Epidemiological studies have demonstrated that meth use is particularly common among HIV-infected patients.10,40
However, very little is known about the deleterious effect of meth on the host's immune response and the role of meth in the immunopathogenesis of HIV infection. It has been proposed that the modulatory effects of meth on the immune functions related to response to HIV infection may increase the susceptibility of an individual to initial HIV infection and promote the development of HIV infection toward AIDS.14
One of the ways to address the complex interactions between meth use and HIV is to use a permissive cell system such as macrophages.
Macrophages play a central role in the immunopathogenesis of HIV disease. Monocytes/macrophages are involved in HIV infection during all stages of disease in which they serve as major target cells, reservoirs, vehicle to other tissues, and transmitters of the virus to CD4+
T cell. Thus, it is necessary to determine whether meth has the ability to enhance HIV infection of macrophages. Our findings that meth increased HIV replication in macrophages () provide direct in vitro
evidence to support the clinical study14
showing that plasma virus loads were higher in meth users. In addition, our study is in agreement with the investigation showing that meth exposure can accelerate feline immunodeficiency virus replication.15
Direct action of meth on cellular functions may require its interaction with the dopamine receptors on the target cells. Because D1R has long been implicated in mediating the persistent dopaminergic deficits caused by meth,41,42
we postulated that the D1R expressed on macrophages is involved in immunoregulating macrophage functions. We showed that human blood monocyte-derived macrophages expressed D1R (). Most importantly, we demonstrated that D1R expressed on macrophages is functional, because the D1R antagonists blocked the action of meth on HIV infection of macrophages (). This finding is supported by a recent report43
showing that meth-mediated up-regulation of DC-SIGN on monocyte-derived dendritic cells was reversed by the D1R antagonist SCH23390. Because both dendritic cells and macrophages are antigen-presenting cells, it is possible that D1R is involved in the meth action in the both cell systems. We also examined the hypothesis that meth has the ability to stimulate D1R expression by macrophages. It has been reported that D1R protein is elevated in nucleus accumbens of human, chronic methamphetamine users.44
However, our experiments examining the impact of meth on D1R failed to reveal the evidence that meth stimulates D1R expression (data not shown), suggesting that up-regulation of D1R is not a mechanism responsible for the meth action on HIV. In addition to dopamine receptors, dopamine was also shown to be involved in the regulation of HIV gene expression in both neuronal cells and cells of the immune system.45
Dopamine activates HIV expression in chronically infected T cells.46
Thus, it is possible that meth, through the induction of endogenous dopamine in macrophages, enhanced HIV replication. We, however, were unable to detect the expression of endogenous dopamine by primary macrophages. This finding is in disagreement with the report that a macrophage cell line produced endogenous dopamine.47
This discrepancy could be due to the difference in the cell types used. In our study, we used primary monocyte-derived macrophages. Nevertheless, the in vivo
interpretations of these observations remain to be determined.
In the present study, we have demonstrated two potential mechanisms by which meth may enhance HIV replication. We first showed that meth enhanced HIV infection and replication by inducing the expression of CCR5 receptor on macrophages. This finding supports the report23
that meth up-regulates CCR5 receptor expression in monocyte-derived mature dendritic cells. Our data also are in agreement with the observations of Gavrilin et al15
showing that meth influences the first step of virus (feline immunodeficiency virus) interaction during cell-to-cell transmission of virus. The effect of meth on CCR5, however, is not mediated by D1R, because the D1R antagonists failed to block the meth action (data not shown), suggesting that meth modulates CCR5 expression by a different mechanism. As a key HIV entry co-receptor, CCR5 plays an important role in macrophage tropic or nonsyncytium-inducing HIV strain infection of macrophages.34,48,49
Thus, our finding that meth up-regulated CCR5 expression () provides a plausible mechanism involved in meth-mediated enhancement of HIV infection of macrophages.
In addition, we investigated the impact of meth on the expression on endogenous IFN-α
, a potent antiviral cytokine, in macrophages. The role of meth in modulating cytokine expression has been examined by others. For example, meth exposure significantly inhibits Th1 cytokine (interleukin-2 and IFN-γ
) production in splenocytes.50,51
Meth is also able to significantly increase the expression of tumor necrosis factor-α
the cytokines that have potential to enhance HIV replication.52
However, it is unclear whether meth can modulate IFN-α
expression. Our study for the first time demonstrates that meth has the ability to suppress the expression of intracellular IFN-α
in macrophages (). This meth action on IFN-α
is mediated by D1R, because the D1R antagonists completely blocked the effect of meth on IFN-α
expression by macrophages (). IFN-α
is a key element of the innate defense mechanism against viral infections. It has been demonstrated that IFN-α
is a potent inhibitor of HIV infection of CCR5+
Thus, the suppression of intracellular IFN-α
expression by meth would provide a favorable microenvironment for HIV replication in macrophages. To further determine whether meth, through suppressing the IFN signaling pathway, inhibits IFN-α
expression in macrophages, we examined the hypothesis that meth inhibits the expression of STAT1, a crucial factor in mediating IFN-dependent biological responses, including the activation of the antiviral state and the induction of type I IFN expression.53–55
The finding that meth suppressed STAT1 expression () supports our hypothesis and provides a mechanism for the meth-mediated down-regulation of endogenous IFN-α
in macrophages. These data also support the studies by others22,23
showing that meth is immunosuppressive.
Taken together, meth, through the enhancement of CCR5 expression and the suppression of intracellular IFN-α/STAT1 expression, promotes HIV infection of macrophage. These findings provide direct evidence at cellular and molecular levels to support the concept that meth has a cofactor role in enhancing HIV infection and replication. However, further clinical studies are required to validate our in vitro observations and to delineate the mechanisms of meth-mediated enhancement of HIV infection in vivo. These studies will be critical not only for our basic understanding of meth-mediated HIV immunopathogenesis but also for the design and development of innate immunity-based intervention and treatment strategies for meth users with HIV infection.