Evasion of cytotoxic T lymphocytes is a functional constraint maintaining HIV-1 Nef expression

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Abstract
Nef expression is not required for HIV‐1 replication and is highly targeted by CD8+ CTL, raising the question of why Nef expression is not lost in order to evade immunity in vivo. We explore whether MHC class I (MHC‐I) down‐regulation to evade CTL in general is a selective pressure maintaining Nef. HIV‐1 with functional Nef (wild type, WT) is compared to virus containing a Nef point mutation (M20A) that selectively ablates MHC‐I down‐regulation. WT‐infected cells are relatively resistant to cytolysis and less suppressed for viral replication by Gag‐ and RT‐specific CTL compared to M20A. These viruses grow similarly in vitro in the absence of CTL, but the presence of Gag‐ or RT‐specific CTL strongly favors WT overgrowth of M20A. Finally, while in vitro selection by Nef‐specific CTL readily drives disruption of the nef reading frame, the addition of Gag‐ or RT‐specific CTL markedly limits such escape. These data indicate that MHC‐I down‐regulation is an important function favoring Nef maintenance due to a net selective advantage in the setting of the general CTL response.