Envelope-dependent restriction of human immunodeficiency virus type 1 spreading in CD4(+) T lymphocytes: R5 but not X4 viruses replicate in the absence of T-cell receptor restimulation

The human immunodeficiency virus (HIV) replicates in activated CD4(+) T lym phocytes. However, only CD4(+) Th2 and Th0, but not Th1, CD4(+) T-cell clon es have been reported to efficiently support HIV-1 replication. This dichot omous pattern was further investigated in the present study in Th1, Th2, or Th0 cell lines derived from umbilical human cord blood and in T-cell clone s obtained from the peripheral blood mononuclear cells (PBMC) of healthy ad ults. Both primary and laboratory-adapted HIV-1 strains with CCR5 as the ex clusive entry coreceptor (R5 viruses) efficiently replicated in Th1, Th2, a nd Th0 cells, In sharp contrast, CXCR4-dependent (X4) viruses poorly replic ated in both polarized and unpolarized CD4(+) T cells, including adults' PB MC infected several days after mitogenic stimulation. Unlike the X4 HIV-1(N L4-3), a chimera in which the env gene had been replaced with that of the R 5 HIV-1(NL(AD8)), efficiently replicated in both Th1 and Th2 cells. This X4 -dependent restriction of HIV replication was not explained by either the a bsence of functional CXCR4 on the cell surface or by the inefficient viral entry and reverse transcription. T-cell receptor stimulation by anti-CD3 mo noclonal antibodies fully rescued X4 HIV-1 replication in both Th1 and Th2 cells, whereas it did not alter the extent and kinetics of R5 HIV-1 spreadi ng. Thus, R5 HIVs show a replicative advantage in comparison to X4 viruses in their ability to efficiently propagate among suboptimally activated T ly mphocytes, regardless of their polarized or unpolarized functional profiles . This observation may help to explain the absolute predominance of R5 HIVs over X4 viruses observed after viral transmission and during early-stage d isease.