Viral phenotypes and antibody responses in long-term survivors infected with attenuated human immunodeficiency virus type 1 containing deletions in the nef and long terminal repeat regions

Abstract

The Sydney Blood Bank Cohort (SBBC) consists of eight blood transfusion recipients infected with nef-attenuated human immunodeficiency virus type 1 (HIV-1) acquired from a single donor. Here, we show that viral phenotypes and antibody responses differ considerably between individual cohort members, despite the single source of infection. Replication of isolated virus varied from barely detectable to similar to that of the wild-type virus, and virus isolated from five SBBC members showed coreceptor usage signatures unique to each individual. Higher viral loads and stronger neutralizing antibody responses were associated with better-replicating viral strains, and detectable viral replication was essential for the development of strong and sustained humoral immune responses. Despite the presence of strong neutralizing antibodies in a number of SBBC members, disease progression was not prevented, and each cohort member studied displayed a unique outcome of infection with nef-attenuated HIV-1.

FIG. 1.

Replication kinetics of SBBC isolates. HIV-1 isolated from members of the SBBC was used to infect selected activated PBMC derived from healthy seronegative donors. Virus replication was measured by cell-free RT activity, and replication of HIV-1_C54IV, HIV-1_C54XV, and HIV-1_C64IV was confirmed by quantitation of extracellular p24 antigen (not shown). The error bars indicate standard deviations.

FIG. 2.

Total IgG responses in individuals infected with nef-attenuated (a) or non-nef-attenuated (b) HIV-1. Total IgG reactivity to HIV-1 lysate in plasma derived from HIV-1-infected individuals was analyzed by Western blotting. Strips were probed with biotinylated anti-human IgG polyclonal antibody and streptavidin-alkaline phosphatase conjugate and visualized using 5-bromo-4-chloro-3-indolylphosphate/nitroblue tetrazolium phosphate substrate (56). Plasma samples are identified by the number of years postinfection (a) or after identification of infection (b) and do not correspond to those used for neutralization assays. Reactivities were compared with those of a recently seroconverted individual (+) and a seronegative individual (−).