IL-7 is a potent and proviral strain-specific inducer of latent HIV-1 cellular reservoirs of infected individuals on virally suppressive HAART - PubMed (original) (raw)

. 2005 Jan;115(1):128-37.

doi: 10.1172/JCI22574.

Yan Xu, Julie Sullivan, Emily Souder, Elias G Argyris, Edward A Acheampong, Jaime Fisher, Maria Sierra, Michael M Thomson, Rafael Najera, Ian Frank, Joseph Kulkosky, Roger J Pomerantz, Giuseppe Nunnari

Affiliations

IL-7 is a potent and proviral strain-specific inducer of latent HIV-1 cellular reservoirs of infected individuals on virally suppressive HAART

Feng-Xiang Wang et al. J Clin Invest. 2005 Jan.

Abstract

The persistence of HIV-1 in virally suppressed infected individuals on highly active antiretroviral therapy (HAART) remains a major therapeutic problem. The use of cytokines has been envisioned as an additional therapeutic strategy to stimulate latent proviruses in these individuals. Immune activation therapy using IL-2 has shown some promise. In the present study, we found that IL-7 was significantly more effective at enhancing HIV-1 proviral reactivation than either IL-2 alone or IL-2 combined with phytohemagglutinin (PHA) in CD8-depleted PBMCs. IL-7 also showed a positive trend for inducing proviral reactivation from resting CD4(+) T lymphocytes from HIV-1-infected patients on suppressive HAART. Moreover, the phylogenetic analyses of viral envelope gp120 genes from induced viruses indicated that distinct proviral quasispecies had been activated by IL-7, as compared with those activated by the PHA/IL-2 treatment. These studies thus demonstrate that different activators of proviral latency may perturb and potentially deplete only selected, specific portions of the proviral archive in virally suppressed individuals. The known immunomodulatory effects of IL-7 could be combined with its ability to stimulate HIV-1 replication from resting CD4(+) T lymphocytes, in addition to other moieties, to potentially deplete HIV-1 reservoirs and lead to the rational design of immune-antiretroviral approaches.

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Figures

Figure 1

Figure 1

Phylogenetic analyses of HIV-1 envelope gene sequences of proviral DNA and cytokine-induced virion RNA from the same cell populations. The full-length of gp120 V1 to V5 regions were cloned and sequenced directly from proviral DNA of PBMCs and purified, resting CD4+ T lymphocytes, and IL-7 or PHA/IL-2–induced virion RNA for 4 patients (numbers 1–4, A–D). Proviral DNA sequences are presented by black stars (open stars for those strains from PBMC and filled for those of resting CD4+ T lymphocytes). IL-7–induced viral RNA sequences are indicated by blue squares (open squares for PBMC and IL-7–induced and filled squares for resting CD4+ T lymphocyte and IL–induced). PHA/IL-2–induced viral RNA sequences are indicated by red circles (open circles for those induced by PBMC with PHA/IL-2 and filled circles for those induced by resting CD4+ T- lymphocyte with PHA/IL-2). Growth of patient 4’s virus from PBMCs with PHA/IL-2 was from 10/04/2001. All sequences are shown with HXB2 (GenBank accession no. K03455) as the reference outgroup. Branch lengths are drawn in proportion to the number of nucleotide substitutions per site, and bootstrap probabilities (1,000 iterations) exceeding 70% for each node are noted.

Figure 2

Figure 2

Stimulatory patterns of resting CD4+ T lymphocytes by IL-7. (A and B) Detection of cell activation markers in IL-7–treated or PHA/IL-2–treated human resting CD4+ T lymphocytes. Freshly isolated resting CD4+ T lymphocytes stimulated with IL-7 or PHA/IL-2 were stained with FITC-conjugated anti–KI-67, anti–HLA-DR, and PE-conjugated anti-CD25. Three independent experiments were performed, of which one representative is illustrated. Gm, geometric mean; CV, coefficient of variance. (C) Effects of IL-7 on the cell cycle of human peripheral blood resting CD4+ T lymphocytes. IL-7 alone or PHA/IL-2–stimulated, initially resting CD4+ T lymphocytes are shown with the cell-cycle status indicated in each quadrant. DNA is depicted on the vertical axis and RNA is shown on the horizontal axis. Positions indicating stages in the cell cycle are illustrated in the third panel. The cell cultures either alone or in the presence of IL-7 were continued for a full 7 days. PHA/IL-2–stimulated cells were treated with PHA (5 μg/ml) for 48 hours and then IL-2 (10 ng/ml) for 3 days.

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