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. 1999 Sep;73(9):7515-23.
doi: 10.1128/JVI.73.9.7515-7523.1999.

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

E Vicenzi  1 , P P Bordignon, P Biswas, A Brambilla, C Bovolenta, M Cota, F Sinigaglia, G Poli
Affiliations

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

E Vicenzi et al. J Virol. 1999 Sep.

Abstract

The human immunodeficiency virus (HIV) replicates in activated CD4(+) T lymphocytes. However, only CD4(+) Th2 and Th0, but not Th1, CD4(+) T-cell clones have been reported to efficiently support HIV-1 replication. This dichotomous 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 clones obtained from the peripheral blood mononuclear cells (PBMC) of healthy adults. Both primary and laboratory-adapted HIV-1 strains with CCR5 as the exclusive entry coreceptor (R5 viruses) efficiently replicated in Th1, Th2, and Th0 cells. In sharp contrast, CXCR4-dependent (X4) viruses poorly replicated in both polarized and unpolarized CD4(+) T cells, including adults' PBMC infected several days after mitogenic stimulation. Unlike the X4 HIV-1(NL4-3), a chimera in which the env gene had been replaced with that of the R5 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 absence of functional CXCR4 on the cell surface or by the inefficient viral entry and reverse transcription. T-cell receptor stimulation by anti-CD3 monoclonal 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 spreading. Thus, R5 HIVs show a replicative advantage in comparison to X4 viruses in their ability to efficiently propagate among suboptimally activated T lymphocytes, 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 disease.

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Figures

FIG. 1
FIG. 1
R5 but not X4 laboratory-adapted HIV-1 strains replicate in Th1 and Th2 CB lines and T-cell clones. All cells were infected with equal amounts of RT activities of laboratory-adapted BaL (R5) (●) and LAI/IIIB (X4) (○). Ten independent experiments were performed, with similar results.
FIG. 2
FIG. 2
R5 but not X4 primary HIV-1 isolates replicate in Th1 and Th2 CB lines and T-cell clones. HIV isolates were obtained from infected individuals and characterized for MT-2 cell tropism and chemokine receptor usage, avoiding further in vitro passages. This experiment is representative of four independently performed. ●, BER (R5); ○, BON (X4).
FIG. 3
FIG. 3
R5 but not X4 HIVs replicate in unpolarized T cells. (A) Three independent cell clones from a single donor were infected by equal amounts of virus. Solid symbols, BAL (R5); open symbols, LAI/IIIB (X4). (B) CB cells were stimulated by PHA and IL-2 without Th1 or Th2 polarizing stimuli and maintained in IL-2-enriched medium. When restimulated with PMA and ionomycin, these cells coexpressed both IFN-γ and IL-4. These cells were infected with the laboratory-adapted strains LAI/IIIB (○) and BaL (●) and with the primary X4 BON virus (□).
FIG. 4
FIG. 4
Long-term culture of PHA-activated PBMC (PHA blasts) results in loss of X4 virus replication and persistent R5 production. PBMC were freshly isolated from an individual and stimulated with PHA. At 3 days after stimulation, cells were washed and resuspended in an IL-2-enriched medium. Cells were immediately infected with either LAI/IIIB or BaL or were left uninfected in culture for an additional 4 or 8 days, respectively, at which time points they were infected with the same MOI of both viruses.
FIG. 5
FIG. 5
A virus chimeric for R5 Env acquires the ability to efficiently replicate in Th1 or Th2 cells. Th1 and Th2 CB lines were infected with comparable amounts of NL4-3 (X4) (Th1 [○] and Th2 [□] or its chimera NL(AD8) (Th1 [●] and Th2 [▴]). Five independent experiments provided similar results.
FIG. 6
FIG. 6
Expression of functional CXCR4 molecules on Th1 and Th2 CB lines. (A) Comparable expressions of CXCR4 and IL-8, but lack of SDF-1 expression, were observed in CB lines of Th1 or Th2 phenotype. (B) Chemotaxis of Th1 and Th2 cells to exogenous SDF-1. Both types of cells show a comparable concentration-dependent response to the chemokine.
FIG. 7
FIG. 7
Lack of X4 HIV spreading among Th1 and Th2 CB lines. Comparable levels of HIV DNA from X4 and R5 HIV are retrotranscribed in both cell types up to 72 h postinfection, after which only R5 viruses efficiently propagated in the cell cultures.
FIG. 8
FIG. 8
Anti-CD3 MAb reactivation of X4 virus replication. CB lines were infected and were either left unstimulated (○) or were stimulated with mitogenic concentrations of anti-CD3 mAb (●). No substantial effects were observed upon infection by R5 viruses, whereas a potent upregulation of viral replication occurred in X4-infected cells.
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