Replication-dependent pathogenicity of attenuated nef-deleted HIV-1 in vivo

BACKGROUND: The Sydney Blood Bank Cohort (SBBC) of long-term survivors consists of 8 individuals infected with an attenuated nef-deleted strain of HIV-1 by means of contaminated blood products donated from a common blood donor between 1981 and 1984. We report the outcome of a 26-year prospective study documenting the clinical course of nef-deleted HIV-1 infection in 7 SBBC members. METHODS: CD4 T-cell counts and plasma HIV-1 RNA levels were measured by flow cytometry and the COBAS AMPLICOR HIV-1 monitor version 1 or 1.5 (Roche Molecular Diagnostic Systems, Branchburg, NJ), respectively. Changes in these parameters with time were determined by least-squares analysis using STATA (StataCorp, College Station, TX) statistical software. RESULTS: Four subjects had persistent low-level viremia. Of these, progression to AIDS and/or evidence of CD4 T-cell loss occurred in 3; the fourth viremic individual died of non-HIV-1-related causes in 1995, only 12 years after infection. Three subjects have persistently undetectable plasma HIV-1 RNA levels and remain long-term nonprogressors. CONCLUSIONS: Our study shows that even weakened highly attenuated HIV-1 strains with nef deletions are ultimately pathogenic in humans unless replication is completely and persistently suppressed in vivo. This finding underscores the importance of aiming to achieve nothing less than complete and sustained suppression of HIV-1 replication by antiretroviral drugs and vaccines.