Pathogens and Disease Advance Access published June 29, 2015
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MINI REVIEW
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HIV-associated lymphoma in the era of combination antiretroviral therapy: shifting
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the immunological landscape
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Virginia Carroll* and Alfredo Garzino-Demo* †
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*Institute of Human Virology, and Department of Microbiology and Immunology,
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University of Maryland School of Medicine, Baltimore, MD, USA; †Department of
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Molecular Medicine, University of Padova, Italy
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Correspondence: Virginia Carroll, Institute of Human Virology, University of Maryland
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School of Medicine, 725 West Lombard St., Baltimore, MD 21201-1009. Tel. 410-706-
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4664; Fax 410-706-4694; e-mail:
[email protected] 11
Running Title: Lymphoma in HIV patients after cART
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Abstract
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HIV infection increases the risk of many types of cancer, including lymphoma.
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Combination antiretroviral therapy (cART) has reduced, but not eliminated, the risk of
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HIV-associated lymphoma. There has been a substantial shift in the subtypes of
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lymphoma observed in HIV-infected patients treated with cART. In this review, we will
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first outline these changes based on epidemiological studies and describe the impact of
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cART on lymphoma risk and mortality. Then, we will discuss some immunological
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factors that may contribute to the increased risk of lymphoma persisting after the
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administration of cART, including immunological nonresponse to therapy, chronic B cell
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activation and dysfunction, T follicular helper cells, natural killer cells, and altered
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lymphopoiesis. A better understanding of the pathophysiologic mechanisms of HIV-
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associated lymphoma under effective cART will inform future treatment strategies.
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Keywords: HIV-1; virus; lymphomagenesis; antiretroviral drugs; immune activation;
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chronic infection
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Subtypes of HIV-associated Lymphoma Lymphomas in HIV-infected patients are heterogeneous and can be subdivided
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into different histologic types (Carbone 2002). Non-Hodgkin lymphoma (NHL) is one of
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three AIDS-defining cancers. Prior to cART, the incidence of NHL in AIDS patients was
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approximately 100-fold higher than in the general population, occurring in 2-10% of
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cases of AIDS (Carbone 2002; Goedert et al. 1998). Overall, Epstein-Barr virus (EBV) is
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found in ~40% of HIV-associated NHL, though it is more common in some subtypes
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(Dunleavy and Wilson 2012). The major NHL subtypes include Burkitt’s lymphoma (BL,
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characterized by MYC activation), and diffuse large B cell lymphoma (DLBCL), which
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has distinct genetic lesions in HIV+ subjects as compared to seronegatives (Capello et al.
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2010). DLBCL can be further divided into two groups based on gene expression
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profiling: centroblastic/germinal center B-cell type and immunoblastic/activated B-cell
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type (Dunleavy and Wilson 2012). Primary central nervous system lymphoma (PCNSL),
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a form of DLBCL found in the brain, is uniformly EBV-positive and represented ~20%
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of NHL cases pre-cART, but the incidence of this disease has decreased significantly
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with cART treatment (Carbone 2002). Other rare subtypes, such as primary effusion
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lymphoma and plasmablastic lymphoma of the oral cavity, are typically EBV- and human
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herpesvirus-8- positive and found in severely immunocompromised individuals including
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immunosuppressed transplant recipients and thus are not limited to HIV infection.
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Finally, HIV patients had a 12-fold increased risk for Hodgkin’s lymphoma (HL) in the
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pre-cART era (Patel et al. 2008), prevalently EBV-positive, while only 48% of HL is
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EBV-positive overall (Lee et al. 2014; Thompson et al. 2004). The role of EBV in HIV-
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lymphoma has been reviewed elsewhere (Carbone et al. 2009; Dolcetti et al. 2013; White 3
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et al. 2014). Given that the majority of HIV-lymphomas are EBV-negative (Chao et al.
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2012; Dunleavy and Wilson 2012), this review will explore other immune factors that
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may contribute to lymphomagenesis.
