Immune activation and HIV persistence: implications for curative approaches to HIV infection

Abstract

Despite complete or near-complete suppression of human immunodeficiency virus (HIV) replication with combination antiretroviral therapy, both HIV and chronic inflammation/immune dysfunction persist indefinitely. Untangling the association between the virus and the host immune environment during therapy might lead to novel interventions aimed at either curing the infection or preventing the development of inflammation-associated end-organ disease. Chronic inflammation and immune dysfunction might lead to HIV persistence by causing virus production, generating new target cells, enabling infecting of activated and resting target cells, altering the migration patterns of susceptible target cells, increasing the proliferation of infected cells, and preventing normal HIV-specific clearance mechanisms from function. Chronic HIV production or replication might contribute to persistent inflammation and immune dysfunction. The rapidly evolving data on these issues strongly suggest that a vicious cycle might exist in which HIV persistence causes inflammation that in turn contributes to HIV persistence.

Fig. 1. HIV initiates and sustains a ‘vicious cycle’

(A). Acute HIV infection causes damage to the mucosal integrity of the gastrointestinal tract, resulting in continuous local and systemic exposure to gut microbial products. HIV and these microbial products cause activation of T cells and expansion of CD4⁺ T cells, resulting in more target cells and higher levels of HIV replication. Direct and indirect mechanisms lead to CD4⁺ T-cell loss, broad immunodeficiency, and higher levels of both HIV and microbial translocation. (B). Chronic activation of the immune system results in direct damage to lymphoid tissues, which in turn contributes to failure to regenerate T cells and overall decrease in function of adaptive and innate immune systems. The resulting immunodeficiency results in excess pathogens (e.g. HIV, gut microbes, herpes viruses) and, as a result, yet more immune activation. This chronic inflammatory state predicts and presumably causes development of AIDS and non-AIDS conditions such as early cardiovascular disease.

Fig. 2. Immune activation sustains HIV persistence during antiretroviral therapy

HIV-associated damage to the lymphoid system is only partially reversible. During long-term antiretroviral therapy, the residual immune dysfunction (which is due in part to loss of thymic tissue, fibrosis in germinal centers of secondary lymphoid structure, hematopoietic stem cell loss, and mucosal barrier breakdown) results in immunodeficiency, excess amounts of pathogens and chronic immune activation. The immune activation in turn leads to migration of CD4⁺ T cells to foci of HIV replication, generation of activated and susceptible target cells, and production of virus from latently infected cells (all of which enable more efficient cell-to-cell spread of HIV and replenishment of infected cells). The inflammatory environment also leads to proliferation and maintenance of latently infected cells. The residual HIV replication/production in turn contributes to sustained tissue damage and immune activation.

Fig. 3. Mechanisms by which immune activation causes HIV persistence

The chronic immune dysfunction of antiretroviral-treated HIV infection contributes to HIV persistence by (1) enabling HIV replication via generation of activated CD4⁺ T cells, (2) enabling infection of resting cells, (3) reducing the capacity of the adaptive immune system to clear infected cells, (4) causing differentiation and proliferation of infected cells, and (5) increasing expression of cell-surface negative regulators, which in turn contributes to persistence of latently infected cells. Detailed knowledge regarding the mechanisms which contributes to each of these steps might lead to the development of immune-based therapeutics which could contribute to an HIV cure.