Immune Reconstitution Following Allogeneic Stem Cell Transplantation in HIV infected Individuals: Years of Living Danger-ously
Year: 2021
Type: article
Abstract: (See the Major Article by Murray et al on pages 1141–6, in V72N7 – 1 April 2021 issue) Human immunodeficiency virus (HIV) infection is controlled but not eradicated by combination antiretroviral therapy (cART), and lifelong treatment is necessary for the great majority of persons living with HIV (PWH) to prevent morbidity and mortality from progressive immunodeficiency [1]. Long-term cART is associated with substantial side effects, including endocrine and cardiovascular complications, chronic immune activation that have been linked to all-cause mortality, and development of antiretroviral drug resistance in nonadherent individuals [1, 2]. As such, long-term therapy is not an acceptable long-term solution. As increasing numbers of PWH have access to cART worldwide, the numbers of individuals at risk for adverse events continue to grow. Developing strategies that eradicate or control HIV without therapy is a public health imperative and an important HIV research priority [3]. To date, the few individuals who have been “cured” of HIV infection (ie, living with no evidence of active disease and not undergoing cART) have undergone allogeneic stem cell transplantation (ASCT) for comorbid neoplastic diseases. Response rates of ASCT for neoplastic diseases in PWH with suppressed HIV RNA levels are similar to uninfected individuals with comparable neoplasms [4, 5], and HIV infection should not be an exclusion a priori for ASCT. HIV cures in the context of ASCT are rare, however, so much so that they are referenced individually (eg, “The Berlin Patient” [6] and “The London Patient” [7]). These individuals received donor cells homozygous for the delta32 deletion in the CCR5 gene, rendering the donor cells refractory to infection by HIV via CCR5 coreceptor utilization. The reasons for the success and failure of ASCT for HIV eradication remain uncertain. Much has been learned regarding HIV-infected cell reservoirs, but less is known about the function of the donor graft, and understanding fundamental characteristics of graft function after transplant is essential [8]. In this issue of Clinical Infectious Diseases, Polizzotto and colleagues (Murray et al. [9]) report important progress in understanding immune reconstitution after allogeneic stem cell transplant. The effects of ASCT on HIV-infected cell populations is a complex interplay between the state of the host, the pretransplant composition of HIV-infected cell populations, and the transplant interventions including conditioning and post-transplant immunosuppression. Typically, PWH referred for transplant have been undergoing cART for a prolonged period, which fundamentally reshapes the size, composition, and structure of HIV-infected cell populations. HIV populations are large and genetically diverse; upon initiating cART, virus replication is blocked, and infected cells are progressively eliminated over time with half-life c. 1 day for short-lived cells and half-life c. 2–68 weeks for some long-lived cells. Additional long-lived cells containing HIV proviruses are relatively infrequent, but they may persist for many years and undergo clonal expansion, effectively maintaining the HIV reservoir by cell replication [10]. Only a small fraction of HIV-infected cells contain replication-competent HIV, which is the virus responsible for HIV rebound when cART is interrupted. The majority of proviruses are defective due to mutations and deletions. Although incapable of sustaining ongoing infection, these defective proviruses may play an important role in driving chronic immune activation. Infected cells may persist for many years by undergoing clonal expansion, and most cells persisting after years of cART are members of clones. The proviral landscape is dynamic and shaped during cART, with a progressive enrichment in defective proviruses [11–13]. In turn, HIV transcription in individual clones is heterogeneous; Kearney et al demonstrated that, at any given moment, some HIV-infected cells within a clonal population may have no detectable RNA while others produce substantial copies of viral RNA [14]. Therefore, at the time of ASCT, HIV-infected cells targeted for elimination consist of clonal populations of infected cells with genetically diverse proviruses and variable HIV RNA production. Allogeneic stem cell transplantation is initiated with conditioning regimens followed by delivery of donor cells. Conditioning may utilize regimens that are myeloablative (MA) with irreversible cytopenia or regimens that involve variable degrees of incomplete cytoreduction, including reduced intensity conditioning (RIC) or non-MA (NMA) regimens [15]. Myeloablative conditioning typically consists of total body irradiation (TBI) with agents that interfere with DNA replication (typically cyclophosphamide, busulfan, or etoposide), or combinations of cytotoxic chemotherapeutic regimens without TBI. Reduced intensity conditioning regimens consist of combinations of chemotherapeutic agents (eg, busulfan, fludarabine, melphalan), while NMA regimens are designed to reduce but not eliminate all cells in combination with reduced TBI and cytotoxic agents. To date, successful HIV cure has been achieved with MA (Berlin patient) or RIC regimens (London patient) [6, 16]. In PWH, ASCT with either MA or RIC regimens that successfully treat the underlying neoplasm have also been associated with profound decreases, but not elimination, of HIV-infected cells in blood and anatomic compartments [17, 18]. The allogeneic haplo-identical graft typically consists of cells that are partially matched at human leukocyte antigen (HLA) loci. Various post-transplant regimens, including colony-stimulating factors and immunosuppressive agents, have been designed to support the graft, permit its ability to expand, promote its power to eliminate neoplastic cells, and prevent its potential to damage the host cells. Successful grafts establish a robust population in the new host comprising over 99% of all peripheral blood cells. CD4+ and CD8+ lymphocyte populations from the graft generally recover numerically to pretransplant levels after 12–16 months [8]. Functional recovery is likely to be slower, however, and postengraftment complications are the result of damage to tissues, including acute graft-versus-host disease (GVHD), hepatic sinusoidal obstruction syndrome, and infections from bacterial, viral, or fungal sources. The postengraftment period presents the donor graft with a variety of new pathogen- and damage- associated molecular