Anatomical Distribution of Myeloid-Derived Suppressor Cells During HIV Infection

Abstract

In recent years, expansion of myeloid-derived suppressor cells (MDSCs) has been reported to play a detrimental role in the pathogenesis of human immunodeficiency virus (HIV) infection. Much effort has been focused to comprehend the mechanisms and factors that regulate the expansion of such unwanted immune cell populations. Of particular interest has been the mechanisms by which MDSCs could contribute to the pathogenesis of HIV infection. So far, the studies have been restricted to MDSCs in the circulatory system of HIV patients, but not in other tissue compartments. In fact, lymphatic tissues/organs are the primary sites where HIV replication and immune depletion/dysfunction occur during the course of HIV infection. Therefore, investigating the anatomical distribution of MDSCs in such compartments is essential to understand the role that they play in the pathogenesis of HIV infection. Hence, we aim to shed light on the available literature about the anatomical distribution of MDSCs during HIV infection and compare it with the distribution of MDSCs in other pathological conditions, mainly cancer.

Introduction

Year after year since the discovery of the human immunodeficiency virus (HIV) as the cause of acquired immunodeficiency syndrome (AIDS) in the early 1980s, we become one step closer to solving the dilemma of this virus. This reflects the huge advances in technology and knowledge attained for the past four decades, as a result of extensive investigation of HIV and its interactions with host cells and molecules (1,3,31,34,35).

In recent years, new pieces of knowledge have been added to the puzzle of HIV infection. One important finding is that myeloid-derived suppressor cells (MDSCs) play an important role in the pathogenesis of HIV infection. Although MDSCs are not a single population of immunosuppressor cells, rather they comprise heterogeneous populations of immune cells. When addressing the role of MDSCs, investigators focus their efforts on the two major populations, namely the monocytic and granulocytic MDSCs (g-MDSCs and m-MDSCs, respectively). For more details about the biological properties of such cells we encourage the reader to refer to our recently published studies (32,33).

In fact, when addressing the expansion of MDSCs in any pathological condition, in general, there are five aspects of information that we should be aware of. First, we have to determine the impact of MDSC expansion on the clinical status of a given pathological condition—is it negative (Yin) or positive (Yang)? Second, we have to determine the anatomical distribution of such cells to clearly understand their impact on that pathological condition.

Third, we have to determine the mechanisms and factors that regulate the expansion of MDSCs in that pathological condition, especially because the expansion of MDSCs is regulated by different signaling pathways. Fourth, the mechanisms by which MDSCs contribute to the pathogenesis of that pathological condition should be also determined. Five, all of the latter can help in the development of effective drugs and/or in determining the best therapy/therapeutic approach that could revert back the normal physiological levels and functions of MDSCs.

In the case of HIV infection, it is now well established that MDSCs are expanded during HIV infection (Fig. 1). In other words, since 2012, several groups of investigators have reported that MDSC expansion is stimulated during the early days post-HIV infection and such expansion extends/continues to the late phases of HIV infection, namely chronic HIV infection and AIDS phases (2,4,9,10,23,27 –29,37). Similar to what has already been observed in many pathological conditions, including cancer (32,33), MDSCs have been shown to play a detrimental role in the pathogenesis of HIV infection (2,4,9,10,23,27 –29,37). Furthermore, to some extent, the factors that regulate the expansion of MDSCs during HIV infection have also been investigated.

FIG. 1.

Kinetics of MDSC expansion during SIV infection in peripheral blood and bone marrow (6,26). MDSC, myeloid-derived suppressor cell; SIV, Simian immunodeficiency viruses.

Currently, we recognize that various factors are involved in stimulating the expansion of MDSCs during HIV infection, including the virus itself and its proteins (such as gp120 and Tat proteins), Gram-negative bacterial byproducts consequent to microbial translocation such as lipopolysaccharide, and inflammatory molecules produced in response to both HIV replication and microbial translocation. In contrast, MDSCs contribute to the pathogenesis of HIV infection by four major mechanisms: (i) inhibition of anti-HIV immune responses, (ii) enhancing HIV replication, (iii) hampering with the recovery of normal CD4⁺ T cells counts even under successful antiretroviral therapy, and possibly (iv) MDSCs may be directly infected by the virus and resist the killing mediated by cytotoxic T cells (2,4,9,10,15,23,25,27 –29,37). All of these mechanisms, particularly the latter one, indicate that MDSCs could provide a strategy for the virus to establish a chronic infection, one way or another.

