The impact of human immunodeficiency virus type 1 entry on drug development, drug resistance and viral fitness

HIV-1 entry is a complex process that involves binding of HIV-1 gp120 to the CD4 receptor, inducing a conformational shift that allows binding to the CCR5 coreceptor. The RANTES derivative are HIV-1 CCR5 binding inhibitors that block coreceptor usage through internalization of the CCR5 receptor, as well as competitive binding. The Partial agonist effects of these compounds can cause stimulation of HIV-1 replication. This mechanism is not due to increased virus entry, reverse transcription, increased receptor expression, or activation of transcription from the HIV-1 LTR. However, an increased amount of integration was detected in AOP-RANTES treated cells that corresponded with induction of the MAPK/ERK signaling pathway. It is our conclusion that AOP-RANTES stimulates a cell signaling event stimulating viral replication, most likely through the mechanism of nuclear translocation.; The diversity observed in the HIV-1 genome limits the study of drug susceptibility, drug resistance, and viral fitness due to the lack of availability of diverse HIV-1 molecular clones. We have devised a unique yeast recombination cloning system that allows for the insertion of any region of the HIV-1 genome into a vector without the use of restriction endonucleases.; This yeast recombination system was used to examine the contribution of HIV-1 env to viral fitness. Prior observations in the laboratory found that HIV-1 subytpe C isolates were much less fit than subtype B isolates in dual competition experiments. We have traced this difference in fitness to early events in the viral lifecycle, indicating that entry is responsible for viral fitness. The yeast recombination system was used to construct chimeric env viruses to determine to what extent env drives fitness. Dual competition experiments yielded nearly identical results to competitions performed with the chimeric virus parental strains. The difference in fitness of the chimeric isolates could only be attributed to the different gp120 regions that had been inserted into an neutral HIV-1 backbone virus. It is our conclusion that the env gene determines fitness of an HIV-1 isolate and may be the primary influence in HIV-1 pathogenicity and susceptibility to entry inhibiting drugs.