HIV-1 in Monocytes and Macrophages: An Overlooked Reservoir?

To the Editor:

Interest in eradicating HIV infection has re-emerged in recent years due to the reporting of a number of cases, suggesting eradiation might be possible: first, the “Berlin patient” who remains HIV free (10), second, the two “Boston patients” whose viral load ultimately rebounded (1), and, finally, the perinatally infected “Mississippi Baby” in whom administration of antiretroviral therapy (ART) at 30 h of age resulted in a 2-year period of viral control, after ART discontinuation before the virus rebounded (2). These findings indicate that there is a need to either eradicate all replication competent viruses or to enhance the host immune system capability to contain the residual virus that may persist after therapeutic intervention.

Macrophages and CD4⁺ T cells are natural target cells for HIV-1, and both cell types contribute to the establishment of the viral reservoir responsible for continuous residual virus replication during ART and viral load rebound upon treatment interruption. Like T cells, macrophages can be infected with HIV, and even become a reservoir of ongoing virus replication throughout the body. HIV can enter the macrophage through binding of gp120 to CD4 and second membrane receptor, CCR5. Both circulating monocytes and macrophages serve as a reservoir for the virus and HIV has evolved mechanisms to prolong the lifespan of infected macrophages (7,8).

It has been proposed that monocytes serve as a direct source of plasma virus by producing infectious HIV-1 in peripheral blood (11). In patients on ART, viruses produced by monocytes/macrophages might be responsible for a large proportion of the virus load in the face of declining CD4⁺ T cells (3), possibly due to differences in metabolism and cofactor requirements (9). Further evidence of higher levels of HIV-1 transcripts and sequence evolution in monocytes than in resting CD4⁺ T cells of patients on ART suggests a relatively higher level of viral replication in monocytes than in resting CD4⁺ T cells (4). Although monocytes circulate in the peripheral blood for only 1–3 days before differentiating into macrophages in tissues, findings of persistent HIV-1 in blood monocytes suggest ongoing renewal of infected monocytes by virus replication and/or recent infection of monocytes or their precursor cells in the bone marrow (11). HIV-1 is able to infect nondividing cells such as tissue macrophages productively because postentry viral nucleoprotein complexes are specifically imported into the nucleus in the absence of mitosis.

Since memory CD4⁺ T cells do not develop until after birth, monocytes/macrophages may have been the crucial viral reservoir in the “Mississippi baby” case (2). It is clear now that even with very early treatment within hours of birth, when typically neonates lack central memory T cells, HIV establishes reservoirs that persist despite effective ART. Proposed as proof of concept have been the studies of Luzuriaga et al. that have shown that babies born to untreated HIV mothers when initiated on ART very early in infancy often fail to develop HIV antibody (2), have limited HIV proviral DNA reservoirs (5), and likely have marked reduction of latent replication competent virus (6). The question why viral rebound was delayed in the “the Mississippi baby” and the “Long Beach baby” may be due to the low frequency of infected cells. However, when viral reactivation occurred, as no HIV-specific CD8⁺ T-cell responses had been generated, viremia could not be controlled. Studies are needed to address the parameters that affect the time to HIV rebound and to identify the cellular sources of rebound virus.

The dramatic rebound effect strengthens the idea that latent viral reservoirs are the major driver to HIV lifelong persistence. These reservoirs are in essence invisible to ARTs, and are undetectable by conventional assays but are capable of producing productive virus in large quantities should the right environment be created in a short period of time. The macrophage is an ideal candidate for this nonmemory T-cell latent reservoir for HIV, as first, macrophages are able to evade the immune response and second, macrophages express CD4 receptors that provide the anchor for the virus. As such, monocytes may not be the “main” target of HIV infection, but the immunological environment induced in the host postinfection contributes to monocyte activation, which not only helps propagate the virus even further but also acts as a reservoir of virus and impedes HIV eradication.

Major research efforts are currently underway to understand the biology of the viral reservoir, the mechanism of viral latency, and the potential of various therapeutic approaches to target the reservoir. Numerous studies are attempting to explore the concept of purging CD4⁺ T-cell latency by using a “shock and kill” strategy, whereby HIV-1 reservoirs in resting CD4⁺ T cells are activated, thus making the cells more susceptible to be eliminated by immunological effector mechanisms and cytotoxic drugs. Although it is true that the majority of HIV-1 replication occurs in T cells, monocyte/macrophages nonetheless represent an important HIV reservoir since replication in macrophages does not trigger cytokine production or cell death. HIV-1 behaves differently in different cell types whether due to different cofactor requirements or availability. However, the characterization of the differences and similarities between replication and latency in these cell types will be critical for a full understanding of transmission and pathogenesis as well as the development of new therapies and vaccines.