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

Abstract

Non-Hodgkin lymphomas are highly increased in incidence in individuals infected with HIV, and this continues to be the case in spite of highly effective combined antiretroviral therapy (cART). New evidence has demonstrated that while successful virtual recovery of CD4 counts and elimination of HIV from peripheral blood can be achieved with cART, viral replication can still occur in lymphoid tissues. In addition, recent studies have suggested that adipose tissue provides an additional reservoir for HIV-infected macrophages and T lymphocytes even in the context of successful cART therapy. In this review article, we discuss possible mechanisms leading to the development of lymphoma in the cART era.

Figure 1. Model of intra-follicular dysfunction leading to lymphoma in chronic HIV infection

(A) In normal lymph nodes, Tfr regulate the proliferation and function of Tfh, which, in turn, suppress replication of lymphotrophic pathogens KSHV and EBV and regulate the germinal center reaction and production of memory B lymphocytes and plasma cells. (B) HIV infection results in expansion of both Tfr and Tfh subsets, but dysregulates their interaction as well as the ability of Tfh to provide appropriate help to B cells, creating a decrease in memory B cell production and dysregulation of plasma cell differentiation. Suppression of Tfh function could allow proliferation of lymphotrophic pathogens KSHV and EBV and allow direct lymphomagenesis by viral mechanisms. Additionally, HIV gene products and virions accumulating in lymph nodes contribute directly to both B cell dysfunction and viral lymphomagenesis.