We investigated the potential involvement of BTBD1 and BTBD2 in restricting HIV-1 infection based on the observations that: 1) BTBD1 and BTBD2 co-localize with TRIM5δ [13], a splice variant of TRIM5α; 2) hu-TOP1 residues E236/N237 are required for the infectivity enhancement provided to virions by the expression of hu-TOP1 in AGM virion-producer cells; and, 3) these same human residues are required for the physical interaction of hu-TOP1 with BTBD1 and BTBD2. This evidence concerns the gene BTBD2 and HIV-1 infection.