Dynamic range of Nef functions in chronic HIV-1 infection

HIV-1 Nef is required for efficient viral replication and pathogenesis. However, the extent to which Nef's functions are maintained in natural sequences during chronic infection, and their clinical relevance, remains incompletely characterized. Relative to a control Nef from HIV-1 strain SF2, HLA class I and CD4 down-regulation activities of 46 plasma RNA Nef sequences derived from unique chronic infected individuals were generally high and displayed narrow dynamic ranges, whereas Nef-mediated virion infectivity, PBMC replication and CD74 up-regulation exhibited broader dynamic ranges. 80% of patient-derived Nefs were active for at least three functions examined. Functional co-dependencies were identified, including positive correlations between CD4 down-regulation and virion infectivity, replication, and CD74 up-regulation, and between CD74 up-regulation and PBMC replication. Nef-mediated virion infectivity inversely correlated with patient CD4± T-cell count. Strong functional co-dependencies and the polyfunctional nature of patient-derived Nef sequences suggest a phenotypic requirement to maintain multiple Nef functions during chronic infection.

► Comparative functional analysis is performed on plasma HIV-1 RNA-derived Nef sequences from 46 chronic infected individuals.
► Nefs from the chronic stage of HIV-1 infection display a broad dynamic functional range.
► Nefs from the chronic stage of HIV-1 are generally polyfunctional.
► Nef CD74 up-regulation correlates with Nef-mediated viral replication capacity.
► Nef-mediated viral infectivity is inversely correlated with patient CD4+ T-cell count.