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Background:
Hypothesis

Metal Pollution as a Risk Factor for HIV Infection

by
Joel Henrique Ellwanger
1,*,
Jacqueline María Valverde-Villegas
2,3,
Marina Ziliotto
1 and
José Artur Bogo Chies
1
1
Laboratory of Immunobiology and Immunogenetics, Postgraduate Program in Genetics and Molecular Biology (PPGBM), Department of Genetics, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre 91501-970, RS, Brazil
2
Wellcome Sanger Institute, Cambridge CB10 1SA, UK
3
Cambridge Infectious Diseases Interdisciplinary Research Centre (CID IRC), University of Cambridge, Cambridge CB2 1TN, UK
*
Author to whom correspondence should be addressed.
Immuno 2025, 5(3), 34; https://doi.org/10.3390/immuno5030034
Submission received: 23 June 2025 / Revised: 2 August 2025 / Accepted: 8 August 2025 / Published: 11 August 2025
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Abstract

The human C-C chemokine receptor type 5 (CCR5) is a molecule primarily expressed on the surface of inflammatory cells, acting as the main HIV co-receptor. In order to penetrate host cells, HIV interacts with both CCR5 and the CD4 molecule during the infectious process. Emerging evidence suggests that pollution by metals, such as aluminum, lead, and manganese, triggers CCR5-mediated inflammation, which may have important implications for the risk of HIV infection. Specifically, we hypothesize that exposure to pollution by metals causes inflammation and elevated CCR5 expression on the surface of CD4+ cells, resulting in an increased risk of HIV infection. Our hypothesis is supported by toxicogenomic data, which shows that both air pollutants and some metals (e.g., arsenic, cadmium, nickel) induce CCR5 expression. Finally, approaches to evaluate the hypothesis are suggested. If confirmed, our hypothesis introduces environmental pollution to the set of biological factors influencing the risk of HIV infection.

1. Introduction

The infectivity of HIV, and, therefore, the risk of viral transmission and infection, is modulated by several individual, social, and biological factors. Risk behaviors, including having multiple sexual partners (or a high number of times of potential exposure to the virus), practicing vaginal or anal sex without a condom, drug use, and sharing needles among injectable drug users, significantly increase the risk of HIV infection [1]. Additionally, structural factors such as gender inequality and lack of social support further amplify this risk [2]. Biological factors are also important modulators of HIV infection risk, including the amount of virus in body fluids (viral load) that comes into contact with the potential new host, some characteristics of the virus (e.g., viral structural features), the presence of other sexually transmitted infections in the host [1], hormonal factors, immunological characteristics of mucous membranes [3], and host genetic traits, especially the variant CCR5Δ32 [4]. Interestingly, HIV infection risk per exposure is relatively low for many exposure routes [5,6], and, therefore, it is quite important to determine which factors or actions could be associated with increased risk of transmission and infection.
A greater number of CD4+ inflammatory cells (CD4 is the main HIV receptor) at the site of exposure (e.g., mucosal membrane) and increased expression of the human C-C chemokine receptor type 5 (CCR5), the main HIV co-receptor, are recognized risk factors for HIV infection [1,7,8]. The CCR5 protein is observed in inflammatory cells, such as memory T lymphocytes, dendritic cells, and macrophages [1,8].
The levels of CCR5 expressed on the surface of CD4+ cells and the recruitment of inflammatory cells to the mucous membranes (e.g., due to other infections or trauma) influence the risk of HIV infection [1,3,9,10,11]. In general, up-regulation of CCR5 is associated with increased infection risk [7,12,13,14] and, conversely, down-regulation of CCR5 (or the absence of the protein due to genetic factors) is associated with reduced infection risk [8,11,15].
The influence of ecological factors on HIV infection risk should receive more attention. Exposure to environmental pollutants (e.g., particulate matter, cadmium (Cd)) triggers both acute and chronic inflammation in humans [16,17], increasing the circulating levels of monocytes and CD4+ T lymphocytes [16], and altering susceptibility to microbial infection [17]. Of note, individuals at higher risk of HIV infection show increased blood levels of metals [18], and HIV-infected individuals usually have higher levels of metals in their bodies compared to non-infected people [19,20]. It is possible that socioeconomic, occupational, nutritional, and lifestyle factors linked to HIV infection/risk also increase exposure to metals, explaining these results. However, a greater susceptibility to HIV caused by biological effects of metal exposure cannot be ruled out.
In a previous study using a toxicogenomic approach, we demonstrated that environmental chemicals modulate CCR5 expression, with a tendency for increased expression due to exposure to environmental pollutants [21]. Also, a robust study using rodents and BV2 microglia cells demonstrated that metals, such as aluminum (Al), lead (Pb), and manganese (Mn), present in air pollution (i.e., particulate matter) trigger Ccr5 up-regulation and increased CCR5-mediated neuroinflammation [22]. We argue that these findings have an important impact on the risk of HIV infection. Understanding the factors that influence the expression of HIV receptors in potential hosts is crucial for enhancing our comprehension of HIV infection, elucidating the dynamics of HIV global epidemiology, and informing effective public health decision-making.

