Recent comments by Noursadeghi et al. show that HIV-1 BaL establishes uniform infection of monocyte-derived macrophages (MDM) and does not induce apoptosis or necrosis based on cell viability and genomic transcriptional profiling (1). These comments, together with our recent publications (2, 3), highlight the dynamic process of HIV-1 infection of macrophage populations. HIV-1 establishes a reservoir of infection in macrophages that may contribute to viral persistence in vivo (4, 5, 6). However, we have extensively studied macrophage apoptosis in vitro and found remarkable cytopathy and apoptosis 5–7 days after infection, the peak of productive infection in our MDM system (2). Accordingly, HIV-1 does not induce significant apoptosis at earlier time points (<3 days) except following stimulation with recombinant human TRAIL (3). We have also compared primary HIV-1 isolates with laboratory strains, and a similar course of infection and cell loss were found (Fig. 1). The data presented by Noursadeghi et al. raise a few questions such as whether typical syncytia were observed in MDM following infection with BaL (not apparent in provided image), whether cell viability and genomic transcriptional profiling was performed throughout the infection course, and whether DNA fragmentation was absent throughout the course of infection. One additional point is that in vitro HIV-1 infection is unlikely to be a “uniform” process, where all cells in the culture are in the same status of infection, but rather a heterogenous culture of variably infected primary cells, particularly early in the infection.

FIGURE 1.

Primary and laboratory-adapted HIV-1 clade B replication in human MDM. HIV-1 clade B isolate titration was determined with a standard 50% tissue culture-infective dose (TCID50) assay using TZM-bl cells obtained through the National Institutes of Health AIDS Research and Reference Reagent Program (78 ). This titration was used to ensure an equal infection of human MDM (400 TCID50/ml) assay when viral strains derived from either patient sources or adapted in the laboratory were used. A, Supernatant was collected on days 4–21 from MDM infected with HIV-1ADA and clade B primary isolate D02-2562 BG. Viral infection was monitored by reverse transcriptase activity assay and results are presented as cpm/ml (×105). B, Cell viability was determined by MTT assay and results are normalized as the percentage of viable cells compared with day-matched control MDM. Data are the means ± SD of triplicate samples and are representative of three independent experiments.

FIGURE 1.

Primary and laboratory-adapted HIV-1 clade B replication in human MDM. HIV-1 clade B isolate titration was determined with a standard 50% tissue culture-infective dose (TCID50) assay using TZM-bl cells obtained through the National Institutes of Health AIDS Research and Reference Reagent Program (78 ). This titration was used to ensure an equal infection of human MDM (400 TCID50/ml) assay when viral strains derived from either patient sources or adapted in the laboratory were used. A, Supernatant was collected on days 4–21 from MDM infected with HIV-1ADA and clade B primary isolate D02-2562 BG. Viral infection was monitored by reverse transcriptase activity assay and results are presented as cpm/ml (×105). B, Cell viability was determined by MTT assay and results are normalized as the percentage of viable cells compared with day-matched control MDM. Data are the means ± SD of triplicate samples and are representative of three independent experiments.

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HIV-1 alters apoptotic processes in host cells in an effort to survive and proliferate. As stated by Cui et al.: “a large number of macrophages in the brain and lung are infected with HIV-1 during late stage disease. Although macrophages are usually resistant to HIV-1-mediated cell death, targeted cell death of infected macrophage in tissue is likely a host immune response … ” (2). Studies have shown that HIV-encoded proteins are able to manipulate apoptotic pathways, modifying the cellular machinery that regulates host cell death in either a pro- or anti-apoptotic manner (9). RNA transcription in infected macrophages indicates a conflicted state where proapoptotic and antiapoptotic cascades are modified as the cells respond to HIV infection. Death factors such as TRAIL, TNF, and Fas are up-regulated and the anti-apoptotic factors BCL-2, NAIP, and Akt-3 are significantly down-regulated 5 days postinfection, but survival factors including XIAP, MDM2, and SOD2 are up-regulated (N. Erdmann et al. manuscript in preparation). The MDM system represents a unique model of HIV-1 infection, allowing the evaluation of human cells and various isolates of HIV-1. Study of the survival-apoptotic equilibrium in HIV-1-infected MDM should continue, and identifying a comprehensive list of factors and cascades could bring further understanding of HIV-1 pathogenesis. Although macrophages in vivo are resistant to induction of apoptosis, the clinical course of disease may be subject to modification with appropriate intervention of macrophage survival.

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