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]

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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

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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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505 506

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506 507

Figure 1. Development of HIV-associated lymphoma after cART: Contribution of

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Immunological Changes. After cART, many aspects of immunity remain altered in HIV-

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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)

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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

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of both HIV replication and B cell transformation. C) Chronic B Cell Activation. Residual

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immune activation, i.e. IL-6, CD40L, and/or TLR ligands, leads to polyclonal B cell activation.

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Prolonged stimulation may lead to genetic errors via aberrant immunoglobulin class switching or

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somatic hypermutation in germinal center- or post-germinal center- B cells. D) T Follicular

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Helper Cells (TFH) Expansion. High numbers of TFH cells in lymph nodes from treated or

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untreated HIV patients correlate with B cell abnormalities, including increased germinal center B

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cells, increased plasma cells, and reduced memory B cells. E) Altered Lymphopoiesis. In the bone

25

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marrow, increased hematopoietic progenitor cell (HPC) turnover may lead to accumulation of

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genetic errors. Also, persistent HIV infection of stroma or HPCs may functionally alter responses

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to normal cytokine signals for B cell development and may change the bone marrow

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microenvironment to encourage lymphoma colonization. Persistent or latent HIV infection of

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lymph node and bone marrow cells may play a direct role in C, D, and E.

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HIV-associated lymphoma in the era of combination antiretroviral therapy: shifting the immunological landscape.

HIV infection increases the risk of many types of cancer, including lymphoma. Combination antiretroviral therapy (cART) has reduced, but not eliminate...
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