Antiretroviral therapy in macrophages: implication for HIV eradication

Abstract

HIV type-1 (HIV-1) accounts for more than 25 million deaths and nearly 40 million people are infected worldwide. A significant obstacle in clearing virus from infected individuals is latently infected viral reservoirs. Latent HIV-1 can emerge with recrudescence as a productive infection later in disease progression and could provide a source for the emergence of resistant HIV-1. It is widely recognized that macrophages represent a latently infected viral reservoir and are a significant and critical HIV-1 target cell in vivo. Macrophages can be divided into multiple subsets of macrophage-like cells, all of which are susceptible to HIV-1 infection, including dendritic cells, Langerhans cells, alveolar macrophages, mucosal macrophages and microglial cells. Current antiretroviral therapy (ART) often displays differential antiviral activity in macrophages relative to CD4(+) T-lymphocytes. Significant work has been performed to establish antiviral activity of many clinically approved ART in macrophages; however, a direct link between antiviral activity and specific mechanisms responsible for these antiviral effects are incompletely understood. This review identifies many understudied areas of research, along with topics for further research in the field of HIV therapy and eradication. Discussion focuses upon the known cellular pharmacology and antiviral activity of antiretroviral agents in macrophages and its relationship to latency, chronic HIV-1 infection and therapeutic strategies to eradicate systemic HIV-1 infection.

Figure 1

Mechanisms for establishment and maintenance of HIV-1 reservoirs in macrophages Acute HIV type-1 (HIV-1) infection results in establishment of infection in macrophages in the central nervous system (CNS) and every organ or tissue. Chronic infection results in increased recruitment of activated CD16⁺/CD69⁺ monocytes/macrophages to the brain, increased reactive oxygen species (ROS) and apoptosis followed by onset of HIV-associated dementia (HAD). These mechanisms increase the productive infection in brain microglia and contribute to maintenance of an HIV-1 viral reservoir in the CNS. Resistant HIV-1 in the brain or CNS along with latently infected macrophages originating from other tissues and organs contributes to maintenance of macrophage viral reservoirs. Together, these factors contribute to the inability to eradicate systemic HIV-1 infection [2,4,7,13,16,24,27,28,31-33,75,77-79,84-90,110].