The chemokine analog, AOP-RANTES effectively blocks HIV-1 entry into host cells bearing the CCR5 receptor. However, this inhibition is limited to those non-syncytium-inducing (NSI), macrophage (M)-tropic HIV-1 isolates predominating in early HIV-1 disease and responsible for establishing new infections. Syncytium-inducing (SI), T cell lines (TCL)-tropic HIV-1, found in patients with advanced disease, are resistant to this chemokine antagonist. These findings suggest that the administration of AOP-RANTES or other agents that target CCR5 may be useful in post-exposure prophylaxis, in prevention of perinatal HIV-1 infection, or in combination with other anti-retrovirals in the treatment of HIV infected persons harboring NSI strains. As with all HIV-1 chemotherapies, emergence of resistant HIV-1 isolates would lead to increased viral loads and the failure of chemokine analog therapy. Furthermore, we have shown that some primary NSI, M-tropic isolates may be intrinsically resistant to AOP- RANTES. The primary objective of this project will be identification and analysis of both intrinsic and selected resistance by different HIV-1 isolates to chemokine analogs (e.g. AOP-RANTES).
SPECIFIC AIM 1 will screen for chemokine analog-resistance in several primary isolates of various HIV-1 subtypes.
In SPECIFIC AIM 2, we select for AOP-RANTES and chemokine analog resistance in vitro by applying drug pressure to replicating virus. Using the resistant isolates identified in SPECIFIC AIMS 1 and 2, we determine like mechanisms responsible for the decreased sensitivity analogs (SPECIFIC AIM 3). Resistance is likely due to one of two mechanisms, i.e. (i), HIV-1 binding to a new co-receptor which does not interact with chemokine analog and (ii), binding to the same chemokine co-receptor but at site not involved in chemokine analog interactions. Our last objective in SPECIFIC AIM 3 will be the identification of sequences/regions in the HIV-1 envelope glycoprotein responsible for chemokine analog resistance. This analysis of chemokine analog resistance in vitro will benefit future treatment strategies employing chemokine analogs by predicting the pre-existence and emergence of resistant HIV-1 isolates in patients and by identifying the specific changes in HIV-1 associated with this resistance.