However, the consequences of the differing anatomical distribution of MDSCs are still unaddressed. To this end, in this study, we address the available information about the anatomical distribution of MDSCs in both HIV and Simian immunodeficiency viruses (SIV) infections of humans and rhesus macaques, respectively.

Anatomical Distribution of MDSCs During Health and HIV and SIV Infections

In fact, according to the available literature, the anatomical distribution of MDSCs is well established in mice and to a lesser extent in nonhuman primates, such as rhesus macaques, when compared with humans. Under normal physiological conditions, in mice and nonhuman primates (rhesus macaques), the baseline level of MDSCs is kept at low levels, particularly in the liver, spleen, lymph nodes, and peripheral blood. In contrast, the highest percentage of MDSCs are reported to be in the bone marrow, indicating that the bone marrow is the major anatomical compartment for MDSCs (Table 1). However, in certain pathological conditions—particularly in cancer—the levels of MDSCs in mice and rhesus macaques dramatically increase to reach levels that sometimes exceed the baseline level by 10-fold or even more (8,12 –14,22,26,38).

Table 1.

Anatomical Distribution of Myeloid-Derived Suppressor Cells (%) in Mice, Nonhuman Primates “Rhesus Macaques,” and Humans Under Normal Conditions

	Mice	Nonhuman primates	Humans
Number of enrolled mice, nonhuman primates, and humans	NA	12 SIV mac251-infected animals 12 SHIV-infected macaques 68 naive animals	20 Patients with pancreatic cancer 12 Normal controls 10 Breastfeeding mothers
Peripheral blood	2–4%	>0.5%	>1%
Liver	5%	>2%	NA
Spleen	2–4%	NA	NA
Lymph nodes	>1%	NA	NA
Bone marrow	20–30%	20–25%	∼22%
Breast milk	NA	NA	∼52%
Pancreas	∼2%	NA	0%

The references for the results in mice (8,13,14,38), rhesus macaques (26), and humans (12,22).

NA, not available; SHIV, simian–human immunodeficiency virus; SIV, simian immunodeficiency viruses.

Similarly, in humans, MDSCs are kept at very low levels in peripheral blood, and such levels are increased dramatically in various pathological conditions, such as cancer and chronic infections, including HIV infection (2,4,9,10,23,27 –29,32,33,37). Unfortunately, the data about the anatomical distribution of MDSCs in healthy humans (Table 1) and HIV-infected patients as well as other pathological conditions are still relatively limited (32,33). This is mainly because of the difficulty and ethical issues related to the invasiveness of taking tissue samples, other than peripheral blood samples, especially bone marrow samples.

Nonetheless, Sui et al. (26) were the first to study the distribution of MDSCs during the course of SIV infection in rhesus macaques, from different anatomical compartments. Of note, they used this animal model because it recapitulates the pathogenesis of HIV infection in humans, as previously mentioned. Sui et al. (26) confirmed that both m-MDSC and g-MDSC populations are expanded in different anatomical sites such as bone marrow, peripheral blood, liver, and spleen upon establishing a chronic infection with a pathogenic strain of SIV (SIV_mac251), but not with a less pathogenic strain (simian–human immunodeficiency virus [SHIV]_SF162P4). Indeed, it is important to remember that in the setting of chronic inflammatory conditions such as cancer, in animal models, MDSCs are expanded in the bone marrow and peripheral blood (11,33,38).

However, one major shocking finding, in this particular study, was the remarkable decrease in MDSCs in the bone marrow but not the peripheral blood of chronically infected rhesus macaques, 14 months post-SIV infection, as well as the direct association of such decreases in the bone marrow with disease progression markers. For the purpose of providing an explanation for this highly unexpected observation, Sui et al. (26) conducted a series of experiments. Generally, they provided three possible mechanisms to explain the decrease of MDSCs in the bone marrow of chronically SIV-infected rhesus macaques.

