131 Characteristics of Transmitted Founder Viruses

Abstract

The predominant mode of HIV-1 infection is heterosexual transmission, where a genetic bottleneck is imposed on the virus quasispecies, and in a majority of cases a single genetic variant is transmitted. Transmitted, subtype C founder viruses exhibit reduced Env glycosylation, a requirement for high levels of CD4 and CCR5, and infect macrophages with low efficiency. Cellular immune responses in the transmitting partner can impact the replicative phenotype of the transmitted variant by driving the selection of deleterious HLA-associated polymorphisms. The transmission of a virus containing multiple HLA-I associated polymorphisms within Gag CTL epitopes results in a lower early set-point viral load. This appears to reflect the reduced ability of the virus to replicate, since a statistically significant correlation was observed between the in vitro replicative capacity of more than 150 MJ4 proviruses, engineered to contain individual founder gag genes, and the set-point viral load in the linked recipients. For a majority of the viruses, replicative capacity is directly correlated to the number of non-compensatory HLA associated polymorphisms in Gag. Defining regions of Gag that are structurally constrained and result in a high fitness cost when mutated will be integral to understanding how the cellular immune response can effectively suppress HIV replication.