Interdisciplinary Training

Dara Lehman

"The Emergence and Persistence of Antiretroviral Resistant HIV-1 Variants"

In resource-poor settings, where formula-feeding is not recommended due to the lack of access to clean water, transmission through breast milk contributes to over one-third of infant HIV infections. The use of short-course antiretrovirals to reduce breastfeeding transmission is currently being studied. An important consideration, however, is that short-course regimens many lead to the emergence of antiretroviral-resistant mutations that compromise the effectiveness of subsequent treatment for the mother or infant. Here we propose to study the emergence and persistence of antiretroviral-resistant virus in breast milk of HIV+ women in Kenya, where subtypes A, D and C are prevalent. Initially, I will sequence dominant virus variants (>20% of the patient's viral population) to determine the prevalence of resistance in women treated with short-course regimens. Concurrently, I am developing a high-throughput assay to detect rare drug-resistant variants of subtypes A, D and C. The assay utilizes a variation of allele-specific PCR with a goal of detecting one copy of mutant virus in 102-103 copies of wild-type virus. The approach has been successful for a subtype A variant, and I am optimizing it for use across subtypes D and C. With this sensitive assay, I will track the temporal dynamics of resistance in both women and infants after various short-course regimens. These studies will help provide guidance in the design of antiretroviral regimens to reduce breast milk transmission while maintaining the effectiveness of existing drugs.

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