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Lymphoma after cART: Risks and Mortality
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The introduction of cART has drastically reduced the risk of NHL and other
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AIDS-defining cancers and has improved survival. For example, a recent French cohort
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study found that the incidence of HIV-NHL was 117-fold higher than the general
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population in the period before cART (1992-1996), but was 9-fold higher during the
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period when a majority of HIV patients were undergoing treatment with cART (2005-
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2009) (Hleyhel et al. 2013). Decreased viral load and improved immunity are often
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proposed as key factors mediating this decline. Yet, the risk of NHL in people with HIV
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after cART became available is still elevated 9-fold compared to the general population
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(Hleyhel et al. 2013). Underlying causes of the elevated risk for NHL in cART-treated
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HIV patients are unclear, but a recent report suggests that poor response to treatment,
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either virological or immunological, is responsible. In the same French cohort study,
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NHL risk was similar to the general population when including only those HIV patients
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on cART with HIV RNA 500 cells/μl for at
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least 2 years (Hleyhel et al. 2013). Furthermore, a Swiss cohort study of approximately
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13,000 HIV-positive patients found that risk of NHL in HIV-patients was halved in the
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first 5 months of cART, and declined to a hazard ratio of 0.1 after continuing therapy for
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2-10 years compared to non-users (Polesel et al. 2008). The most striking difference
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between cART vs. non-cART users was the loss of influence of CD4 count at enrollment
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on NHL risk, indicating that the incidence of NHL in cART-treated patients, albeit low,
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was the same regardless of immune status at the beginning of the study. Therefore, cART
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seems to be effective at preventing most cases of NHL by improving immune status, even
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among the severely immunocompromised. Nonetheless, during the period of 2005-2009,
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when 86% of HIV patients studied were treated with cART, NHL diagnosis occured at a
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younger median age (41 years) than in the general population (73 years) (Hleyhel et al.
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2013). The reasons for the younger age at diagnosis are unclear, but may be related to
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specific effects of HIV infection despite treatment, or to cART treatment itself (see
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below).
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In contrast to NHL, the incidence of HL has not dropped after the introduction of
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cART (Hleyhel 2014). In a large American cohort, the standardized rate ratio for HL in
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HIV-infected vs. the general population actually increased from 12-fold before cART to
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18-fold after cART was available (Patel et al. 2008). Furthermore, the risk of HL among
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HIV patients with controlled viral load and CD4 recovery on cART remains 9-fold higher
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than the general population (Hleyhel 2014), suggesting that recovery of CD4 cells is
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initially insufficient to control elevated risk for HL after HIV infection; however, the
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incidence of HL declines after the first year of cART, suggesting immune reconstitution
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may be linked to HL development (Kowalkowski et al. 2014).
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Examination of an American cohort of HIV patients with lymphoma shows that
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CD4 count at lymphoma diagnosis is increasing over time, and more patients have
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controlled viral loads with cART (Gopal et al. 2013). After stratifying lymphoma cases
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by histological subtype, the authors found that the relative distribution of subtypes is
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changing. In particular, the proportion of BL has more than doubled, and there was a
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trend toward more HL and less DLBCL (Gopal et al. 2013). The authors noted that CD4
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counts at diagnosis differed between lymphoma types, with the highest CD4 count among
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BL and HL and the lowest CD4 count among PCNSL. These data highlight the
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heterogeneity of lymphomas with respect to immune status. Along with appropriate chemotherapy, cART has improved the prognosis of HIV-
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associated lymphoma, closing the survival gap between HIV-positive and -negative
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patients (Bohlius et al. 2009; Diamond et al. 2006; Montoto et al. 2012). However, HIV
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infection remains an independent risk factor for NHL mortality in the United States, in
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addition to low CD4 count (Chao et al. 2010). A large European study, subsequently
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confirmed in an American cohort, found that NHL that develops while on cART is more
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aggressive, since cART-naïve patients had better survival than those previously treated
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with cART (Bohlius et al. 2009; Gopal et al. 2013). While the benefits of cART are
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undisputed, these data underscore the need for new prognostic factors associated with
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NHL in treated patients and for the study of immunological changes after cART and their
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consequences (Figure 1).
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Immunological Changes after cART and Relation to Lymphoma
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Immunological Nonresponders
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Despite controlling viral replication and improving immune status in a majority of
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patients, cART does not always result in immune restoration. About 20% of HIV patients
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experience immunological non-response (INR), defined by no or limited CD4 T cell
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rebound to pre-cART levels (Wilson and Sereti 2013). CD4 T cell recovery is best
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predicted by nadir counts pre-cART, emphasizing the need for early initiation of therapy
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prior to severe impairments in T cell homeostasis, i.e. collagen deposition in lymphoid
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tissues (Wilson and Sereti 2013). The mechanisms to explain INR are being elucidated,
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and include exhausted lymphopoiesis, reduced thymic output, homing defects, and/or NK
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cell killing of CD4 cells (Gaardbo et al. 2012; Sennepin et al. 2013). Considering that
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immunological nonresponders are 2.4-fold more likely to develop serious clinical events
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or death (Lapadula et al. 2013), further research to understand INR is warranted.
