Immunologic Strategies Directed Toward HIV Infection

使用有效的抗逆转录病毒疗法（ART）治疗艾滋病毒感染者极大地改变了许多患者的临床结果，并导致艾滋病发病率和与艾滋病有关的死亡率大幅下降。然而，现在很清楚的是，抗逆转录病毒治疗对血浆病毒血症的长期抑制不太可能根除大多数感染者的艾滋病毒。此外，长期抗逆转录病毒治疗可能导致药物引起的毒性、难以坚持用药方案以及产生耐药病毒。因此，更好地了解宿主免疫系统是如何控制HIV复制的，对于开发旨在有效抑制HIV感染个体的替代免疫策略非常重要。

The use of effective antiretroviral therapy (ART) to treat HIV-infected individuals has dramatically changed the clinical outcome for many patients and has led to a substantial decline in the incidence of AIDS and in AIDS-related mortality. However, it is now clear that prolonged suppression of plasma viremia by ART is not likely to eradicate HIV in most infected individuals. In addition, long-term ART may lead to drug-induced toxicities, difficulties in adhering to drug regimens, and development of drug-resistant virus. Thus, a better understanding of how the host immune system controls HIV replication is important in developing alternative immunologic strategies aimed at efficient suppression of HIV in infected individual. pDCs are important mediators of innate immunity and act mainly through secretion of interferon (IFN)-a. Previous studies have found that these cells can suppress HIV in vitro. Additionally, pDCs have been shown to be severely reduced in the peripheral blood of HIV-infected individuals. Over the past year, we sought to determine the ability of pDCs to directly suppress viral replication ex vivo and to delineate the potential mechanisms whereby pDCs are depleted in HIV-infected individuals. We demonstrated that activated pDCs strongly suppress HIV replication in autologous CD4+ T cells via a mechanism involving IFN-a as well as other antiviral factors. Of note, unstimulated pDCs from infected individuals who maintained low levels of plasma viremia without antiretroviral therapy were able to suppress HIV ex vivo via mechanisms requiring cell-to-cell contact. Our data also demonstrated that death of pDCs by apoptosis and necrosis is induced by fusion of HIV with pDCs. Taken together, our data suggested that pDCs play an important role in the control of HIV replication and that high levels of viral replication in vivo are associated with pDC cell death via apoptosis and necrosis. Elucidation of the mechanisms by which pDCs suppress HIV replication in vivo may have clinically relevant implications for future therapeutic strategies.