A potent short hairpin RNA (shRNA734) directed to human Hypoxanthine Guanine Phosphoribosyltransferase (HPRT) improves the rate of gene-modified stem cell engraftment by a conditioning and in vivo selection strategy to confer resistance to a clinically available guanine analog antimetabolite, 6TG, for efficient positive selection of gene-modified stem cells. Uses for polynucleotides comprising the shRNA734 include methods for knocking down HPRT in a cell, for conferring resistance to a guanine analog antimetabolite in a cell, for producing selectable genetically modified cells, for selecting cells genetically modified with a gene of interest from a plurality of cells, for removing cells genetically modified with a gene of interest from a plurality of cells, and for treating a subject infected with HIV.