A lymphomagenic role for HIV beyond immune suppression?

Abstract

Despite the immune reconstitution promoted by combined antiretroviral therapy (cART), lymphomas still represent the most common type of cancer in HIV-infected individuals. Cofactors related to immunodeficiency such as oncogenic viruses, chronic antigenic stimulation, and cytokine overproduction are thought to be the main drivers of HIV lymphomagenesis, although the current scenario does not convincingly explain the still-high incidence of lymphomas and the occurrence of peculiar lymphoma histotypes in HIV-infected patients under cART. Recent findings are challenging the current view of a mainly indirect role of HIV in lymphoma development and support the possibility that HIV may directly contribute to lymphomagenesis. In fact, mechanisms other than immune suppression involve biologic effects mediated by HIV products that are secreted and accumulate in lymphoid tissues, mainly within lymph node germinal centers. Notably, HIV-infected patients with lymphomas, but not those not affected by these tumors, were recently shown to carry HIV p17 protein variants with enhanced B-cell clonogenic activity. HIV p17 protein variants were characterized by the presence of distinct insertions at the C-terminal region of the protein responsible for a structural destabilization and the acquisition of novel biologic properties. These data are changing the current paradigm assuming that HIV is only indirectly related to lymphomagenesis. Furthermore, these recent findings are consistent with a role of HIV as a critical microenvironmental factor promoting lymphoma development and pave the way for further studies that may lead to the design of more effective strategies for an early identification and improved control of lymphomas in the HIV setting.

Role of Autophagy in HIV-1 Matrix Protein p17-Driven Lymphangiogenesis

“…Our data showing that a B-cell clonogenic p17 variant (NHL-a105) also displays lymphangiogenic activity through activation of autophagy makes it possible to formulate the hypothesis that these variants, because of their peculiar biologic properties on both B cells and ECs, are the most favorable microenvironmental proteins to promote lymphoma development and spreading in HIV ϩ patients. This hypothesis needs to be sustained by the development of evidence that B-cell clonogenic p17 variants are expressed in blood and in the lymph node microenvironment, as fully demonstrated for p17 (10)(11)(12). Interestingly, a recent study further supports the lymphomagenic ability of p17 since it shows that the expression of the viral protein in lymphoid tissues and bone marrow of HIV-1 transgenic mice carrying a noninfectious provirus is associated with B-cell lymphoma development (41).…”

“…The HIV-1 matrix protein p17 is detected in the blood and bone marrow of HIV ϩ patients (9,10), and, together with other HIV-1 structural proteins, it accumulates in the germinal center of lymph nodes of patients under successful cART and in the absence of any in situ viral replication (11,12). This is not surprising since latently HIV-1-infected resting T cells are capable of producing HIV-1 proteins without supporting spreading infection (13).…”

Mixed cellularity classical Hodgkin lymphoma (MCcHL)

“…These lesions affecting members of the NF-kappaB or JAK/STAT signalling pathways (Küppers and Re, 2007;Hartmann et al, 2008;Steidl et al, 2010;Küppers 2011;Küppers et al, 2012;Pasqualucci and Dalla Favera, 2014). See also the pertinent section within the CARDS describing the general features of cHL (Küppers, 2011;Carbone and Gloghini, 2016).…”

“…See the pertinent sections within the CARDS describing the general features of cHL (Küppers, 2011;Carbone and Gloghini, 2016).…”

Does persistent HIV replication explain continued lymphoma incidence in the era of effective antiretroviral therapy?

“…recently described the association of pre-lymphoma lymphadenopathy associated with increased expression of the HIV proteins p17 and gp120 [49]. Indeed, high levels of p17 persist in lymph nodes of PLWH, even under the influence of cART [50,51]. Working from these observations, Dolcetti and colleagues recently demonstrated that particular p17 sequence variants are expressed in HIV patients presenting with NHL, and that these altered p17 proteins have direct effects on B cell proliferation and signaling to Akt and PTEN [52].…”