Three papers on macrophages and HIV infection

1 December 2014. Related: Cure-related research, Basic science and immunology.

Richard Jefferys, TAG

The question of whether HIV infection of macrophages plays an important role in pathogenesis remains controversial and unresolved.

For cure researchers, the related question of whether macrophages contribute to viral persistence during antiretroviral therapy is crucial, but also unanswered. Three recent papers describe results from studies designed to shed light on this subject.

In the journal Immunity, Jason Brenchley’s research group presents results from experiments in the SIV/macaque model using viruses that do and do not express the Vpx protein, which has previously been reported to be important for infection of myeloid cells (including macrophages). [1]

To their surprise, the researchers found that Vpx did not significantly influence the extent to which SIV was detectable in myeloid cells. Mucosal tissues showed little evidence of myeloid cell infection despite depletion of CD4 T cell targets, but in 40% of animals SIV DNA was detectable in myeloid cells in the mesenteric lymph nodes and spleen. However, further analyses revealed the presence of T cell receptor DNA in addition to the SIV DNA, suggesting that these cells were macrophages that had phagocytosed SIV-infected CD4 T cells. The researchers state: “we believe our data clearly suggest that viral RNA and DNA within myeloid cells can be attributed to clearance of virally infected cells and immune complexes and not bone fide SIV infection of myeloid cells in vivo.”

An open access paper in Cell Host & Microbe offers a possible twist to this tale, reporting that phagocytosis of HIV-infected CD4 T cells by macrophages can lead to them becoming productively infected. [2]

The findings are derived from in vitro laboratory experiments. The data indicate that macrophages selectively target HIV-infected CD4 T cells for phagocytosis, although the researchers have yet to identify the exact mechanism for this selectivity. The online version of the paper is accompanied by three quicktime videos of macrophages phagocytosing multiple HIV-infected CD4 T cells. [3]

Lastly, in PLoS Pathogens Luca Micci and colleagues show that artificial depletion of CD4 T cells in SIV-macaques (using a CD4-targeting monoclonal antibody) produces evidence of extensive infection of macrophages, as well as microglial cells in the brain. [4]

In lymphoid tissues of non-depleted animals, T cells made up more than 80% of the cells containing SIV RNA, whereas in the setting of CD4 T cell depletion more than 80% of the cells containing SIV RNA displayed macrophage markers. The macrophages showed evidence of high levels of activation and were shorter-lived than was expected based on previous studies. Since CD4 T cells were not completely depleted in the animals, it seems possible that phagocytosis of SIV-infected CD4 T cells might have contributed to the presence of SIV RNA in macrophages in this study, but the researchers do not specifically assess the possibility.

Unfortunately, it appears that the publication of these papers within a short time period precluded the authors from being able to comment on each other’s work, which would have been helpful in understanding how the data fit together. Because it involves in vivo results from macaques without any manipulations, the Immunity paper may arguably represent the most reliable gauge of the contribution of macrophages in SIV infection.

The results imply that previously reported studies documenting the presence of HIV DNA in macrophages are explained, at least in part, by phagocytosis of infected CD4 T cells. However, the study published in Cell Host & Microbe suggests that additional work might be needed to fully distinguish between macrophages containing viral DNA solely due to phagocytosis and those that are also productively infected.

None of the papers offer a definitive answer to the question of whether infected macrophages make up part of the long-lived HIV reservoir that persists despite antiretroviral therapy. Brenchley and colleagues argue that, based on their findings, therapeutic interventions aiming to target latent HIV should continue to focus on CD4 T cells.

Source:

TAG basic science blog. (25 Nov 2014).
http://tagbasicscienceproject.typepad.com

References:

1. Calantone N et al. Tissue myeloid cells in SIV-infected primates acquire viral DNA through phagocytosis of infected T cells. Immunity. 2014 Sep 18;41(3):493-502. doi: 10.1016/j.immuni.2014.08.014.
   http://www.cell.com/immunity/abstract/S1074-7613(14)00308-2
2. Baxter AE et al. Macrophage Infection via Selective Capture of HIV-1-Infected CD4+ T Cells. Cell Host & Microbe, Published Online: November 20, 2014. Open access.
   http://www.sciencedirect.com/science/article/pii/S1931312814003886
3. Ibid, Baxter et al. (Click the video tab under the Images/Data menu).
   http://www.cell.com/action/showImagesData?pii=S1931-3128%2814%2900388-6
4. Micci L et al. CD4 depletion in SIV-infected macaques results in macrophage and microglia infection with rapid turnover of infected cells. PLoS Pathog. 2014 Oct 30;10(10):e1004467. doi: 10.1371/journal.ppat.1004467. eCollection 2014. Open access.
   http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1004467