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JAIDS Journal of Acquired Immune Deficiency Syndromes:
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Interleukin-7 Induces HIV Type 1 Outgrowth From Peripheral Resting CD4+ T Cells

Lehrman, Ginger BS*; Ylisastigui, Loyda PhD*; Bosch, Ronald J. PhD†; Margolis, David M. MD*‡

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*Division of Infectious Diseases, Department of Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390; † Harvard School of Public Health, Boston, MA; ‡ North Texas Veterans Health Care Systems, Dallas, TX

To the Editor:

We confirm that interleukin (IL)-7 is a viable clinical candidate for use in inducing expression of latent HIV in resting CD4+ cells obtained from highly active antiretroviral therapy (HAART)-treated, aviremic, HIV-infected adults.

Thus far, no one with HIV infection has been cured, despite the availability of potent antiretroviral agents. Nevertheless, cure of infection is the ultimate goal of any antimicrobial therapy. Although eradication of HIV infection is currently regarded as unattainable, advances in the understanding of HIV pathogenesis have led many to reevaluate the obstacles to the clearance of virus.

Eradication of HIV seems to be prevented by several factors, chief among them the presence of a stable population of long-lived quiescently infected CD4+ T cells. 1–5 Suppression of plasma viremia is achieved with the use of HAART; however, cessation of therapy uniformly results in the return of virus, thought to be primarily derived from these persistently infected resting memory T cells. 6–12 The generation of latency occurs after HIV infection of a transcriptionally active cell, which predominantly results in productive infection and cell death. If cellular transcription ceases before either viral or immunologic cytopathic effects, however, the virus can become dormant. 13–17

New treatment paradigms are needed to target and clear persistent infection in this latent viral reservoir. Such strategies must neither reduce immune function nor propagate new infection. Using a SCID-hu mouse model, Scripture-Adams et al 18 demonstrated that IL-7 stimulation of primary human T cells and thymocytes induced substantial expression of latent HIV while having minimal effects on cell phenotype. Latently infected T cells in this model system are derived from naive CD4+ cells, whereas most latently infected cells in HIV-infected individuals are resting memory CD4+ cells. As reported by Pier-son et al, 19 latent infection is up to 30-fold more frequent in the memory T-cell population.

Because phase 1 studies of the administration of IL-7 to HAART-treated HIV-infected patients are now being planned, we sought to test whether IL-7 allowed the recovery of HIV from peripheral cells of HIV-infected patients in whom viremia is suppressed by HAART. Resting memory CD4 cells would be expected to represent most of the latently infected cells in the peripheral blood of such patients. We measured the frequency of viral recovery after the exposure of peripheral resting CD4+ cells obtained from HAART-treated, aviremic, HIV-infected adults to this cytokine compared with nonspecific mitogen activation.

Four HIV-infected volunteers in whom the plasma levels of HIV-1 RNA (Roche Amplicor, Branchburg, NJ) had been durably suppressed (>6 months) to <50 copies/mL were studied after receiving institution review board–approved informed consent. Resting CD4+ T cells obtained by leukophoresis were isolated on 6 occasions as described by Chun and colleagues, 6,20 with modifications as described. 16,17 Resting CD4+ cells were cultured in a limiting dilution format in 4 replicate dilutions of 5.0 to 0.625 million cells per well. These cells were activated with phytohemagglutinin (PHA) and irradiated seronegative feeder peripheral blood mononuclear cells (PBMCs) or exposed to 10 ng/mL of IL-7 (R&D Systems, Minneapolis, MN) for 72 hours. CD8-depleted, PHA-activated, seronegative donor PBMCs (up to 1.5 million per well) were then added to these limiting dilution cultures. Cultures were grown in 20U/mL of IL-2 (Chiron, Emeryville, CA), fresh activated seronegative donor PBMCs were added weekly, and p24 was assayed in culture supernatant. Infectious units per million resting cells were estimated by a maximum likelihood. 21

Cells that express the α-chain of the IL-7 receptor, CD127, have the potential to respond to the IL-7 treatment. Analysis of the isolated resting T cells (CD3+/CD4+/human leukocyte antigen–D-related [HLA-DR]-) determined that 40% to 70% were CD127+. Fifty percent to 60% of these cells could be identified as naive because of the presence of phenotypic markers (CD45RA, CCR7, and CD62L). Therefore, the IL-7 receptor–positive cells within the resting T cells were approximately equally divided between the naive and memory T-cell populations. As expected, receptor levels were downregulated 10-fold after exposure to IL-7 (data not shown).

HIV was recovered from patients’ resting cells in every instance after maximal activation with PHA, irradiated allogeneic PBMCs, and IL-2 (Table 1). HIV was recovered in 5 of 6 experiments after exposure to IL-7 and IL-2. HIV was not recovered in 1 of 2 experiments in 1 patient (A) in whom infectious units per million resting cells (IUPM) calculated from outgrowth after PHA activation was low.

Table 1
Table 1
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Frequency of viral outgrowth (IUPM) was higher after activation than after exposure to IL-7 in 4 of 6 experiments. HIV was more frequently recovered from the resting cells of subject A after PHA activation on a single occasion, however, and more frequently after exposure to IL-7 in another experiment. Because of the rarity of latent HIV and the few experiments performed so far, a comparison of the frequency with which activation of IL-7 results in the outgrowth of latent HIV cannot yet be made. Given the infrequency of latent infection in naive cells and the frequency with which cells without naive markers displayed IL-7 receptor, it is possible that IL-7 induced viral expression from naive as well as memory cells.

Eradication of HIV infection is not yet feasible. This achievement requires advances in the potency of antiretroviral therapy, and perhaps immunotherapeutics that augment the antiviral response. Rational therapeutics that target latent HIV within resting CD4+ cells are required. Because IL-7 is now entering human trials as an immunotherapeutic, it may be a candidate for such an application.

Ginger Lehrman, BS*

Loyda Ylisastigui, PhD*

Ronald J. Bosch, PhD†

David M. Margolis, MD*‡

*Division of Infectious Diseases, Department of Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390; † Harvard School of Public Health, Boston, MA; ‡ North Texas Veterans Health Care Systems, Dallas, TX

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