HIV-Associated Immune Dysregulation in the Skin: A Crucible for Exaggerated Inflammation and Hypersensitivity

Abstract

Skin diseases are hallmarks of progressive HIV-related immunosuppression, with severe noninfectious inflammatory and hypersensitivity conditions as common as opportunistic infections. Conditions such as papular pruritic eruption are AIDS defining, whereas delayed immune-mediated adverse reactions, mostly cutaneous, occur up to 100-fold more during HIV infection. The skin, constantly in contact with the external environment, has a complex immunity. A dense, tightly junctioned barrier with basal keratinocytes and epidermal Langerhans cells with antimicrobial, innate-activating, and antigen-presenting functions form the frontline. Resident dermal dendritic, mast, macrophage, and innate lymphoid cells play pivotal roles in directing and polarizing appropriate adaptive immune responses and directing effector immune cell trafficking. Sustained viral replication leads to progressive declines in CD4 T cells, whereas Langerhans and dermal dendritic cells serve as viral reservoirs and points of first viral contact in the mucosa. Cutaneous cytokine responses and diminished lymphoid populations create a crucible for exaggerated inflammation and hypersensitivity. However, beyond histopathological description, these manifestations are poorly characterized. This review details normal skin immunology, changes associated with progressive HIV-related immunosuppression, and the characteristic conditions of immune dysregulation increased with HIV. We highlight the main research gaps and several novel tissue-directed strategies to define mechanisms that will provide targeted approaches to prevention or treatment.

INTRODUCTION

The skin represents an organ of major morbidity during HIV infection, with both infective and inflammatory pathologies common. Certain skin manifestations such as papular pruritic eruption (PPE) or opportunistic skin infections are considered AIDS defining (Garg and Sanke, 2017). Severe cutaneous infections as well as delayed immune-mediated adverse reactions such as Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are associated with high morbidity and can be life threatening (Peter et al., 2017). The skin and mucosa, being in constant contact with the external environment, have complex immunity and are also the most common site of HIV viral entry. HIV-related immune pathology, defined most specifically by declining CD4 T cells, progresses with specific changes at cutaneous and mucosal surfaces. This review details normal skin immunology and our current understanding of the cutaneous changes associated with progressive HIV-related infection and immunosuppression and the consequent conditions of immune dysregulation increased among persons living with HIV. We highlight the main research gaps in our pathophysiological characterization of these conditions, particularly delayed immune-mediated adverse reactions, and discuss several novel sites of disease techniques being applied to unpick the specific immune pathways involved.

NORMAL SKIN IMMUNOLOGY

Skin barrier

Skin is composed of three major layers: the epidermis, dermis, and subcutis. Keratinocytes (KCs) are the main cell type in the epidermis. The stratum corneum, which consists of piles of dead KCs (corneocytes) and intercellular lipids, forms the outermost layer of the epidermis and is responsible to the largest extent for barrier function (Kabashima et al., 2019). In the deeper granular layer of the epidermis, physical contact of the KCs is maintained by tight junctions, creating another protective layer that is nearly impermeable to microbes (Coates et al., 2019). However, the presence of skin appendages such as hair follicles and sweat ducts creates a weakness in the armor and a point of entry for low-molecular-weight compounds such as haptens, microorganisms, or small-molecule drugs and chemicals (Kabashima et al., 2019). As such, the skin requires a robust immune system ready to act against pathogens.

Innate defenses

Innate and adaptive immune cell populations residing in normal skin and their protective interactions are highlighted in Figure 1a. KCs have multiple immune functions, expressing pattern recognition receptors, for example, toll-like receptors, which induce secretion of proinflammatory cytokines and chemokines, which further activate skin-resident immune cells or recruit them to the skin (Nestle et al., 2009; Richmond and Harris, 2014). The presence of skin commensals such as Staphylococcus epidermidis also directs KC immune responses and can either induce immune activation or suppress inappropriate immune responses (Lai et al., 2009; Linehan et al., 2018). Mast cells, bearing the receptor MRGPRX2, which is a receptor for host-defense antimicrobial peptides (Chompunud Na Ayudhya et al., 2020), are also important for immune defense. MRGPRX2-mediated mast cell activation helps to clear skin bacterial infection, promotes healing, and protects against reinfection (Chompunud Na Ayudhya et al., 2020). Innate lymphoid cells (ILCs), which include ILC1, ILC2, and ILC3 populations, have recently been identified as an important intermediary between innate and adaptive immune responses. They have many parallel functions to adaptive CD4 T cells and produce T-cell–associated cytokines without stimulation by a specific antigen (Panda and Colonna, 2019; Polese et al., 2020).