2. The Hypothesis

Exposure to metal pollution induces inflammation and elevated CCR5 expression on the surface of CD4+ cells, thereby enhancing the availability of this viral co-receptor and subsequently amplifying the risk of HIV infection (Figure 1).

3. Preliminary Data and Hypothesis Evaluation

3.1. Toxicogenomic Data Supports the Hypothesis

In order to verify the existence of data supporting our hypothesis, we performed a brief toxicogenomic analysis using The Comparative Toxicogenomics Database (CTD), a golden set database for the discovery and evaluation of gene–chemical interactions [23,24]. A gene search for “CCR5” was performed in CTD (Revision 17565M) on 3 January 2025, and the raw data for “chemical interaction” (Excel file) was downloaded from the platform. Then, we manually collected data on “chemical name”, “chemical ID”, “CAS RN” (Chemical Abstracts Service Registry Number, when available), “interaction”, “interaction actions” (meaning the standardized form synthesis of interactions), and “reference counts” (number of studies supporting interactions) of the chemicals classified by us into the groups of “air pollutants” that may contain metals/metalloids (encompassing particulate matter and particulate matter-like pollutants) and “metals” (encompassing metals/metalloids and related compounds from any source). For readability reasons, in this article the word “metals” is used to refer to both metals and metalloids (e.g., arsenic (As)).
We found that a total of 147 different chemicals interact with the CCR5 mRNA or protein, with a total of 233 individual interactions. Table 1 shows different types of air pollutants (particulate matter and particulate matter-like pollutants) that interact with CCR5. They generally increase CCR5 protein or mRNA expression: of the 10 “references” from CTD, 6 (60.0%) support increased expression of CCR5. This confirms that pollutants found in the atmosphere have the ability to induce CCR5 expression.
Table 1 also details interactions between metals and related compounds (represented by As, Cd, and nickel (Ni), among others) with CCR5 (mRNA or protein), with a clear trend towards an increased expression pattern compared to other types of chemical–CCR5 interactions. Of the 15 “references” from CTD, 11 (73.3%) support increased expression of CCR5. In conclusion, our preliminary analysis of toxicogenomic data highlights the potential for a promising validation of the hypothesis through wet-lab experiments and epidemiological data.