First, they demonstrated that the pathogenic SIV strain (SIV_mac251), but not the nonpathogenic one (SHIV_SF162P4), can infect isolated MDSCs from both the peripheral blood and bone marrow of SIV-infected rhesus macaques in vitro, which is consistent with the results of Qin et al. (23), as well as in vivo. As such, in part, they referred the depletion of MDSCs in the bone marrow to direct SIV infection. However, we could argue against this explanation by the fact that the direct cytotoxic activity of SIV infection on such cell populations was neither confirmed by their study nor by other studies (23,26). Furthermore, one way or another, recent investigations refute the first explanation provided by Sui et al. (26), since it has been shown that HIV-infected MDSCs even resist apoptosis mediated by cytotoxic T lymphocytes ¹².

Accordingly, it will not be conceivable to say that HIV-infected MDSCs are resistant to killing by cytotoxic T cells, whereas they are susceptible to killing by the virus upon infection at the same time. Moreover, even if we assumed that the virus has a direct cytotoxic effect on MDSCs, such a reasoning is still insufficient to be considered an explanation of the observation. This is especially because both the decrease and the increase in the level of MDSCs in the bone marrow and other body compartments, including the peripheral blood, respectively, occurred within the same infected animal. It could be considered as a possible explanation if the reduction was observed in both the bone marrow and peripheral blood. Given that such results were documented after “14 months” post-SIV infection, and this time is sufficient to decrease both the bone marrow and peripheral blood MDSCs, as the case with CD4⁺ T cells “the primary HIV target cells” (19,36).

Alternatively, it could also be considered a plausible explanation if the depletion occurred peripherally but not in the bone marrow, as would be the case with other peripherally depleted immune cells, including dendritic cells, macrophages, and polymorphonuclear neutrophils as we illustrated elsewhere (3,34). In addition, we could say that the first explanation is acceptable if they confirmed that (i) the origin of MDSCs in the bone marrow is different from the origin of MDSCs in other compartments, including peripheral blood, and/or (ii) the MDSCs in the bone marrow of SIV-infected macaques are more susceptible to the viral cytotoxic effects than those in the peripheral blood. Unfortunately, none of these assumptions were confirmed by their investigations, and thus the first explanation cannot be accepted to clarify the unexpected reduction in MDSCs in the bone marrow after 14 months of SIV infection in rhesus macaques.

To further investigate other possible mechanisms for their unexpected results, they moved to the second round of investigations. In brief, they reported that the direct effect of SIV infection on the process of hematopoiesis in the bone marrow could also, in part, provide an explanation for the depletion of MDSCs in the bone marrow of SIV-infected rhesus macaques. Although the second explanation is more realistic than the earlier one, we believe that it failed to explain the increase in the levels of the MDSCs in the peripheral blood, especially, if we took into consideration that the origin of MDSCs in the peripheral blood is the bone marrow. This is mainly because according to their scenario, the virus has a cytotoxic effect on MDSCs upon infection, which according to our argument will result in depletion of MDSCs (in both bone marrow and peripheral blood) over time (namely 14 months).

Importantly, it is widely known that the reduction of hematocytes in peripheral blood activates hematopoiesis and thereby increases the output of the bone marrow to compensate for the reduction (3,34). As such, SIV infection will normally activate hematopoiesis in the bone marrow to replenish the decreased levels of MDSCs in peripheral tissues; otherwise, the reduction in the levels of MDSCs in peripheral blood will not be compensated, and thus the second explanation of Sui et al. (26) cannot resolve this contradiction. Indeed, their second explanation would be plausible if they confirmed that the origin of MDSCs in circulating blood is not the bone marrow [note that emerging evidence shows that the expansion of MDSCs is not exclusive to myelopoiesis in the bone marrow; please refer to our recent reviews (32,33)], or if the depletion occurred in the peripheral blood but not in the bone marrow.