Figure 1. A figure showing normal cutaneous immunology and immune dysregulation as a result of HIV infection.

(a) LCs and KCs, and a small number of CD8+ T_RM are immune cells residing in the epidermis, whereas dermal DCs, mast cells, T_RM (CD8+/CD4+), macrophages, and ILC populate the dermis. KCs express TLRs that recognize PAMPs and DAMPs and are also a source of AMPs, β-defensins, and cathelicidins. AMPs also activate mast cells through the MRGPRX2 receptors, helping to clear bacterial infections and promote healing. LCs express CD207 (Langerin), which also recognizes PAMPs and also expresses CD1a and MHC class-II molecules, which present antigens to CD4 T cells and cross present to CD8 T cells. In response to pathogens, APCs (LCs or DCs) migrate into skin-draining lymph nodes, presenting antigens to naive CD4 and CD8 T cells and stimulating their clonal expansion and differentiation into T_eff cells. Chemokines and cytokines secreted by resident immune cells upregulate the expression of endothelial adhesion molecules (i.e., E-selectin) and skin-homing receptors on other circulating immune cells, which bind specific chemokine ligands (cell receptors 1–4). T_eff cells differentiate into memory T cell subsets (T_CM, T_EM, and T_RM). T_CM express CCR7 and CD62L, limiting their movement to secondary lymph nodes only. T_EM cells lack CCR7 but express tissue-homing addressins, allowing them access into peripheral tissue, that is, skin. T_RM cells express markers of tissue residency, that is, CD69 ± CD103; lack CCR7 and CD62L; and reside indefinitely in the skin. (b) HIV infection results in the alteration of both innate and adaptive immune response pathways. LCs and DCs, being the first immune cells to encounter HIV, transmit it to T cells in the skin-draining lymph nodes. CD4+ T cells homing to the skin are depleted, and an expansion of antiviral CD8+ and NK cells follows. A shift toward a Th2 cytokine profile is observed in advanced HIV infection, resulting in increased monocyte and eosinophils infiltration as well as B-cell activation. This results in a state of high immune activation and dysfunction of immunoregulatory mechanisms, leading to the onset of inflammatory and hypersensitivity skin disorders. AMP, antimicrobial peptide; DAMP, damage-associated molecular pattern; DC, dendritic cell; ILC, innate lymphoid cell; KC, keratinocyte; LC, Langerhans cell; MHC, major histocompatibility complex; PAMP, pathogen-associated molecular pattern; T_CM, central effector memory T; T_eff, effector T; T_EM, effector memory T; Th, T helper; TLR, toll-like receptor; T_RM, tissue-resident memory.

Skin is home to several antigen-presenting cell (APC) populations, including resident subsets and those recruited during inflammatory responses. The primary role of skin-resident APC populations is to lead off immune responses during antigen encounters through the activation of resident immune cells as well as linking innate with the adaptive immune system (Kupper and Fuhlbrigge, 2004). In the steady state, Langerhans cells (LCs) are the main dendritic cell (DC) subset in the epidermis, whereas CD1a+CD1c+ and CD141^hiCD14− DCs constitute dermal DCs (Haniffa et al., 2015). LCs express CD207 (langerin), a C-type lectin receptor that recognizes pathogen-associated molecular patterns, as well as CD1a and major histocompatibility complex class-II molecules, which activate T helper (Th) responses and cross present antigens to CD8 T cells (Klechevsky et al., 2008; Zaba et al., 2009). Similar to LCs, CD1a+CD1c+ DCs are capable of polarizing Th1 and Th2 responses and cross-presenting exogenous antigens to CD8+ T cells (Clausen and Stoitzner, 2015; Haniffa et al., 2015), whereas CD141^hiCD14− DCs are superior cross-presenting cells (Haniffa et al., 2012). Macrophages are another population of APCs residing in the skin as CD14+AF-mo-Mac (monocyte) and FXIIIa+CD14+AF^hiMac (macrophage) subsets (Haniffa et al., 2015).