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B Cell Activation and Dysfunction
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Chronic polyclonal B cell activation, increased B cell turnover, and
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hypergammaglobulinemia are hallmarks of untreated HIV infection. Prolonged B cell
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activation may increase chances for genetic errors through aberrant immunoglobulin gene
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class-switch recombination or somatic hypermutation, possibly leading to
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lymphomagenesis. In HIV-positive individuals, it is thought that B cells are stimulated
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largely via antigen-independent pathways involving cytokines and TLR ligands (Haas et
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al. 2011). Non-specific activation of B cells may result from gut microbial translocation
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and/or HIV viremia. The hypergammaglobulinemia found in HIV viremic patients is
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partially reduced after cART-induced viral suppression (Buckner et al. 2013; Regidor et
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al. 2011). However, less than 1.5% of circulating antibody-secreting cells are specific to
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viral envelope/gp140 after early or chronic HIV infection, and contribute ~1% to total
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IgG (Buckner et al. 2013). Various HIV proteins persist in lymph nodes for at least one
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year post cART and represent a potential source of chronic antigenic stimulation
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(Popovic et al. 2005).
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Apart from an antigenic role, extracellular HIV proteins can directly promote B
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cell hyper-proliferation (Lefevre et al. 1999) and class-switch recombination (He et al.
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2006). Matrix protein/p17 is of particular interest in this context, as it has been shown to
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lead to B cell growth via signaling through cellular receptors (Caccuri et al. 2012; De
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Francesco et al. 2002; Fiorentini et al. 2006; Giagulli et al. 2011) and has angiogenic
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activity, which might facilitate spread of lymphomas (Caccuri et al. 2012; Caccuri et al.
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2014; Basta et al. 2015). Interestingly, expression of HIV proteins in transgenic mouse
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models correlates with development of B cell lymphoma (Curreli et al. 2013; Kundu et al.
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1999). In addition, Tat may lead to epigenetic dysregulation of the cell cycle (Luzzi et al.
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2014), and induce elements of human endogenous retrovirus K, which are found in
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plasma of lymphoma patients (Contreras-Galindo et al. 2008; Gonzalez-Hernandez et al.
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2014). CD40L-stimulation from activated CD4 T cells and virion-associated CD40L
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could also contribute to hyperactivation of B cells (Martin et al. 2007).
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In a study of 290 HIV-infected men, cART reduced, but did not normalize, some
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biomarkers of B cell activation including sCD27, sCD30, CXCL13, and serum IgG after
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two years of therapy (Regidor et al. 2011). However, the same study showed that IL-6 (a
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biomarker preceding HIV-NHL (Vendrame et al. 2014)) and C-reactive protein levels
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were unaffected by cART, suggesting that B cell hyperactivation persists. Thus, these
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results help to explain the remaining elevated risk for NHL in cART-treated individuals.
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Another study has evaluated the effect of cART on spontaneous apoptosis of naïve and
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memory B cells from HIV-infected patients (Titanji et al. 2005). After 6 months of
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therapy, cART reduced spontaneous apoptosis of both B cell subsets, but survival of
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memory B cells did not return to normal (Titanji et al. 2005) Therefore, B cell
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dysfunctions remain after cART. Recovery of total B cell counts is generally observed
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after cART (Moir et al. 2008); however, older individuals treated with long-term cART
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exhibit expansion of naïve B cells in peripheral blood above control levels (Van Epps et
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al. 2014). This finding is counterintuitive, since a decline in naïve B cell numbers is
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observed in older uninfected individuals. Lymphopoiesis is altered after HIV infection,
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despite suppression of viral replication, as discussed below (Sauce et al. 2011). The
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relevance of an expanded naïve B cell population in older individuals on cART to risk of
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B cell lymphoma remains unclear.
