National Reference Center for AIDS, Microbiology Department, School of Medicine, University of Buenos Aires, Buenos Aires, Argentina.
PLoS One. 2009 Dec 14;4(12):e8246. doi: 10.1371/journal.pone.0008246.
Cells of monocyte/macrophage lineage are one of the major targets of HIV-1 infection and serve as reservoirs for viral persistence in vivo. These cells are also the target of the protozoa Trypanosoma cruzi, the causative agent of Chagas disease, being one of the most important endemic protozoonoses in Latin America. It has been demonstrated in vitro that co-infection with other pathogens can modulate HIV replication. However, no studies at cellular level have suggested an interaction between T. cruzi and HIV-1 to date.
METHODOLOGY/PRINCIPAL FINDINGS: By using a fully replicative wild-type virus, our study showed that T. cruzi inhibits HIV-1 antigen production by nearly 100% (p<0.001) in monocyte-derived macrophages (MDM). In different infection schemes with luciferase-reporter VSV-G or BaL pseudotyped HIV-1 and trypomastigotes, T. cruzi induced a significant reduction of luciferase level for both pseudotypes in all the infection schemes (p<0.001), T. cruzi-HIV (>99%) being stronger than HIV-T. cruzi (approximately 90% for BaL and approximately 85% for VSV-G) infection. In MDM with established HIV-1 infection, T. cruzi significantly inhibited luciferate activity (p<0.01). By quantifying R-U5 and U5-gag transcripts by real time PCR, our study showed the expression of both transcripts significantly diminished in the presence of trypomastigotes (p<0.05). Thus, T. cruzi inhibits viral post-integration steps, early post-entry steps and entry into MDM. Trypomastigotes also caused a approximately 60-70% decrease of surface CCR5 expression on MDM. Multiplication of T. cruzi inside the MDM does not seem to be required for inhibiting HIV-1 replication since soluble factors secreted by trypomastigotes have shown similar effects. Moreover, the major parasite antigen cruzipain, which is secreted by the trypomastigote form, was able to inhibit viral production in MDM over 90% (p<0.01).
CONCLUSIONS/SIGNIFICANCE: Our study showed that T. cruzi inhibits HIV-1 replication at several replication stages in macrophages, a major cell target for both pathogens.
单核细胞/巨噬细胞谱系的细胞是 HIV-1 感染的主要靶标之一，也是体内病毒持续存在的储存库。这些细胞也是原生动物克氏锥虫的靶标，克氏锥虫是恰加斯病的病原体，是拉丁美洲最重要的地方病原生动物病之一。已经在体外证明，与其他病原体的合并感染可以调节 HIV 的复制。然而，迄今为止，在细胞水平上还没有研究表明 T. cruzi 和 HIV-1 之间存在相互作用。
方法/主要发现：通过使用完全复制的野生型病毒，我们的研究表明，T. cruzi 在单核细胞衍生的巨噬细胞（MDM）中几乎抑制了 HIV-1 抗原的产生 100%（p<0.001）。在不同的感染方案中，使用带有荧光素酶报告基因 VSV-G 或 BaL 假型化的 HIV-1 和锥虫滋养体，T. cruzi 在所有感染方案中都显著降低了两种假型的荧光素酶水平（p<0.001），T. cruzi-HIV（>99%）比 HIV-T. cruzi（大约 90%为 BaL 和大约 85%为 VSV-G）感染更强。在已建立 HIV-1 感染的 MDM 中，T. cruzi 显著抑制了荧光素酶活性（p<0.01）。通过实时 PCR 定量 R-U5 和 U5-gag 转录本，我们的研究表明，在存在锥虫滋养体的情况下，两种转录本的表达均显著减少（p<0.05）。因此，T. cruzi 抑制病毒整合后步骤、早期进入后步骤和进入 MDM。锥虫滋养体还导致 MDM 表面 CCR5 表达减少约 60-70%。在 MDM 内繁殖的锥虫似乎不是抑制 HIV-1 复制所必需的，因为锥虫滋养体分泌的可溶性因子表现出类似的效果。此外，主要寄生虫抗原克氏锥虫蛋白酶，它是由锥虫滋养体形式分泌的，能够抑制 MDM 中超过 90%的病毒产生（p<0.01）。
结论/意义：我们的研究表明，T. cruzi 在巨噬细胞中抑制 HIV-1 的复制，在几种复制阶段，巨噬细胞是这两种病原体的主要靶标。
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