Adaptive defenses: resident and circulatory

Activation of T cells in skin-draining lymph nodes results in the production of antigen-specific effector T (T_eff) cells. T_eff cells migrating to the skin express skin-homing receptors, specifically the carbohydrate epitope cutaneous lymphocyte antigen (CLA), which binds to E-selectin (Kupper and Fuhlbrigge, 2004). These T_eff cells further differentiate into memory T cells, which include central memory, effector memory (T_EM), and tissue-resident memory (T_RM) cells (Sallusto et al., 1999). T_RM cells are a memory T-cell subset residing in epithelial barrier tissue, and their role in health and disease is increasingly being appreciated (Park and Kupper, 2015). They lack cell molecules that enable them to migrate into lymph nodes (CCR7 and CD62L) and express markers of tissue residency (CD69 ± CD103) (Schunkert et al., 2021), strategically positioning them for rapid on-site immune protection against known pathogens (Nestle et al., 2009). They are best phenotypically characterized as CD44^high, CD3+, CD4+/CD8+, CD45RO+CD69+CLA+CCR7−CD62L^low, and CD103+/− (Schunkert et al., 2021). Similar to T cells, B cells are recruited to the skin through endothelial adhesion molecule and chemokine receptor–ligand interactions (Egbuniwe et al., 2015) and play a role in synthesizing antigen-specific antibodies that are crucial in defense against pathogenic bacterial skin infections such as Staphylococcus aureus.

HIV SKIN IMMUNOLOGY

The main cutaneous immunological changes after HIV infection are highlighted in Figure 1b.

CD4+ T-cell depletion is the hallmark of HIV infection (Okoye and Picker, 2013). In addition, there is a significant decrease in CD4+ T-cell proliferative capacity, increased expression of inhibitory molecules CTLA-4 and PD-1, and an increased percentage of CD4+ T cells undergoing apoptosis (Boasso et al., 2009). An expansion of CD8+ and terminal effector T cells is also reported in HIV-infected normal skin (Galhardo et al., 2004). These cells attempt to control ongoing retroviral infection but also mediate cell/tissue damage, which may contribute to skin disorder onset. For example, CD8+ T-cell–mediated granulysin secretion induces KC cell death as observed in TEN (Chung et al., 2008; Yang et al., 2014). The declining CD4+ T-cell counts associated with HIV infection results in a switch from Th1 to Th2 cytokine polarization, which presents as a progressive decline in the levels of IFN-γ and cytotoxic T lymphocyte functioning and successive incline in IL-4, IL-5, and IgE (Clerici and Shearer, 1994, 1993; Klein et al., 1997).

There is increasing circumstantial evidence that T_RM cells play a role in mediating skin disorders, with psoriasis and allergic contact dermatitis being the best described (Cheuk et al., 2014; Clark, 2015; Gaide et al., 2015; Suárez-Fariñas et al., 2011). Within drug reactions, their roles in fixed drug eruptions are best characterized to date (Mizukawa et al., 2002; Schunkert et al., 2021; Teraki and Shiohara, 2003). Despite little evidence in the context of HIV infection, it has been reported in other viral infections such as herpes simplex virus (HSV) that HSV-specific CD8+ cells are retained in the genital mucosa as T_RM cells and mediate antiviral function (Zhu et al., 2013, 2007); therefore, it is possible that HIV-specific T_RM cells in the skin might be increased during the course of HIV infection and contribute to the onset of skin disorders. It has been proposed that virus-specific T_RM cells (i.e., the human herpesvirus family) can cross react with drug-induced self-peptides presented by HLA risk allele, resulting in drug hypersensitivity reactions (Schunkert et al., 2021; White et al., 2015). The function of immunosuppressive regulatory T cells (Tregs) in inflammatory skin lesions is poorly characterized in the context of HIV infection. Outside HIV infection in skin disorders such as psoriasis and TEN, Tregs are reported to be decreased in numbers and suppressor activity (Takahashi et al., 2009; Wölfer et al., 1998). In HIV infection, conflicting data have been reported on the effect of HIV on Treg frequency and suppressive capabilities in circulation (Chevalier and Weiss, 2013).