patterns (PAMPs and DAMPs, respectively). These “danger” signals represent potent contextual forces driving innate and adaptive immunity and reconstituting the immune system [19, 20]; in individuals with HIV, viral gene products represent potentially potent PAMPs. The role of these signals in immune reconstitution is not understood. In a comparative analysis of individuals with and without HIV undergoing ASCT, Polizzotto and colleagues identified new findings that shed light on the early immune reconstitution period and of the graft “living dangerously.” Study participants with hematologic disorders (leukemia, myelodysplastic syndrome, aplastic anemia, or lymphoma) underwent conditioning with either MA or RIC and achieved more than 99% donor chimerism. All individuals with HIV remained free of neoplastic disease 1 year post-transplantation. Both individuals with and without HIV experienced comparable levels of reconstituted CD4+ cell populations. In contrast, the cohort with HIV reconstituted significantly higher levels of CD8+ cells after transplant compared with the cohort without HIV. Mechanisms of the CD8+ cell increases are uncertain. In Murray et al, the expanded CD8+ cell populations were phenotypically and functionally heterogeneous. Some individuals had clear expansions of memory CD8+ T cells, including cells expressing gut homing (alpha4/B7 integrin) receptors that may play a central role in GVHD [21], but others had little or no detectable specific responses. Immune reconstitution after ASCT included responses to HIV antigens, including Nef. The precise origin of these HIV-reactive cells remains unclear. They have been detected in other recent studies [22, 23], but HIV-reactive cells were not detected in the London or Berlin patients. Given that the levels of Nef reactivity were low (<1%) in the host before the transplant, it is unlikely that the signal detected after transplant is from residual Nef-reactive host cells that were not eliminated by conditioning, especially so as more than 99% of peripheral blood mononuclear cells were derived from the donor. Rather, it is more likely that these responses arose from cells in the graft. The source of Nef driving reactivity is unknown. One possibility is that these HIV antigens are derived from a residual reservoir of HIV-infected cells in the recipient after conditioning, and the response detected represents a graft-versus-virus effect. Alternatively, Eberhard et al [22] have suggested that donor cells may be infected in the peri-transplant period when they are highly activated, and these Nef responses are against these newly infected donor cells. HIV antigens, including Nef, are potential danger signals, but it remains uncertain whether they drive an authentic or effective PAMP response in the post-ASCT period. Eberhard et al [22] have reported that the responses are not potent, suggesting they do not represent an effective graft -ersus-virus effect capable of eliminating infected cells. These and other studies highlight the early post-ASCT period as a critical time in immune reconstitution in individuals with HIV; if such antiviral immune responses were sufficiently potent, perhaps the HIV eradication rate would be higher. Murray et al and Eberhard et al [22] shed light on the dynamic nature of HIV reservoirs in the early post-transplant period. Engraftment, GVHD, PAMPs, and DAMPs represent potent forces that could drive residual HIV reservoirs to undergo clonal expansion. Detecting the presence of the residual reservoir will be challenging. There is now a comprehensive portfolio of assays to characterize the HIV reservoir, including methods to quantify low-level viremia and HIV RNA production in cells, estimate levels of potentially infectious proviruses, and determine frequencies of deleted and defective proviruses, and characterize the genetic composition of the residual HIV proviruses present in clonal populations [13, 24–29]. These assays have excellent performance characteristics, but they may not be sufficiently sensitive in all cases to detect residual infection [29]. Henrich et al [30, 31] performed exhaustive analyses of several transplants, which yielded no evidence of HIV; nevertheless, rebound emerged after treatment interruption. In Eberhard et al, immune responses were detectable in settings where HIV DNA was below the limit of detection; incorporating sensitive immune response assays, including single cell assays, may be useful in evaluating the persistence of HIV-infected cells [22, 32]. Clearly, studies like that of Murray et al need to be repeated in larger and well-matched cohorts, using additional assays to characterize immune reconstitution after ASCT. New research in transplantation may shed additional light on ASCT that is specifically germane to individuals with HIV. Currently, ancillary therapies to augment graft-versus-tumor effects are of great interest, and studies of the effects of immune checkpoint inhibitors, infusions, or donor lymphocytes or natural killer cells are ongoing in clinical trials [33]. Several of these modalities may improve innate immune responses, which may represent important components of graft-versus-virus activities and modulate HIV transcription [34]. HIV has a number of strategies to evade innate pathogen recognition [35, 36], and investigating individuals with HIV undergoing ASCT may reveal specific vulnerabilities of HIV-infected cells in the post-transplant period that may tip the balance in favor of the host. Allogeneic stem cell transplantation in individuals with HIV remains a high-risk procedure reserved for individuals with serious comorbid neoplasms. As demonstrated here and in a number of additional studies [4, 5, 37–40], the procedure can be performed with great effect in PWH and eliminate the malignancy. Understanding the early post-transplant events, as the graft is exposed to PAMPs and DAMPs and living dangerously, will yield important benefits in developing strategies that target HIV with the same curative intent. Acknowledgments. The authors thank Kathryn Lurain and Ramya Ramaswami of the HIV and AIDS Malignancies Branch, National Cancer Institute (NCI), for insights and suggestions. Financial support. This work was supported by Intramural. Potential conflicts of interest. The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest.
Source: Clinical Infectious Diseases
DOI: 10.1093/cid/ciab565
Authors: Camille Lange, Frank Maldarelli
Institution: National Cancer Institute
Language: English
Topic: HIV Research and Treatment
Subfield: Virology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,052
Funder: National Cancer Institute
OpenAlex ID: W3173296109