3.2. Other Approaches to Evaluate the Hypothesis

Approach (I): Going beyond our toxicogenomic analysis, we suggest conducting studies that evaluate metal levels and CCR5 expression in humans, in a combined manner. Importantly, it is necessary to control CCR5 expression levels by genetic factors such as the variant CCR5Δ32, which robustly affects CCR5 expression [8]. An evaluation could include the analysis of CCR5 expression in peripheral T cells of individuals differentially exposed to metals and related compounds. For instance, it would be valuable to evaluate coal mining workers by simultaneously assessing metal levels and CCR5 expression, and comparing the results with those of control individuals (e.g., office workers) from the same regions. It is also necessary to take into consideration that the CCR5 expression on the cell surface is transient. That is, CCR5 is externalized in the cell in response to a stimulus and then internalized to be recycled [8]. This process may complicate the observation of direct associations between metal exposure and CCR5 protein expression. Therefore, analyzing CCR5 mRNA levels may be a better option.
Approach (II): The bioavailability of trace elements in the environment, such as selenium, potentially influences the dynamics of viral epidemics and even the evolution of RNA viruses, including HIV [25]. In this sense, considering the claim that positive correlations between metal levels and CCR5 expression in humans would be a strong indicator of an increased risk of HIV infection, a step further would be performing epidemiological studies focused on determining the frequency of HIV infection in different groups, exposed or not to metals. We suggest comparing HIV infection rates between individuals living in regions with high and low levels of metal pollution, controlling the analysis for confounding factors. Notably, socio-environmental confounders should be carefully considered in Approaches (I) and (II), as factors such as healthcare access and socioeconomic status may confound or interact with the potential observed effects of metal pollution on HIV infection risk.
Approach (III): We also suggest evaluating the impacts of metal exposure on CCR5 expression in vitro, using CCR5-expressing cells (e.g., leukocytes) or human cell linages in a similar approach to that performed by Wei et al. [22], but using other cell types. Evaluating HIV infectivity in cells with different levels of CCR5 expression would provide highly relevant complementary data. For this approach to be valid, the inclusion of a proper control group (e.g., HIV-susceptible cells without metal exposure) is needed.
Figure 2 summarizes these three different approaches to evaluate the hypothesis. The optimal strategy would involve combining these different methodologies to test the hypothesis in a very robust way.

4. Discussion

Environmental pollution is often associated with limited socioeconomic conditions [26,27] and may be compounded by other risk factors for HIV infection. Currently, the greatest health impacts of HIV are indeed observed in countries and communities with high levels of social disparity [28], many of which also suffer from significant environmental problems. Notably, exposure to air pollution is associated with a higher risk of mortality in HIV-infected individuals [29]. Due to the high concentrations found in particulate matter, metals are the main toxic agents present in air pollution, along with toxic organic compounds [22]. Our hypothesis expands the role of pollution in HIV infection, suggesting that metals may affect not only HIV pathogenesis but also susceptibility to infection.
A comprehensive discussion of the effects of environmental pollutants on CCR5 expression is available in a previous toxicogenomic study conducted by Ellwanger and Chies [21]. The ability of environmental pollutants to cause inflammation and associated CCR5 up-regulation [21] is the most likely mechanism supporting our hypothesis. However, other mechanisms unrelated to inflammation may explain a pollution-induced CCR5 up-regulation. Methylation patterns of the CCR5 cis-regions are a major determining factor of CCR5 expression levels in CD4+ cells, with hypermethylation triggering reduced CCR5 expression and, on the contrary, demethylation resulting in increased CCR5 expression [10]. Of note, metals can alter methylation patterns in both DNA and RNA [30,31]. For instance, a robust body of evidence shows that environmental exposure to metals can induce hypomethylation of several human genes [32,33,34,35]. Reduced metal-associated methylation may represent an epigenetic mechanism of gene regulation that also supports our hypothesis. However, it is important to consider factors such as potential reversibility and temporal dynamics in the influence of metals on the epigenetic regulation of CCR5. We also stress that multiple other mechanisms (e.g., genetic, epigenetic, receptor transport, and recycling) affect CCR5 expression levels [11], and the influence of metals on these mechanisms remains to be deciphered.
We speculate that specific world regions with high levels of metal pollution may place populations at increased risk for HIV infection. For instance, gold mining activities in the Brazilian Amazon, where high levels of mercury pollution occur [27], may increase the risk of HIV infection in the Amazon’s population. Of note, some states in the Brazilian Amazon region, such as Roraima, Pará, and Amazonas, are among those most impacted by HIV in Brazil [36], with the virus even affecting Indigenous populations [37].
The risk of HIV infection is determined by several complex factors. If confirmed, our hypothesis introduces environmental pollution, especially by metals (alone or in association with particulate matter), as a significant addition to the set of biological factors influencing the risk of HIV infection. What makes this especially intriguing is that pollution represents an ecological factor that is distinct from other biological HIV risk factors typically associated with the host or the virus itself.
The role of environmental pollution in the emergence and spread of infectious diseases has been evidenced recently, although the molecular mechanisms linking pollution with infection are still being described [38]. In this sense, more than just drawing connections between metals, CCR5 and HIV, our hypothesis can also be used as an example of how pollution can affect the risk of infectious diseases in a broader sense. Finally, considering the consequences of our hypothesis and the precautionary principle [39], the control of pollution by metals should be intensified not only due to their ecological impacts and ability to cause chronic diseases, but also as a potential way to reduce the risk of HIV infection. As previously mentioned, understanding the factors that affect the expression of HIV receptors in potential hosts is vital for gaining deeper insights into HIV infection, deciphering the patterns of its global epidemiology, and guiding informed public health decision-making.

