Can macrophages form a latent reservoir of HIV?

Antiretroviral therapy (ART) can suppress HIV replication and reduce plasma viral loads to below detectible levels using standard clinical assays. These lifesaving combinations of drugs typically prevent disease progression and eliminate transmission of virus. However, ART alone does not cure the infection, meaning that people living with HIV require very strict and life-long medical care. Additional problems with current ART drugs include ongoing immune activation, development of virologic resistance, adverse drug-associated side effects and the fact that many people living with HIV around the world have limited access to ART [1]. Together, these issues make finding a cure for HIV a centrally important research goal. The best-understood reservoir of HIV during ART is within latently-infected CD4+ T cells [2,3]. When a host cell becomes infected by an HIV virion, the virus reverse transcribes its RNA genome and then inserts the resultant dsDNA genome into the host cells chromosomal DNA. Usually the integrated HIV DNA would then express RNA and proteins to produce new virus particles. However, in the case of latency, the integrated viral DNA remains in a reversible nonexpressing state that can persist not only for the life of the host cell but also in daughter cells if the host cell divides [4]. These latently-infected CD4+ T cells can readily be isolated from the blood and tissues of ART-treated individuals and stimulated to produce infectious virus. The ‘latent reservoir’ in very long-lived memory CD4+ T cells is thus a well-accepted and formidable barrier to HIV cure [5]. Yet an outstanding question in the field is whether other sources of persistent HIV also exist that could maintain infection over long periods of ART. Defining all the reservoirs of HIV that can sustain the infection during ART is critically important to developing effective cure strategies. One reason for this is that successful approaches for eliminating viral reservoirs in CD4+ T cells may not be effective in other infected cell types. If additional reservoirs are identified, then approaches to target them might be developed in parallel with those directed toward latency in CD4+ T cells. Conversely, if potential reservoirs can be ruled out then more focus can be appropriately placed on those that represent true barriers to cure. In addition to CD4+ T cells, certain myeloid cells including tissue macrophages and microglia in the brain are also infected by HIV [6]. Studies of differentiated tissue macrophages are more challenging than investigating HIV latency in CD4+ T cells. CD4+ T cells can readily be isolated from peripheral blood, whereas differentiated macrophages are primarily present in tissues and are thus difficult to access in most clinical studies. Nevertheless, prior research into HIV persistence in macrophages using samples from ART-treated individuals has often uncovered rare populations of HIV-infected macrophages in these ART-suppressed individuals, with evidence for persistent macrophage infection identified by analysis of HIV DNA, RNA, protein or (much more rarely) infectious virus production [6]. It is currently uncertain whether this infection arises from some low-level viral spread from latentlyinfected CD4+ T cells, the presence of defective proviruses, or a bona fide reservoir in myeloid cells. Therefore, the