Human immunodeficiency virus type 1 (HIV-1) infects many cells in the human host, but there are two major targets — macrophages and CD4+ T cells. Over the years, the list of complicated ways in which the virus is known to behave has grown. In their paper on page 213 of this issue, Swingler et al.1 add to the list. They show how, through stimulating interaction between various host cells, HIV-1 sets up new potential viral reservoirs in 'resting' T cells.
At one time, the dogma was that HIV-1 could infect only actively replicating T cells that are going through the cell cycle. These are cells that have left the resting stage on encountering antigen of an invader, and in response have become activated and have started to reproduce themselves. But this dogma has been shown to be overly simplified. For example, low levels of the intercellular signalling molecules known as cytokines are enough to produce HIV-1 infection of resting human T cells2. The evidence of this induction of 'viral permissivity' in resting cells has meant that cytokines such as interleukin-7 have received much attention of late3. Complementary in vivo data have come from studies with both HIV-1 and simian immunodeficiency virus (SIV). From these it seems that T cells that have not been fully activated can replicate SIV and HIV-1, and act as low-level producers of virus and as residual viral reservoirs in infected monkeys and humans, respectively4. How exactly HIV-1 infects resting cells has been controversial, but such infection clearly occurs in vivo5, 6.
Into this complex mix of studies comes the paper by Swingler and colleagues1. They have carried out an exciting series of experiments that provide an indication of the complexity involved in developing a permissive viral reservoir in relatively inactive T cells. As depicted in Fig. 1, the authors show that HIV-1 infection of macrophages leads to the production of at least two soluble factors, sCD23 and sICAM-1. These factors then stimulate the production of accessory surface molecules on another component of the immune system, B cells, when the B cells are in close proximity to the HIV-1-infected macrophages — that is, when the two cell types are occupying the same microenvironment. When, in turn, these B cells come into contact with non-cell-cycling T cells, they allow the T cells to become permissive for HIV-1 infection. These events can occur without the T cells being fully activated and in the absence of cell-cycle activity.
Figure 1: Cell-to-cell cross-talk, and the induction of HIV-1 infection in resting CD4+ T cells.
![Figure 1 : Cell-to-cell cross-talk, and the induction of HIV-1 infection in resting CD4|[plus]| T cells. Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, or to obtain a text description, please contact npg@nature.com](/nature/journal/v424/n6945/images/424136a-f1.0.jpg)
The sequence of events described by Swingler et al.1 begins with the production of the viral accessory protein, Nef, in HIV-1-infected macrophages. Nef prompts the production of soluble factors (sICAM-1 and sCD23), which stimulate B cells to become the intermediates in making resting, non-cell-cycling T cells become 'permissive' for viral infection. Finally, viral replication and production can also be induced in certain non-cell-cycling T cells.
High resolution image and legend (28K)What is especially interesting about these studies1 is the demonstration that the HIV-1 accessory protein Nef is involved. Nef is a key viral protein in disease induction in vivo by both HIV-1 and SIV, acting in the pathways that induce changes in the activation state of an infected cell7, 8. When expressed from HIV-1, or even alone from another non-HIV-1 viral vector, Nef leads to increased production of sICAM-1 and sCD23 molecules from infected macrophages. This is similar to the pathway of induction of selected macrophage-derived factors from the natural ligand CD40 found on uninfected macrophages9. In some cases, Nef may even be produced directly in 'pre-integration latently infected' T cells10, 11. So Nef seems to engage in molecular piracy, taking over an existing cellular pathway and allowing HIV-1 to replicate in T cells in diverse activation states.
This would be complicated enough, but it is only part of the story. It seems that sCD23 first has to alter B cells before they in turn can make non-cell-cycling T cells into fertile fields for HIV-1 infection and replication. Yet another signal — CD80, induced by sICAM-1 — has to be expressed on the surface of B cells to allow productive replication of HIV-1 in the target T cells, rather than just allowing infection. Otherwise, the T cell becomes infected but has a provirus that may act as a 'Trojan Horse of non-production'12, allowing viral expression and release to take place only after a second signal, such as CD80, is applied from a further activated subset of B cells. In previous work, the Swingler group13 had demonstrated that HIV-1 Nef produced from macrophages may, through chemotaxis, also actually attract T cells into physical proximity with the infected macrophage.
If this sounds complex, it is — even for experts in the study of retroviruses. But no one said that understanding HIV-1's reservoirs would be simple. The data presented by Swingler et al. are unique in that they demonstrate that viral reservoirs during highly active antiretroviral therapy in HIV-1-infected patients may be far more intricate than consisting simply of low-level replication in activated T cells and latency in fully resting T cells12. These new data indicate ways in which productive replication from certain viral reservoirs can be upregulated, and also may explain how some non-cell-cycling T cells can become a latent but inducible viral reservoir in vivo. Overall, they show that there is an entire spectrum of interactions between the virus and host cells, which together produce the general pattern of HIV-1 reservoirs and residual disease.
Cell-to-cell cross-talk, such as that described here, may represent a series of mechanisms by which viruses alter a particular microenvironment, and change the cellular milieu to one that is conducive to viral replication and maintenance. We need to understand these mechanisms, so as to manipulate that milieu to favour antiviral therapies. The aim will be not only to decrease the production of HIV-1 but also to destroy the cellular reservoirs that have so far kept us from being able to eradicate HIV-1 infection14.