LCs and dermal DCs are the first cells to encounter HIV at mucosal sites and are therefore the preferred targets for HIV infection (Gray et al., 2020; Miller and Bhardwaj, 2013). Th17 cells that contribute to epithelial barrier integrity are also targets for HIV infection because they have been reported to be depleted in mucosal tissue of the gastrointestinal tract (Brenchley et al., 2008; Klatt and Brenchley, 2010). However, there is limited evidence of cutaneous Th17 cell depletion in HIV infection. Although DCs plays a central role in viral transmission, target cell infection, and presentation of HIV antigens (Manches et al., 2014), other APCs such as macrophages also contribute to increased viral load. Activation of TREM-1 on macrophages by HIV has been shown to prolong macrophage survival, rendering them suitable hosts for HIV latent reservoirs (Campbell et al., 2019; Yuan et al., 2017). Although KCs do not directly become infected with HIV, they are capable of secreting immunomodulatory cytokines that may facilitate viral replication and dissemination (Galhardo et al., 2004). Mast cells also express CCR5 and CXCR4 and have been found to be a source of latently infected HIV (Marone et al., 2016; Sundstrom et al., 2007). Patients with untreated HIV, in particular, have been found to have enhanced non-IgE–mediated responses to fluoroquinolones such as ciprofloxacin, which is a small-molecule ligand for MRGPRX2 (Kelesidis et al., 2010). TAT, a fragment of HIV-1 TAT protein, has also been shown to activate MRGPRX2 (Grimes et al., 2019).

CURRENT STATE OF KNOWLEDGE: SKIN DISORDERS ASSOCIATED WITH HIV

Inflammatory skin disorders

PPE and eosinophilic folliculitis.

PPE often arises during early HIV infection and is therefore used as a marker for early diagnosis of HIV infection (Samanta et al., 2009), and incidence and severity of the disease are reported to be inversely proportional to CD4+ T-cell counts (Uthayakumar et al., 1997). PPE is proposed to be the result of an exaggerated immunological reaction to arthropod bites or stings, with increased total IgE reported in patients who develop the condition (Jiamton et al., 2014). PPE has a clinical overlap with eosinophilic folliculitis (EF) of HIV. EF is thought to be mediated by a Th2 response to unknown pathogen or agents, likely to be Pityrosporum ovale or Demodex folliculorum (follicular mite), an autoimmune reaction to sebocyte or a component of sebum (Brenner et al., 1994; Oladokun et al., 2018b). Elevated levels of IL-4, IL-5, RANTES, and eotaxin have been reported in lesional skin, suggesting a Th2 pattern (Amerio et al., 2001; McCalmont et al., 1995).

Seborrheic dermatitis.

Seborrheic dermatitis (SD) is an inflammatory condition that occurs in up to 40% of HIV-infected patients (Mathes and Douglass, 1985) and only about 3% in HIV-uninfected patients (Fröschl et al., 1990; Mathes and Douglass, 1985; Valia, 2006). In HIV-infected individuals, SD often has a sudden onset, is more severe, and is often recalcitrant to treatment. It occurs early during HIV infection, worsening with decreasing CD4 T-cell counts, and is used as an early marker of HIV infection and disease progression (Ippolito et al., 2000; Uthayakumar et al., 1997). Although the pathogenesis of SD is not well-understood, there is an association with skin colonization with the yeast of the genus Malassezia. As a result of the immune dysregulation in patients with HIV, the immune system is unable to clear the yeast, leading to yeast overgrowth and severe inflammation (Garg and Sanke, 2017). In addition to unhindered Malassezia proliferation, disruption in skin microbiota of the affected SD skin has been reported compared with that in healthy areas, and this disruption is thought to contribute to many other inflammatory skin disorders, including atopic-like dermatitis (AD) (Fercek et al., 2021).

