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Following transmission, HIV-1 evolves into a diverse population, and nextgeneration sequencing enables us to detect variants occurring at lowfrequencies. Studying viral evolution at the level of whole genomes washitherto not possible because next generation sequencing delivers relativelyshort reads. We here provide a proof of principle that whole HIV-1 genomes canbe reliably reconstructed from short reads, and use this to study the selectionof immune escape mutations at the level of whole genome haplotypes. Usingrealistically simulated HIV-1 populations, we demonstrate that reconstructionof complete genome haplotypes is feasible with high fidelity. We do notreconstruct all genetically distinct genomes, but each reconstructed haplotyperepresents one or more of the quasispecies in the HIV-1 population. We thenreconstruct 30 whole genome haplotypes from published short sequence readssampled longitudinally from a single HIV-1 infected patient. We confirm thereliability of the reconstruction by validating our predicted haplotype geneswith single genome amplification sequences, and by comparing haplotypefrequencies with observed epitope escape frequencies. Phylogenetic analysisshows that the HIV-1 population undergoes selection driven evolution, withsuccessive replacement of the viral population by novel dominant strains. Wedemonstrate that immune escape mutants evolve in a dependent manner withvarious mutations hitchhiking along with others. As a consequence of thisclonal interference, selection coefficients have to be estimated for completehaplotypes and not for individual immune escapes.

Reliable reconstruction of HIV-1 whole genome haplotypes reveals clonal interference and genetic hitchhiking among immune escape variants