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T Follicular Helper Cells
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T follicular helper cells (TFH) are a specialized T cell subset within lymph nodes
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that support the differentiation of B cells into long-lived memory cells and plasma cells
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via development and maintenance of germinal centers (Crotty 2011). Remarkably, TFH
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cells are expanded 10-fold in lymph nodes from HIV-infected patients compared to HIV-
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negative controls (Lindqvist et al. 2012). cART reduced the frequency of TFH cells ~2-
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fold, suggesting a link between viremia and their expansion. Regardless of cART
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treatment, TFH frequency in lymph nodes correlated with several B cell abnormalities,
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including loss of memory B cells and increase in germinal center B cells and plasma
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cells. It is possible that increased TFH cell numbers, together with persistent antigen,
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lowers competition for B cell selection. Theoretically, high frequencies of germinal
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center B cells undergoing somatic hypermutation may increase the risk for genetic errors
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and lymphoma. Subsequently, it was found that TFH cells represent a major site of HIV
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replication and persistence, potentially affecting their interactions with B cells (Perreau et
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al. 2013). Crosstalk between TFH and germinal center B cells is bidirectional, as high
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expression of programmed cell death ligand 1 (PD-L1, which can be upregulated by
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interferons and TLR ligands (J. Liu et al. 2007)) on lymph node germinal center B cells
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from HIV-infected individuals is involved in deregulation of TFH cell functions in vitro
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(Cubas et al. 2013). One study of 22 aviremic cART-treated patients found that PD-L1
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levels remain high on peripheral blood lymphocytes compared to uninfected controls
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(Rosignoli et al. 2007). Nevertheless, lowering the viral burden may help to partially
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ameliorate TFH-B cell dysfunctions in germinal centers.
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Natural Killer Cells NK cells can directly lyse tumor and virally-infected cells via recognition through
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a diverse array of activating and inhibitory receptors to activate natural cytotoxicity, or
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via CD16/FcγRIIIa to mediate antibody-dependent cellular cytotoxicity (ADCC).
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Functional ADCC is associated with protection from HIV disease progression and
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represents a major mechanism in anti-CD20 mAb therapy for lymphoma (Forthal et al.
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1999; Glennie et al. 2007). It has long been known that phenotype and function of
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peripheral blood NK cells is altered after HIV infection (Hu et al. 1995). cART can
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restore the blood NK cell compartment in terms of distribution of subsets, expression of
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inhibitory and activating receptors, and cytotoxic functions (Mavilio et al. 2003).
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However, certain NK cell defects remain after cART, such as ADCC and activation
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status.
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First, ADCC function is still compromised in treated aviremic patients (Q. Liu et
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al. 2009). NK ADCC function correlated with CD16/FcγRIIIa cell surface levels, which
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are reduced in HIV-infected patients regardless of treatment. Impaired ADCC of NK
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cells from HIV-positive individuals can be restored in vitro by matrix metalloprotease
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inhibitors (Q. Liu et al. 2009), which may have clinical relevance in therapeutic mAb
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anti-tumor immunotherapy (Zhou et al. 2013).
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Second, blood NK cells in cART treated patients are qualitatively different from
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healthy controls. In contrast with T cells, NK cells retain activation markers after cART,
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including CD38 and HLA-DR (Kuri-Cervantes et al. 2014; Lichtfuss et al. 2012). In
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addition, despite virologic control, NK cells show high levels of spontaneous
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degranulation ex vivo and defective CD16-mediated signaling, manifested by
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downregulation of key signaling molecules (Lichtfuss et al. 2012). Thus, elevated
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degranulation is not due to heightened ADCC activity, but instead, may be due to recent
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engagement with target cells that stimulate NK cells through natural cytotoxicity
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receptors, i.e. NKp30, NKp44, NKp46, or KIRs. Few HIV-infected cells remain after
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therapy, so the identity of the target cells is unknown. Could NK cells be engaging and
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killing tumor cells before they are detected clinically? Lichtfuss et al. propose that
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systemic inflammation from microbial translocation may perpetuate the NK cell
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activation indirectly. For example, endotoxin can induce an NKG2D ligand, MIC-A, on
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monocytes (Kloss et al. 2008). Certain chemokines can also cause spontaneous NK cell
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degranulation in absence of target cells (Taub et al. 1995).
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Finally, the anatomical localization of NK cells after cART remains unexplored.