Author Contributions

Conceptualization, J.H.E.; methodology, J.H.E.; validation, M.Z.; formal analysis, J.H.E.; writing—original draft preparation, J.H.E.; writing—review and editing, J.M.V.-V., M.Z., and J.A.B.C.; visualization, J.H.E.; supervision, J.A.B.C. All authors have read and agreed to the published version of the manuscript.

Funding

Joel Henrique Ellwanger receives a post-doctoral fellowship from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior–CAPES, Brazil (Programa Institucional de Pós-Doutorado, finance code 001). Jacqueline María Valverde-Villegas receives a Janet Thornton post-doctoral fellowship from Wellcome Sanger Institute, United Kingdom. Marina Ziliotto receives a doctoral fellowship from Conselho Nacional de Desenvolvimento Científico e Tecnológico–CNPq, Brazil. José Artur Bogo Chies is funded by Conselho Nacional de Desenvolvimento Científico e Tecnológico–CNPq, Brazil (Bolsa de Produtividade em Pesquisa, Nível 1A) and Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul–FAPERGS, Brazil (Programa Pesquisador Gaúcho).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The data used in this article were obtained from The Comparative Toxicogenomics Database, available at https://ctdbase.org/ (accessed on 3 January 2025).

Acknowledgments

The figures were created using templates from Smart–Servier Medical Art [40], under a CC BY 4.0 license [41], and Microsoft 365.

