Research in the Kwiek Lab focuses on the biology, pharmacology, and public health impact of Human Immunodeficiency Virus (HIV-1). We are currently focusing on three projects.

The biological mechanism of HIV-1 mother-to-child transmission
Approximately 20% of all MTCT occurs in utero, and although many developing countries are testing resource-appropriate MTCT interventions, the vast majority of these strategies will not reduce the frequency of in utero HIV-1 MTCT. Our central hypothesis states that the placenta acts as a virological barrier, allowing only a subset of HIV-1 variants access to the fetus. Using both retrospective and prospective HIV-1 subtype C isolates, we are interrogating the HIV-1 genotypes and phenotypes associated with in utero MTCT. We hypothesize that HIV-1 variants successfully transmitted in utero require phenotypic characteristics that 1) enable efficient replication in the immune-privileged placental milieu, and/or 2) promote penetration/infection of cells prevalent at the maternal-fetal barrier.

The interaction of HIV-1 with host proteins during HIV-1 replication
Owing to the recent setbacks in vaccine and microbicide trails, novel strategies to slow the HIV-pandemic are desperately needed. Development of a small molecule that blocked a host process required for HIV-1 replication could provide such a strategy. Like all retroviruses, HIV-1 requires host proteins to complete its life cycle, and these intracellular host molecules represent an undeveloped pool of novel anti-HIV therapeutics. The goal of this application is to use functional proteomics to identify host proteins that are dispensable to the host but essential for viral replication. A generic proteomic screen would likely identify numerous host proteins induced by HIV-infection, most of which would be poor therapeutic candidates. A functional proteomics screen, which queries a subset of proteins with strong therapeutic potential, would greatly simplify the search for host targets; the host purinome has this potential. The purinome comprises any protein that binds purine-containing molecules (e.g. ATP, NADH), and it includes heat shock proteins, dehydrogenases, and protein kinases. Inhibition of purinome proteins forms the basis of many current therapies, including those targeting cancer, hypertension, and bacterial infections. The central hypothesis of this research states that inhibition of purinome proteins, which are induced or regulated by HIV-infection, will block HIV-1 replication.

Pediatric HIV-1 diagnostics
Despite the evidence that timely antiretroviral treatment (ART) in HIV-infected infants reduced death by approximately 75% (CHER Study, Violari et al., 2009), only 38% of the HIV-infected children in sub-Saharan Africa (SSA) are currently receiving ART (www.unaids.org). The lack of affordable, accessible and accurate HIV-1 infant diagnostic tests is one of the major bottlenecks limiting timely access to ART among children in SSA.

Several published studies have demonstrated the ability of HIV-1 p24 antigen detection assays to diagnose pediatric HIV-infection both from plasma, and dried blood spots from venous blood. Importantly, the p24 assay has been validated against HIV-1 subtype C, which comprises >95% of all HIV-infections in Malawi, and it can be easily adapted to a resource-limited setting. We hypothesize that a simplified p24 antigen assay performed on dried blood spots obtained via heel prick could serve as an accurate, inexpensive, and accessible assay to diagnose pediatric HIV-infection.