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Almost all studies utilize peripheral blood samples, but lymphoid tissue and bone marrow
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are the relevant sites for HIV-infected cells and lymphoma. One study on surgically
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resected axillary lymph nodes from HIV-infected patients and HIV-negative controls
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characterized NK cell distribution after acute infection (Luteijn et al. 2011). Normally,
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cytotoxic CD56dim NK cells expressing killer cell immunoglobulin-like receptors (KIR)
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are excluded from lymph nodes, but found in abundance in blood. HIV infection slightly
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increases the proportion of KIR+ NK cells in blood; however, these effector cells
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continue to be excluded from lymph nodes, potentially providing HIV an opportunity to
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escape NK cell control (Luteijn et al. 2011). One explanation for exclusion may lie in
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differential chemokine receptor expression. KIR+ blood NK cells show reduced
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expression of CX3CR1 and CXCR1 in the setting of acute HIV infection, though this did
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not translate into a significant migratory defect in vitro (Luteijn et al. 2011). Further
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understanding of how NK cells are reprogrammed in treated HIV patients may allow
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harnessing their potential as critical effector cells to target transformed B cells.
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Lymphopoiesis
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HIV infection leads to increased lymphocyte apoptosis, cell turnover, and
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eventually widespread lymphopenia. Over time, the bone marrow shows signs of
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exhaustion, or regenerative failure (Moses et al. 1998). Lymphopoiesis depends on the
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interaction of hematopoietic progenitor cells (HPCs) with auxiliary cells, both of which
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may be infected with HIV (Carter et al. 2010; Moses et al. 1998). Exactly how HIV
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perturbs hematopoiesis and why some HIV patients fail to reconstitute immune cells after
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cART is an area of active research (Corbeau and Reynes 2011; Gaardbo et al. 2012).
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Compensatory increased cell turnover of precursor cells in bone marrow may increase
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chances for genetic errors that predispose for HIV-associated lymphoma. In addition,
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altered cytokine signals during lymphocyte development may result in permanent
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functional changes and predispose to lymphoma, i.e. altering susceptibility to apoptosis
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or response to growth factors.
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Accumulating evidence suggests that damage to lymphopoiesis after HIV
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infection may be irreversible, despite effective cART. Bone marrow-derived CD34+
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HPCs from HIV-infected patients express increased proportions of early T- and B-cell
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markers before cART (Muller et al. 2002). After 6 months of cART, there was a trend
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toward normalization, but the proportions remained elevated compared to uninfected
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controls (Muller et al. 2002). There is evidence that a small fraction of HPCs can be
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latently infected by HIV despite effective cART (Carter et al. 2010), though these cells
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are not always found (Durand et al. 2012). HIV infection did not alter the potential of
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HPCs to form colonies in vitro, making it difficult to estimate the impact of HPC
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infection on lymphopoiesis (Carter et al. 2010).
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Due to poor availability of human bone marrow samples, some groups have
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turned to studying the clonogenic potential of rare circulating CD34+ HPCs directly from
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blood. The ability of circulating HPCs to form white cells in particular was compromised
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after HIV infection (Sauce et al. 2011), in agreement with previous studies on bone
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marrow HPCs (Isgro et al. 2008). The authors surmise that altered lymphopoiesis is a
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consequence of immune activation, rather than HIV replication, based on a) a significant
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inverse correlation between blood CD34+ cell count and the percentage of CD38+CD8+
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T cells (a widely used metric of immune activation); and b) progression toward
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lymphopenia and defective lymphopoiesis despite control of HIV in rare elite controllers
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or after successful cART. Interestingly, though cART reduced markers of immune
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activation to some degree, there was no difference in inflammatory marker levels
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between patients who progressed and those with restored CD4 counts. Altogether, the
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data suggest that cART can partially reduce immune activation and restore lymphopoiesis
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in some patients, but there are additional unidentified factors influencing lymphopoiesis.
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Direct effects of certain antiretroviral drugs on the hematopoietic system are
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documented, both positive and negative. For example, protease inhibitor ritonavir
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stimulates bone marrow cell colony formation in vitro, presumably by blocking caspase-
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dependent apoptosis (Sloand et al. 2000). Zidovudine (AZT) inhibits growth of blood
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HPCs and erythroid- and granulocyte-macrophage- colony formation in particular,
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leading to the common toxicities of anemia and neutropenia (D'Andrea et al. 2008). To
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what extent current antiretroviral drugs and their combinations directly affect
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lymphopoiesis has not been studied in vitro.