Atopic-like dermatitis (in HIV).

Atopic-like dermatitis is a chronic skin condition characterized by xerosis, pruritus, and inflammation of the skin in genetically susceptible individuals (Oladokun et al., 2018b). It is seen in approximately 30–50% of HIV-infected patients compared with 2–20% in HIV-uninfected individuals (Cedeno-Laurent et al., 2011; Lin and Lazarus, 1995) and more common in children (Sodré et al., 2020). There is no specific stage in HIV disease progression that is associated with the onset of the disease; therefore, it is not used as a diagnostic or prognostic indicator (Garg and Sanke, 2017). It is associated with a Th2 cytokine profile with increased IgE levels, increased eosinophils, and elevated IL-4 and IL-5 cytokine levels (Dlova and Mosam, 2006; Ekpe, 2019; Majors et al., 1997). More recently, patients with AD have been shown to have an NK cell deficiency that appears to get better with treatment (Kabashima and Weidinger, 2020; Mack et al., 2020), and HLA and killer Ig-like receptor genetics may also be important risk factors (Margolis et al., 2021). HIV viremia is associated with functional abnormalities in NK cells and may contribute to the permissive environment for atopic-like dermatitis (Fauci et al., 2005).

Chronic actinic dermatitis.

Chronic actinic dermatitis (CAD) is a rare, persistent, and disfiguring photodermatosis, encompassing a spectrum of skin disorders. HIV infection is associated with higher odds of developing photosensitivity (Bilu et al., 2004; Pappert et al., 1994; Vin-Christian et al., 2000), with CAD, photodistributed drug eruptions, pellagra, and porphyria cutanea tarda the most common spectra of photodermatosis that have been reported (Isaacs et al., 2013; Koch, 2017). The clinical features of CAD, including distribution and morphology, are indistinguishable between HIV-infected and -uninfected persons. HIV-infected men of Fitzpatrick skin types V and VI are predominantly affected (Meola et al., 1997; Mercer et al., 2016; Wong and Khoo, 2005, 2003), and in severe cases, HIV-associated late-stage CAD may present with hypopigmented or vitiligo-like depigmentation (Meola et al., 1997; Mercer et al., 2016). HIV-infected cases usually have significant immunosuppression at presentation (CD4 counts < 200 cells/mm³) (Meola et al., 1997; Wong and Khoo, 2003). The pathogenesis of HIV-associated CAD has not been defined, although CD8+ T cells are thought to play a central role. A decrease in CD4:CD8 ratio in lesional skin has been reported in all forms of CAD (Hamada et al., 2017; Hawk, 2004; Pappert et al., 1994). The antigenic molecules in CAD have been postulated to be DNA, RNA, or molecules related to these (Hawk, 2004; Paek and Lim, 2014).

Psoriasis (in HIV).

Psoriasis is a chronic systemic inflammatory disease with cutaneous manifestations. In HIV-infected individuals, the incidence of psoriasis is higher, it often presents atypically with more exuberant clinical features, and it is often recalcitrant to treatment (Cedeno-Laurent et al., 2011). The severity of the disease correlates with the degree of immunosuppression (Garg and Sanke, 2017; Wölfer et al., 1998). Psoriasis outside of HIV infection is associated with a Th1 cytokine profile (Alpalhão et al., 2019). Given the Th2 switch observed in advanced HIV infection, psoriasis in HIV is considered paradoxical (Alpalhão et al., 2019; Morar et al., 2010), with studies revealing that CD8+ T cells, especially the memory subset, play a role in disease pathogenesis, and thus the Th2 shift might be an oversimplification (Cheuk et al., 2014; Fife et al., 2007; Morar et al., 2010; Smoller et al., 1990; Vissers et al., 2004). An interesting observation is that patients with psoriasis appear to be enriched for genetic variants that protect against HIV-1 disease (Chen et al., 2012). This includes HLA class 1 B-alleles that have been associated with the control of HIV-1 replication as well as heightened expression of HLA–C. In addition, HLA-Bw4-80I and the activating KIR3DS1 have been shown to be associated with long-term nonprogression of HIV as well as increased psoriasis susceptibility (Jiang et al., 2013).

