I have recently shown that site-specific amino acid marginal fitness is correlated with among-population mean site-specific amino acid frequency in HIV-1. This provides a simple method of estimating site-specific fitness effects. Here, I explore the fitness effects of interactions among sites, that is, fitness epistasis. Analysis of the intensely studied exterior envelope glycoprotein V3 region reveals strong covariation among sites that may be explained by V3 structure. I show how this covariation is related to fitness epistasis and discuss the application of these methods to investigating the adaptive evolution of HIV-1.