FUNCTIONAL-CHARACTERIZATION OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 NEF GENES IN PATIENTS WITH DIVERGENT RATES OF DISEASE PROGRESSION

We have studied the sequence and function of the human immunodeficienc y virus type 1 (HIV-1) nef genes from nine patients with highly diverg ent rates of disease progression enrolled in a longitudinal study of H IV disease. Over an average of 7.8 years of follow up, three patients had net positive changes in CD4(+) T-cell counts, three patients had n et negative changes in CD4(+) T cells but did not develop AIDS, and th ree patients progressed to AIDS. The nef gene from each of these patie nts was amplified and cloned, and the sequence of 8 to 10 clones was d etermined. Only 2 of 88 (2.3%) nef genes recovered from these nine pat ients were grossly defective. Moreover, there was no relationship betw een the phylogeny of nef sequences and the corresponding rates of dise ase progression from these patients. Representative nef genes from all nine patients were tested for their abilities to downregulate cell su rface CD4 in a transient-transfection assay. There was no correlation found between the functions of the nef genes from these patients and t heir corresponding rates of disease progression. We conclude that the nef gene is not a common mediator of the rate of HIV disease progressi on in natural infection.