The case of Timothy Ray Brown, who received hematopoietic stem cell transplant (HSCT) from a CCR5-Δ32 donor to treat AIDS-related lymphoma, remains the only example of a patient cured from HIV infection . HSCT from CCR5 wild-type donors failed to cure HIV in two other AIDS-related lymphoma patients, but delayed viral rebound after combined antiretroviral therapy (cART) interruption [2,3]. At least one of two conditions must be fulfilled to achieve HIV cure: elimination of all latent HIV reservoirs or protection of CD4+ T cells from de-novo infection.
Purging viral reservoirs requires that all cells bearing functional HIV provirus are accessible for activation and susceptible to viral cytopathicity and/or immune-mediated clearance. For the latter, it is essential that HIV-specific cytotoxic T-lymphocyte (CTL) responses be restored .
Preventing infection of new targets may be more challenging. Transplants of rare heterologous human leukocyte antigen (HLA)-matched CCR5-Δ32 or autologous genetically modified CCR5-KO hematopoietic stem cell  may require immunoablation to ensure total resistance to infection.
There is general consensus on the hypothesis that some degree of graft-vs-host (GVH) reactivity may have reduced the viral reservoir in the HSCT patients who showed delayed viremia rebound . Thus, similar to the extensively studied graft-vs-leukemia phenomenon , a graft-vs-viral reservoir effect (GVVR) could target host cells that survived immunoablation, thus shrinking the HIV reservoir. Could GVVR be independently exploited of immunoablation? Would it be advantageous, and how could it be delivered and tested?
Several independent reports spanning 40 years suggest a strategy for addressing these issues. Exposing nonablated, cART-treated HIV patients to HLA-allogeneic leukocytes could simultaneously induce GVVR; reactivate latent HIV reservoirs; enhance or restore host HIV-specific immunity; and activate restriction factors that prevent CD4+ T-cell infection (Fig. 1).
Approximately 1 : 1000 T lymphocytes recognize allogeneic major histocompatibility complex (MHC) molecules, 1000-fold more frequent than peptide-specific T lymphocytes . MHC-allospecific T-helper cell responses are retained in most asymtpomatic HIV-infected patients , but these responses would be eliminated by immunoablation. Immunization with allogeneic leukocytes in immunocompetent women experiencing recurrent spontaneous abortion caused no major side-effects , and resulted in enhanced resistance of CD4+ T cells to in-vitro HIV infection .
The combined reactions of donor T cells against patient MHC (GVH) and of patient leukocytes against donor's MHC (host-vs-graft) could lead to HIV reactivation and enhanced presentation of retroviral peptides in deep anatomical sites (Fig. 1). Thus, activation of host latent murine leukemia retrovirus was reported in a murine GVH model, including latent provirus in bystander T cells that do not recognize allogeneic MHC . Similar experiments in rats showed increased MHC expression in host epidermal cells, gut epithelium , and MHC-negative nervous tissue .
Treatment with allogeneic donor cells could also promote host HIV-specific CTL-mediated immunity (host-vs-viral reservoir) (Fig. 1). Thus, stimulation with allogeneic leukocytes restored T-cell-mediated help to autologous influenza virus-specific  and HIV-specific CTLs (M.C. and G.M.S., unpublished observations).
Finally, stimulation with allogeneic MHC can activate a broad range of restriction factors (APOBEC3G, RANTES, MIP-1α/β, and CD8-derived suppressor factor) [10,15] that could synergize with cART to protect CD4+ cells from HIV during reservoir reactivation.
Infusion of allogeneic cells into nonablated HIV-positive patients is less likely to cause GVH disease (GVHD) than HSCT [1–3]. The number and type of T cells infused and the number of infusions over time could be optimized to achieve GVVR, while abating the risk of GVHD.
The strategy we propose can be tested in simian immunodeficiency virus (SIV)-infected macaques to determine whether the injection of T cells from uninfected HLA-mismatched macaques into ART-treated, SIV-infected animals results in increased MHC expression, recruitment of donor T cells, and activation of latent SIV in multiple tissues; enhancement of SIV-specific CTL responses; activation of innate antiretroviral factors; and ultimately spontaneous control of viremia after ART interruption. This animal model could also determine the half-life of injected allogeneic T cells to provide critical information on the cell number and frequency of infusions required, as well as monitor signs of GVHD or autoimmunity.
HSCT with CCR5-defective cells proved successful in one case, but is unsuitable for large-scale application because of the risks posed by immunoablation, elevated costs of the procedure, and need for prophylaxis against opportunistic infections. Other strategies aimed at reactivating latent HIV reservoirs using modulators of gene expression and chromatin structure are being investigated, and might require supplementation with immunotherapy to revive HIV-specific T-cell responses . By contrast, the combination of GVVR and host-vs-viral reservoir could simultaneously achieve both goals by exposing latently HIV-infected ‘sleeper cells’ to a crossfire from both host HIV-specific and donor allogeneic T cells.
The authors are grateful to Professor Robert Siliciano (Johns Hopkins University, Baltimore, Maryland, USA), Dr Steven Patterson and Dr Gareth Hardy (Imperial College London, London, UK), and Professor Robert B. Levy (University of Miami, Miami, Florida, USA) for their constructive review and criticism on the ideas presented in this manuscript.
Conflicts of interest
There are no conflicts of interest.
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