Effects of virion surface gp120 density on infection by HIV-1 and viral production by infected cells

The quantity of envelope glycoprotein molecules (Env) on HIV-1 particles is still an issue of debate and, depending on the strain of virus and the nature of the producer cells, it can vary greatly. Here, we have attempted to address how Env density influences HIV-1 fitness. To this aim, we have produced HIV-1-derived viral particles with various amounts of R5 Env (low Env: Envlo; high Env: Envhi), using a regulatable expression system. The infectivity was assayed on human cells, engineered to express the HIV receptor CD4 and the co-receptor CCR5, as well as on peripheral blood lymphocytes and macrophages. In these experiments, low levels of Env were sufficient for cell infection, albeit at low efficiency. Increasing the amount of Env resulted in cooperatively improved infectivity, but a threshold was rapidly attained, indicating that only a fraction of Env was required for efficient infection. Unexpectedly, Env incorporation beyond what gives maximal infection transiently stimulated the expression of proviral genes, as well as retrovirus production, in newly infected cells. This was likely a consequence of induced NF-κB activity, as this transcription factor is triggered by Envhi, but not by Envlo, virions. Thus, our data suggest that one major effect of high Env density on the surface of HIV may not be better infection yields but rather improved viral production by newly infected cells.