While many of the most commonly studied macrophage-tropic SIVs are capable of CD4-independent entry (Table 2), in vitro analyses of SIVsmE543-3, which was derived from a macaque with SIV-induced encephalitis, indicate that this variant is macrophage-tropic but retains the need for CD4 to efficiently enter host cells [15], thus raising the possibility that macrophage-tropic SIVs may either evolve under conditions that select for variants that are CD4-independent or under conditions that select for variants that are dependent on CD4 for efficient entry. This evidence concerns the gene CD4 and viral encephalitis.