Furthermore, if we take into consideration the third explanation provided by Sui et al. (26), it will also support our vision. In other words, the third explanation was that MDSCs in the bone marrow of SIV-infected rhesus macaques tend to have an increased rate of trafficking to the peripheral blood. Indeed, this explanation would be the most conceivable one if the other two explanations are neglected, and if MDSCs in the peripheral blood become accumulated without being infiltrated to the major HIV replication sites or other compartments such as the liver. Deductively, this is true because if the virus has (i) a negative impact on MDSC generation in the bone marrow, and (ii) cytopathic effects on MDSCs, then the level of MDSCs will undeniably be decreased in peripheral blood, especially after 14 months of SIV infection. Therefore, the third explanation cannot fully explain the unexpected reduction in MDSCs in the bone marrow of chronically SIV-infected rhesus macaques.

In fact, several studies have demonstrated that mature myeloid cells in peripheral blood could be reprogrammed into MDSCs or MDSC-like cells (5,7,16 –18,20,21,24,30). In case of HIV infection, it has been demonstrated that exposure of replication-competent or incompetent HIV particles or HIV glycoprotein 120 (gp120) and trans-activator protein (Tat) to normal peripheral blood mononuclear cells can induce the expansion of MDSCs in vitro (9,23,29). Accordingly, we could assume that the increase in MDSC levels in peripheral blood of SIV-infected rhesus macaques in the study of Sui et al. (26), in part, was because of the reprogramming of mature blood myeloid cells into MDSCs.

In Figure 2, we summarized the potential explanations that could solve the perplexing results regarding the expansion of MDSCs in peripheral blood and the reduction in MDSCs in the bone marrow of chronically SIV-infected rhesus macaques. In Figure 2A, the increased frequency of MDSCs in peripheral blood of chronically SIV-infected macaques could be as a result of (i) the increased rate of MDSCs trafficking from the bone marrow to the peripheral blood in a manner that exceeds the rate of MDSCs trafficking form the peripheral blood to other tissues; as well as (ii) the peripheral expansion of MDSCs as a result of reprogramming peripheral mature myeloid cells to become MDSCs or MDSCs-like cells, both of which could provide plausible explanations for the expanded MDSCs in the peripheral blood of chronically SIV-infected rhesus macaques. Whereas in Figure 2B, (i) the defects in hematopoiesis and (ii) the increased rate of MDSCs trafficking from the bone marrow to the peripheral blood in a manner that exceeds the production rate of MDSCs in the bone marrow could provide explanations to the remarkable reduction in MDSCs in the bone marrow of chronically SIV-infected rhesus macaques. Finally, it is essential to realize that the results of Sui et al. (26) do not necessarily mean that a similar scenario occurs in HIV-infected humans, simply because animals, including rhesus macaque, are not humans (32,33,35). Therefore, additional investigations on humans are required to fill the gap of knowledge in this research area.

FIG. 2.

Potential explanations for the MDSC expansion and reduction in the peripheral blood and bone marrow, respectively, in SIV-infected rhesus macaques. (A) Expansion of MDSCs in peripheral blood of chronically SIV-infected rhesus macaques could be as a result of the increased rate of MDSC trafficking from the bone marrow to the peripheral blood, induction of MDSC expansion peripherally (by the virus itself, viral proteins, LPSs, and or inflammatory molecules), and decreased trafficking rate of MDSCs from peripheral blood to other tissues such as the liver. (B) The reduction of the levels of MDSCs during the chronic phase (not the early chronic phase) could be because of the decreased rate of MDSC production in the bone marrow because of the direct effect of the virus on hematopoiesis and increased trafficking rate outside the bone marrow. LPSs, lipopolysaccharides; MDSCs, myeloid-derived suppressor cells.

Conclusion

The anatomical distribution of MDSCs is still lacking in both healthy and diseased humans, including HIV-infected patients, as well as nonhuman primates. Accordingly, this will diminish our understanding of the role of MDSCs in various pathological conditions, such as cancer and chronic infectious diseases. Therefore, additional investigations must be conducted in the near future to fill the gap of knowledge in this area of research. In this study, we focused our discussion on the results of Sui et al. (26). This is mainly because of three reasons: first, their study was the first of its kind to investigate the anatomical distribution of MDSCs in an animal model that mostly recapitulates HIV infection in humans, namely chronically SIV-infected rhesus macaques. Second, their results were highly surprising and unexpected. Third, scientifically, we do not fully agree with the explanations that they provided to the unexpected results in their study. Therefore, additional investigations on the distribution of MDSCs in humans at different anatomical compartments, including the bone marrow and lymphatic tissues, especially the primary anatomical reservoir for HIV, namely gut-associated lymphatic tissues among others, are required to better understand the role of MDSCs in the pathogenesis of HIV infection.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

Funding Information

No funding was received.

