The Impact of CD8 T Cells on Viral Control and Evolution in HIV-Infected Infants
In HIV-infected adults, expression of particular class I HLA molecules is associated with an enhanced ability to control HIV that is evident during the earliest stages of infection, while other alleles are associated with rapid progression to AIDS. These data suggest an important role for the CDS T cell response in establishing viral containment. Although extensive studies have been performed to characterize the CDS T cell response to HIV in adults, the mechanism underlying the critical influence of HLA remains unclear. Mother-to-child transmission of HIV affords several advantages as a model in which to define the immune correlates of viral control during acute infection, and the impact of viral escape mutations on containment of HIV. Vertical infection is a predictable event, enabling prospective study of the infant T cell response from the earliest stages of infection. Moreover study of haploidentical mother-infant pairs permits comparison of the consequences of transmitted maternal escape mutations within epitopes restricted by shared and unshared HLA alleles. Although the ability to contain HIV viremia during early infancy is a strong predictor of survival, little information is available regarding the epitope specificity and functional characteristics of HIV-specific T cells in infants. The overall aim of the proposed studies is to define the correlates of CDS mediated immune control, or lack thereof, following vertical transmission of HIV. We will characterize the CDS T cell responses associated with successful and unsuccessful restriction of viral replication during early perinatal HIV infection, focusing on alleles that are associated with slow and rapid progression in clade B infection. Current methods based on multiparameter flow cytometry will allow us to dissect virus-specific T cell responses of infants in unprecedented detail, as they permit simultaneous assessment of multiple T cell functions using very small samples. In addition, we will determine the extent to which CDS T cell responses select for viral escape mutations during acute perinatal infection, and assess the impact of these mutations on the ability of infants to control viremia. Finally, we will examine the impact of transmitted maternal escape mutations on the CDS response and viral containment in the vertically infected infant. Determination of the frequency with which maternal escape mutations revert following vertical transmission could provide a means to estimate the probable impact of CDS escape on viral evolution at the population level. Moreover, epitopes that rapidly revert to wild-type following transmission represent attractive vaccine targets due to their ability to induce fitness-attenuating viral mutations, as well as the likelihood that they will continue to propagate in the population as the virus evolves.