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Finally, bone marrow provides a stromal niche for lymphoma colonization
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following lymphomagenesis in secondary lymphoid organs. HIV may induce lymphoma
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growth and dissemination via the bone marrow stroma. In general, lymphoma cells
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localize to specific bone marrow niches according to their origin (Sangaletti et al. 2014).
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Germinal center-derived lymphomas are found in the osteoblastic niche, whereas extra-
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follicular lymphomas are found in the vascular niche. Evidence for common stromal
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programs between the lymph node germinal center microenvironment and the bone
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marrow osteoblast niche includes upregulation of a matricellular protein, secreted protein
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acidic and rich in cysteine (SPARC), in both tissues (Sangaletti et al. 2014). Using
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knockout mouse models, the authors demonstrate that SPARC regulates normal B cell
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lymphopoiesis, possibly fostering growth of B-lymphoma cells. This finding raises the
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question of whether expression of SPARC and other key molecules are modified in bone
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marrow stromal cells after HIV infection, with or without cART.
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Conclusions cART lowers the risk of most NHL, but not HL, in HIV-infected patients. Yet, an
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elevated risk for lymphoma persists in cART-treated patients. Beyond its antiviral effects,
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cART can ameliorate some immune activation and preserve T, B, and NK cell counts in
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the blood in the majority of patients. The evidence suggests that cART is most effective
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against lymphoma due to improved immunity, as measured by CD4 counts. However,
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peripheral CD4 count may be a marker for other anti-tumor mechanisms, such as NK
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cells. In addition, the microenvironment encountered by developing and mature B cells is
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modulated by both HIV and antiretroviral drugs. The combinatorial effects of HIV and
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cART on B cell activation, TFH-B cell crosstalk in lymph nodes, and lymphopoiesis are
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being elucidated. Finally, individual antiretroviral drugs have direct effects on tumor
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cells. A direct apoptotic effect of certain protease inhibitors on lymphoma cells has been
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demonstrated in vitro (Kariya et al. 2014). Further understanding of the successes and
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pitfalls of cART will help to improve therapeutic options for HIV-associated lymphoma
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and suggest new avenues for prevention of disease.
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Funding
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This work was supported by the University of Maryland School of Medicine Deans
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Challenge Award to Accelerate Innovation and Discovery in Medicine, and by the
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National Institute of Neurological Disorders and Stroke (NINDS) National Institute of
318
Health (NIH) [grant number NS-066842]. The content is solely the responsibility of the
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authors and does not necessarily represent the official views of the NINDS, or the NIH.
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The authors declare no conflicts of interest.
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Acknowledgments
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The authors thank Dr. Gregory Carey for his helpful discussion and review of the
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manuscript, Dr. Marvin Reitz for critically reading the manuscript, and Dr. R. Gallo for
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supporting this work.
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Figure 1. Development of HIV-associated lymphoma after cART: Contribution of
508
Immunological Changes. After cART, many aspects of immunity remain altered in HIV-
509
infected individuals that may predispose to B cell lymphoma. A) Immunological non-response to
510
cART. About 20% of patients experience limited CD4 T cell recovery or none at all. B)
511
Dysfunctional NK cells. Despite effective cART, cytotoxic NK cells in aviremic patients have
512
impaired ADCC, an activated phenotype, and are excluded from lymph nodes, an important site
513
of both HIV replication and B cell transformation. C) Chronic B Cell Activation. Residual
514
immune activation, i.e. IL-6, CD40L, and/or TLR ligands, leads to polyclonal B cell activation.
515
Prolonged stimulation may lead to genetic errors via aberrant immunoglobulin class switching or
516
somatic hypermutation in germinal center- or post-germinal center- B cells. D) T Follicular
517
Helper Cells (TFH) Expansion. High numbers of TFH cells in lymph nodes from treated or
518
untreated HIV patients correlate with B cell abnormalities, including increased germinal center B
519
cells, increased plasma cells, and reduced memory B cells. E) Altered Lymphopoiesis. In the bone
25
520
marrow, increased hematopoietic progenitor cell (HPC) turnover may lead to accumulation of
521
genetic errors. Also, persistent HIV infection of stroma or HPCs may functionally alter responses
522
to normal cytokine signals for B cell development and may change the bone marrow
523
microenvironment to encourage lymphoma colonization. Persistent or latent HIV infection of
524
lymph node and bone marrow cells may play a direct role in C, D, and E.
525 526
26