SUMMARY Over 150,000 infants acquire HIV-1 from their infected mothers primarily because combination antiretroviral treatment (cART) remains inaccessible in some populations. Surprisingly even in the absence cART, only around 20 – 30% of infants get HIV-1 from their mother although they are constantly exposed to the virus during gestation, birth and breast feeding. Immune factors, such as maternal antibodies, likely prevent transmission. Mother to child transmission (MTCT) cohorts are an ideal way to examine the impact of pre- existing antibodies in preventing HIV-1 transmission in a natural setting because: 1) infants are reliably exposed to the virus; 2) mothers pass their antibodies to the infant; and 3) samples can be obtained from both the mother and the infant prior to and after transmission. Understanding the role of and the types of antibodies that can prevent HIV-1 transmission remains one of the highest priorities especially for vaccine efforts. In contrast to all animal models, MTCT investigations and antibody passive infusion clinical trials demonstrate that pre-existing neutralizing antibodies (nAbs) do not provide significant protection against HIV-1 transmission. The major difference among animal models and HIV-1 transmission is that humans are exposed to a diverse swarm of HIV-1 variants, and some of the strains are neutralization resistant. In setting where the exposed individual already possesses nAbs, they acquire neutralization resistant variants. In contrast, we show that infants with pre-existing antibody dependent cellular cytotoxicity (ADCC) against their mother’s neutralization resistant strains are less likely to acquire HIV-1, and they have lower morbidity up to 1 year after birth in the absence of cART. We have further observed that transmission depends on both the preexisting ADCC breadth and potency in the naïve exposed infant and the ADCC sensitivity of the variants circulating in the maternal variants (exposure strains). We propose to provide more definitive support for the importance of ADCC during MTCT by exploring if newly infected infants acquire ADCC resistant strains. We will further identify host factors and virus characteristics that influence ADCC breadth and potency and ADCC susceptibility. We further hypothesize that ADCC present in infected infants can eliminate cells with infectious virus that can produce virus. Infants with higher ADCC against their autologous virus have a lower number of residual infected cells. A smaller number of infected cells results in lower viremia and plasma inflammation, which decreases morbidity and mortality in the absence of cART. Finally, we will use state of the art techniques to isolate and characterize broad and potent ADCC antibodies. These studies will provide insights about the characteristics of these antibodies and the potential novel ways to elicit them using state of the art vaccine methodologies. The proposed studies will provide clarity about the selection pressure ADCC exerts during transmission, highlight how pre-existing ADCC decreases mortality, and lead to the generation of novel protective antibodies. Cumulatively, this work will provide new strategies for developing an effective HIV-1 vaccine.