Conflicts of Interest

The authors declare no conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

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Immuno 05 00034 g001
Figure 1. The hypothesis. Exposure to pollution by metals, such as aluminum (Al), arsenic (As), cadmium (Cd), lead (Pb), manganese (Mn), and nickel (Ni), from multiple sources (e.g., mining, industry, vehicle pollutants) causes inflammation and elevated CCR5 expression on the surface of CD4+ cells, resulting in an increased risk of HIV infection. Only CCR5 molecules are represented on the cell surface (red receptors with seven transmembrane domains).
Figure 1. The hypothesis. Exposure to pollution by metals, such as aluminum (Al), arsenic (As), cadmium (Cd), lead (Pb), manganese (Mn), and nickel (Ni), from multiple sources (e.g., mining, industry, vehicle pollutants) causes inflammation and elevated CCR5 expression on the surface of CD4+ cells, resulting in an increased risk of HIV infection. Only CCR5 molecules are represented on the cell surface (red receptors with seven transmembrane domains).
Immuno 05 00034 g001
Immuno 05 00034 g002
Figure 2. Three suggested approaches to evaluate the hypothesis.
Figure 2. Three suggested approaches to evaluate the hypothesis.
Immuno 05 00034 g002
Table 1. Interactions between pollutants and CCR5.
Table 1. Interactions between pollutants and CCR5.
Interactions between air pollutants (particulate matter and particulate matter-like pollutants) with CCR5 (mRNA or protein)
Chemical nameChemical IDCAS RNInteractionInteraction actions *Number (n) of works supporting the interactions in CTD **
DustD004391-Dust results in increased expression of CCR5 mRNAIncreases ^ expressionn = 1
Particulate matterD052638-Particulate matter results in decreased expression of CCR5 mRNADecreases ^ expressionn = 1
Particulate matter results in increased expression of CCR5 mRNAIncreases ^ expressionn = 2
SootD053260-Soot results in increased expression of CCR5 mRNAIncreases ^ expressionn = 1
Tobacco smoke pollutionD014028-Tobacco smoke pollution affects the expression of CCR5 mRNAAffects ^ expressionn = 1
Tobacco smoke pollution results in decreased expression of CCR5 mRNADecreases ^ expressionn = 1
Vehicle emissionsD001335-Vehicle emissions affect the methylation of CCR5 geneAffects ^ methylationn = 1
Vehicle emissions results in increased expression of CCR5 mRNAIncreases ^ expressionn = 2
Interactions between metals and related compounds with CCR5 (mRNA or protein)
Chemical nameChemical IDCAS RNInteractionInteraction actionsNumber (n) of works supporting the interactions in CTD *
ArsenicD0011517440-38-2[Sodium arsenite results in increased abundance of arsenic] which results in increased expression of CCR5 mRNAIncreases ^ abundance|increases ^ expressionn = 1
CadmiumD0021047440-43-9[Cadmium chloride results in increased abundance of cadmium] which results in increased expression of CCR5 mRNAIncreases ^ abundance|increases ^ expressionn = 1
Cadmium chlorideD01925610108-64-2[Cadmium chloride results in increased abundance of cadmium] which results in increased expression of CCR5 mRNAIncreases ^ abundance|increases ^ expressionn = 1
Mercuric chlorideD0086277487-94-7CCR5 protein results in increased susceptibility to mercuric chlorideIncreases ^ response to substancen = 1
Mercuric chloride results in increased expression of CCR5 mRNAIncreases ^ expressionn = 1
Mercuric chloride results in increased expression of CCR5 proteinIncreases ^ expressionn = 1
NickelD0095327440-02-0Nickel affects the expression of CCR5 mRNAAffects ^ expressionn = 1
Nickel results in increased expression of CCR5 mRNAIncreases ^ expressionn = 1
Trichostatin A inhibits the reaction [Nickel affects the expression of CCR5 mRNA]Affects ^ expression|decreases ^ reactionn = 1
Nickel monoxideC0280071313-99-1Nickel monoxide results in increased expression of CCR5 mRNAIncreases ^ expressionn = 1
Sodium arseniteC01794713768-07-5[Sodium arsenite results in increased abundance of arsenic] which results in increased expression of CCR5 mRNAIncreases ^ abundance|increases ^ expressionn = 1
Titanium dioxideC00949513463-67-7[Titanium dioxide co-treated with azoxymethane co-treated with dextran sulfate] results in decreased expression of CCR5 mRNAAffects ^ cotreatment|decreases ^ expressionn = 1
Titanium dioxide results in increased expression of CCR5 mRNAIncreases ^ expressionn = 3
Data source: The Comparative Toxicogenomics Database. CTD: The Comparative Toxicogenomics Database. CAS RN: Chemical Abstracts Service Registry Number. The symbol ^ (from CTD) means a “technical hyphen” (words before and after the symbol should be read together as a single concept). * The effects of metals on CCR5 expression showed in the “interaction actions” column should be interpreted as qualitative trends. ** In CTD, the number of works supporting the interactions is referred as “reference count”. After being downloaded from CTD (as Excel file), the reference count becomes anonymized raw data.
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Ellwanger, J.H.; Valverde-Villegas, J.M.; Ziliotto, M.; Bogo Chies, J.A. Metal Pollution as a Risk Factor for HIV Infection. Immuno 2025, 5, 34. https://doi.org/10.3390/immuno5030034

AMA Style

Ellwanger JH, Valverde-Villegas JM, Ziliotto M, Bogo Chies JA. Metal Pollution as a Risk Factor for HIV Infection. Immuno. 2025; 5(3):34. https://doi.org/10.3390/immuno5030034

Chicago/Turabian Style

Ellwanger, Joel Henrique, Jacqueline María Valverde-Villegas, Marina Ziliotto, and José Artur Bogo Chies. 2025. "Metal Pollution as a Risk Factor for HIV Infection" Immuno 5, no. 3: 34. https://doi.org/10.3390/immuno5030034

APA Style

Ellwanger, J. H., Valverde-Villegas, J. M., Ziliotto, M., & Bogo Chies, J. A. (2025). Metal Pollution as a Risk Factor for HIV Infection. Immuno, 5(3), 34. https://doi.org/10.3390/immuno5030034

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