Genetically and epidemiologically related "non-syncytium-inducing" isolates of HIV-1 display heterogeneous growth patterns in macrophages

The objective of this study was to identify phenotypic parameters that could distinguish among seemingly homogeneous non-syncytium-inducing (NSI) viruses and that might provide a surrogate marker for clinical progression in pediatric human immunodeficiency virus type 1 (HIV-1) infection. We undertook a pilot analysis of 15 independent HIV-1 isolates collected prospectively from two mothers and their four children who displayed a spectrum of disease stages ranging from CDC categories A1 to C3. Viruses were evaluated for their ability to replicate in primary cells (including monocyte-derived macrophages MDM]) and cell lines, for their co-receptor preference and for genetic features of the V3 hypervariable domain of env. Virtually all isolates displayed NSI phenotypes that were restricted in their capacity to replicate in cell lines and displayed V3 loops with uniformly low net positive charges. NSI viruses from two symptomatic children and one mother were macrophage-tropic, whereas NSI isolates from two asymptomatic children were unable to replicate in MDM and were designated primary lymphotropic viruses. Only one isolate was syncytium-inducing (SI), replicated in a variety of cell lines and in MDM, used multiple co-receptors, and was dual tropic, rather than a mixture of T-cell tropic and M-tropic viruses, as assessed by genetic analysis. Phenotypic heterogeneity among NSI viruses is revealed in the ability of isolates to replicate in MDM. This characteristic is related to disease stage and provides a potentially new in vitro criterion to distinguish among NSI isolates that is unlinked to other surrogate markers.