(A) Schematic of extended model built to examine the outcome of the evolutionary conflicts. Two HIV strains with different η values compete for transmission across a TIP-exposed population (Eqs. 100–104 in ). When multiple HIV strains co-infect the same individual, the HIV strain with highest η outcompetes all other HIV strains due to its higher replicative fitness (see ); this host-level outcome occurs rapidly compared to dynamics on the population-scale (enabling a time-scale separation). (B) Projected spread of HIV mutants with reduced η values across a TIP-treated HIV population. The wild-type HIV strain has ηwt = 2 and the mutant HIV strain has ηmut = 1. The inter-scale evolutionary conflict is only present when co-infection of an individual host (by both wild-type and mutant HIV strains) is allowed. Co-infection enables host-level selection against the mutant HIV strains with decreased values of η, because of their decreased replicative fitness (despite their population-level transmission advantage). The intra-scale conflict is only significant when P > 3. For example, at P = 2.5, decreasing η results in major increases in transmission from TIP+ individuals () that overwhelm the modest decreases in transmission from TIP- individuals, essentially removing the evolutionary conflict at the population-scale. In contrast, at P = 6, decreasing η causes comparable and opposing changes in transmission rates from TIP+ and TIP− individuals (). Overall, the presence of either co-infection or TIP stability (P > 3) is sufficient to decrease the level of mutant spread, but in the presence of both conflicts, HIV mutants with reduced η are completely prevented from spreading. (C) Pairwise invasability plot showing the initial expansion or contraction rate of a mutant HIV strain (ηmut) upon introduction into a population infected with both TIP and wild-type HIV (ηwt). Each HIV mutant and HIV wild-type combination is represented by an (ηmut, ηwt) point on the plane. At each point, the color of the heatmap shows the maximal expansion rate (i.e., eigenvalue of the Jacobian) for the mutant strain, across all P > 3. The maximal eigenvalue represents the worst-case scenario, when the mutant spreads most easily. When P > 3, the only mutants that can grow are those with ηmut > ηwt. Thus, HIV appears unable to unilaterally mutate away from TIP control by reducing its production of trans elements (i.e., starving the TIP), when TIPs are engineered with P > 3.