Barriers to a cure for HIV: new ways to target and eradicate HIV-1 reservoirs

Abstract

Antiretroviral therapy for HIV infection requires life-long access and strict adherence to regimens that are both expensive and associated with toxicities. There is growing recognition that a curative intervention will be needed to fully stop the epidemic. The failure to eradicate HIV infection during long-term antiretroviral therapy reflects the intrinsic stability of the viral genome in latently infected CD4+ T cells and other cells and perhaps ongoing low-level viral replication. Heterogeneity in latently infected cell populations and homeostatic proliferation of infected cells may influence the dynamics of virus production and persistence. Chronic immune activation, inflammation and immune dysfunction persist despite potent antiretroviral therapy and likely have important effects on the size and distribution of the viral reservoir. The inability of the immune system to recognize cells harboring latent virus and to eliminate cells actively producing virus represents the biggest challenge to finding a cure. In this perspective, we highlight new approaches toward unraveling the complex virus-host interactions that lead to persistent infection and latency and discuss the rationale for combining novel therapeutic strategies with current antiretroviral treatment options with the goal of curing HIV disease.

Interleukin-21 combined with ART reduces inflammation and viral reservoir in SIV-infected macaques

“…Elevated levels of inflammation and immune activation that can persist even in ART-treated HIV-infected individuals with effective viral suppression have emerged as key correlates of morbidity and mortality from non-AIDS complications such as cardiovascular disease, neurocognitive dysfunction, and kidney and bone abnormalities, among others (1,3). Furthermore, residual inflammation may contribute to HIV persistence during ART by several mechanisms, such as favoring de novo infection of activated "target" CD4 + T cells that replenish the reservoir and upregulating the expression of immune checkpoint blockers that may limit the function of HIV-specific immune responses (1,3,4). Therefore, a vicious cycle in which inflammation, poor antiviral responses, and HIV persistence are intimately connected may occur in ART-treated HIV-infected individuals.…”

Relationship between Measures of HIV Reactivation and Decline of the Latent Reservoir under Latency-Reversing Agents

“…Therefore, treatment is required to be lifelong, with possible long-term toxicities. The cause of viral rebound and the most important obstacle to a cure for HIV infection are unclear, but it is generally believed that virus persists, in part, as long-lived latently infected cells (3)(4)(5). Since latently infected cells do not produce virus, they are unaffected by the immune system and are unresponsive to ART (6).…”

Primary HIV infection: a medical and public health emergency requiring rapid specialist management

“…9 Viral dissemination and the establishment of a viral reservoir throughout the body occurs rapidly after acquisition 9 and is the reason why ART cannot cure HIV infection. 10,11 Despite years of successful suppressive ART a latent pool of HIV-infected cells is thought to be the source of viral recrudescence on stopping therapy.…”