References

Abuharfeil

, Yaseen

, and Alsheyab

. Harnessing antibody-dependent cellular cytotoxicity to control HIV-1 infection. ACS Infect Dis, 2019; 5:158–176.

Agrati

, Tumino

, Bordoni

, et al. Myeloid derived suppressor cells expansion persists after early ART and may affect CD4 T cell recovery. Front Immunol, 2019; 10:1886.

Alqudah

MAY

, Yaseen

MMM

, and Yaseen

MMS

. HIV-1 strategies to overcome the immune system by evading and invading innate immune system. HIV AIDS Rev, 2016; 15:1–12.

Bowers

, Helton

, Huijbregts

, et al. Immune suppression by neutrophils in HIV-1 infection: role of PD-L1/PD-1 pathway. PLoS Pathog, 2014; 10:e1003993.

Casacuberta-Serra

, Pares

, Golbano

, et al. Myeloid-derived suppressor cells can be efficiently generated from human hematopoietic progenitors and peripheral blood monocytes. Immunol Cell Biol, 2017; 95:538–548.

Dross

, Munson

, Kim

, et al. Kinetics of myeloid-derived suppressor cell frequency and function during simian immunodeficiency virus infection, combination antiretroviral therapy, and treatment interruption. J Immunol, 2017; 198:757–766.

Dufait

, Schwarze

, Liechtenstein

, et al. Ex vivo generation of myeloid-derived suppressor cells that model the tumor immunosuppressive environment in colorectal cancer. Oncotarget, 2015; 6:12369–12382.

Filipazzi

, Huber

, and Rivoltini

. Phenotype, function and clinical implications of myeloid-derived suppressor cells in cancer patients. Cancer Immunol Immunother, 2012; 61:255–263.

Garg

, and Spector

. HIV type 1 gp120-induced expansion of myeloid derived suppressor cells is dependent on interleukin 6 and suppresses immunity. J Infect Dis, 2014; 209:441–451.

10.

Grutzner

, Hoffmann

, Wolf

, et al. Treatment intensification in HIV-infected patients is associated with reduced frequencies of regulatory T cells. Front Immunol, 2018; 9:811.

11.

Ilkovitch

, and Lopez

. The liver is a site for tumor-induced myeloid-derived suppressor cell accumulation and immunosuppression. Cancer Res, 2009; 69:5514–5521.

12.

Kostlin

, Schoetensack

, Schwarz

, et al. Granulocytic myeloid-derived suppressor cells (GR-MDSC) in breast milk (BM); GR-MDSC accumulate in human BM and modulate T-cell and monocyte function. Front Immunol, 2018; 9:1098.

13.

Kusmartsev

, and Gabrilovich

. Inhibition of myeloid cell differentiation in cancer: the role of reactive oxygen species. J Leukoc Biol, 2003; 74:186–196.

14.

Kusmartsev

, and Gabrilovich

. Role of immature myeloid cells in mechanisms of immune evasion in cancer. Cancer Immunol Immunother, 2006; 55:237–245.

15.

Liu

, Lin

, Peng

, et al. Persistent lentivirus infection induces early myeloid suppressor cells expansion to subvert protective memory CD8 T cell response. EBioMedicine, 2020; 60:103008.

16.

Mao

, Poschke

, Wennerberg

, et al. Melanoma-educated CD14+ cells acquire a myeloid-derived suppressor cell phenotype through COX-2-dependent mechanisms. Cancer Res, 2013; 73:3877–3887.

17.

Millrud

, Bergenfelz

, and Leandersson

. On the origin of myeloid-derived suppressor cells. Oncotarget, 2017; 8:3649–3665.

18.

Moses

, and Brandau

. Human neutrophils: their role in cancer and relation to myeloid-derived suppressor cells. Semin Immunol, 2016; 28:187–196.

19.

