Minority Report: Hidden Memory Genomes in HIV-1 Quasispecies and Possible Clinical Implications

The RNA viruses replicate as complex distributions of closely related genomes termed viral quasispecies.The behavior of the evolving quasispecies and its response to selective pressures such asantiviral treatment is influenced by the ensemble of mutants that compose the viral population. Onesuch influence is the presence of minority subpopulations in the mutant spectra of viral quasispecies.Biologically relevant mutants have long been known to be present as minority components ofreplicating viral populations. However, experiments designed with specific mutants of the animalpathogen foot-and-mouth disease virus in cell culture explained the presence of a class of minoritygenomes termed memory genomes. They descend from those variants that were dominant at anearlier phase of quasispecies evolution, and arise as a consequence of quasispecies dynamics, whenviral populations are subjected to discontinuous selective pressures. The presence of memory genomeshas also been documented during intrahost evolution of HIV-1 in vivo. The analysis of sequentialviral samples of different HIV-1-infected patients showed that two distinct types of memory canoperate in retroviruses: a replicative memory analogous to that observed in foot-and-mouth diseasevirus, as well as a reservoir memory derived from the integrative phase of the retroviral lifecycle.Despite being hidden as minority components of the HIV-1 viral population (ranging from about0.1 to 20% of the total number of genomes in the quasispecies analyzed), memory genomes candrive the evolution of the virus during HIV-1 infections under antiviral therapy. The limited availabilityof current experimental data on minority HIV-1 subpopulations in vivo implies that further studiesare required in order to define the cutoffs of clinically relevant minority genomes. Nevertheless, it isalready evident that such low-abundance genomes remain undetectable by traditional genotypingmethods such as consensus sequencing or conventional hybridization techniques. Several experimentalsystems are currently available for the detection and characterization of minority componentsof the mutant spectra of viral quasispecies including HIV, hepatitis C virus and hepatitis B virus.Some of these biotechnological approaches could, in the near future, be taken over and exploited inthe clinical setting as useful biosensors with which to improve the management of HIV-infected patients.