Nixon

, Vatakis

, Reichelderfer

, et al. HIV-1 infection of hematopoietic progenitor cells in vivo in humanized mice. Blood, 2013; 122:2195–2204.

20.

Obermajer

, and Kalinski

. Generation of myeloid-derived suppressor cells using prostaglandin E2. Transplant Res, 2012; 1:15.

21.

Pillay

, Tak

, Kamp

, et al. Immune suppression by neutrophils and granulocytic myeloid-derived suppressor cells: similarities and differences. Cell Mol Life Sci, 2013; 70:3813–3827.

22.

Porembka

, Mitchem

, Belt

, et al. Pancreatic adenocarcinoma induces bone marrow mobilization of myeloid-derived suppressor cells which promote primary tumor growth. Cancer Immunol Immunother, 2012; 61:1373–1385.

23.

Qin

, Cai

, Pan

, et al. Expansion of monocytic myeloid-derived suppressor cells dampens T cell function in HIV-1-seropositive individuals. J Virol, 2013; 87:1477–1490.

24.

Rodrigues

, Gonzalez

, Zhang

, et al. Normal human monocytes exposed to glioma cells acquire myeloid-derived suppressor cell-like properties. Neuro Oncol, 2010; 12:351–365.

25.

Rosado-Sanchez

, De Pablo-Bernal

, Rull

, et al. Increased frequencies of myeloid-derived suppressor cells precede immunodiscordance in HIV-infected subjects. Front Immunol, 2020; 11:581307.

26.

Sui

, Frey

, Wang

, et al. Paradoxical myeloid-derived suppressor cell reduction in the bone marrow of SIV chronically infected macaques. PLoS Pathog, 2017; 13:e1006395.

27.

Tumino

, Turchi

, Meschi

, et al. In HIV-positive patients, myeloid-derived suppressor cells induce T-cell anergy by suppressing CD3zeta expression through ELF-1 inhibition. AIDS, 2015; 29:2397–2407.

28.

Vollbrecht

, Stirner

, Tufman

, et al. Chronic progressive HIV-1 infection is associated with elevated levels of myeloid-derived suppressor cells. AIDS, 2012; 26:F31–F37.

29.

Wang

, Zhao

, Ren

, et al. Expansion of myeloid-derived suppressor cells promotes differentiation of regulatory T cells in HIV-1+ individuals. AIDS, 2016; 30:1521–1531.

30.

Xiu

, Lin

, Grote

, et al. IL-10 induces the development of immunosuppressive CD14(+)HLA-DR(low/-) monocytes in B-cell non-Hodgkin lymphoma. Blood Cancer J, 2015; 5:e328.

31.

Yaseen

, Abuharfeil

, Alqudah

, et al. Mechanisms and factors that drive extensive human immunodeficiency virus type-1 hypervariability: an overview. Viral Immunol, 2017; 30:708–726.

32.

Yaseen

, Abuharfeil

, Darmani

, et al. Mechanisms of immune suppression by myeloid-derived suppressor cells: the role of interleukin-10 as a key immunoregulatory cytokine. Open Biol, 2020; 10:200111.

33.

Yaseen

, Abuharfeil

, Darmani

, et al. Recent advances in myeloid-derived suppressor cell biology. Front Med, 2021; 15:232–251.

34.

Yaseen

, Abuharfeil

, Yaseen

, et al. The role of polymorphonuclear neutrophils during HIV-1 infection. Arch Virol, 2018; 163:1–21.

35.

Yaseen

, Yaseen

, and Alqudah

. Broadly neutralizing antibodies: an approach to control HIV-1 infection. Int Rev Immunol, 2017; 36:31–40.

36.

Zhang

, and Crumpacker

. Hematopoietic stem and immune cells in chronic HIV infection. Stem Cells Int, 2015; 2015:148064.

37.

Zhang

, Yi

, Zhang

, et al. Myeloid-derived suppressor cells associated with disease progression in primary HIV infection: PD-L1 blockade attenuates inhibition. J Acquir Immune Defic Syndr, 2017; 76:200–208.

38.

Zhao

, Obermann

, von Wasielewski

, et al. Increase in frequency of myeloid-derived suppressor cells in mice with spontaneous pancreatic carcinoma. Immunology, 2009; 128:141–149.