Skin manifestations of immune reconstitution inflammatory syndrome.

Immune reconstitution syndrome is an inflammatory condition to pre-existing microbial, host, or other antigens that may occur when patients with HIV are started on antiretroviral medications (Lehloenya and Meintjes, 2006). Combinational antiretroviral therapy (cART) results in the suppression of HIV viral replication and a decline in the viral load, leading to a recovery in CD4 cell number. The restoration of immunity by cART is beneficial because it reduces opportunistic infections and the need for ongoing treatment. However, immune reconstitution inflammatory syndrome (IRIS) manifests because of this immune restoration, causing temporary worsening of several infections and inflammatory skin disorders (Lawn et al., 2005; Lehloenya and Meintjes, 2006; Oladokun et al., 2018b). IRIS is most common in patients commencing cART with CD4 cell counts <50 cells/mm³. The most common types of skin infections seen as part of IRIS include human papillomavirus, reactivation of varicella-zoster virus, cutaneous mycobacterial infections, or molluscum contagiosum. Inflammatory skin disorders of IRIS include AD and EF (Oladokun et al., 2018c).

Hypersensitivity skin disorders

Maculopapular eruptions.

Maculopapular eruptions (MPEs) or morbilliform rash refers to a rash characterized by flat macules and raised papules on a background of erythema. Causes of MPE include cutaneous adverse reactions and viral infections. MPE is the most common clinical manifestation of cutaneous adverse reactions, although it is usually mild and transient. HIV is a well-recognized cofactor in the elicitation of MPE. MPE has been classified both as a type IVb (Th2) and type IVc (cytotoxic T-cell–mediated) hypersensitivity reaction (Ukoha et al., 2015). Outside HIV infection, immunohistochemistry (IHC) studies have shown that cell infiltrates in MPE are mainly composed of CD4+ and CD8+ T cells, expressing markers of cytotoxic function perforin and granzyme (Yawalkar et al., 2000).

Severe cutaneous adverse reactions.

Severe cutaneous adverse reactions (SCARs) occur at a higher rate in HIV-infected patients than in the general population and cause significant morbidity (Peter et al., 2019). SCARs are type IV hypersensitivity reactions, and in HIV-infected persons, drug reaction with eosinophilia and systemic symptoms (DRESS) and SJS/TEN are the two most frequently encountered treatment-limiting forms (Lehloenya and Dheda, 2012; Peter et al., 2019). SCAR is common in persons living with HIV and occurs at all severities of HIV-associated immunosuppression. Data linking CD4 cell count strata with certain SCAR combinations have been conflicting. For example, early studies identified CD4 cell counts >200 cells/mm³ as a risk factor for nevirapine (NVP)-induced SJS and drug-induced liver injury (Dube et al., 2013; Hasan et al., 2022; Tseng et al., 2014); however, there have been NVP-induced SJS cases with severe immunosuppression (<200 cells/mm³) (Britto and Augustine, 2019) and studies where no association between CD4 counts and disease onset was found (Peters et al., 2010; Phanuphak et al., 2007). Other factors associated with progressive immune dysregulation such as expansion of CD8+ and terminal T_EM cells, chronic immune activation associated with excessive levels of inflammatory cytokines, altered Th subset ratios with Th2 skewing, and possible depletion of Treg cells have been proposed/shown to increase the risk of developing SCARs in HIV (Cardone et al., 2018; Peter et al., 2019; Phillips and Mallal, 2018). HLA–gene associations are a risk for developing SCARs and can be population specific owing to allele frequency variations; an example being the HLA-B*58:01 risk allele for allopurinol-induced SJS/TEN and DRESS in Han Chinese, African American, and patients of European ancestry (Fontana et al., 2021; Gonçalo et al., 2013; Goodman and Brett, 2021; Hung et al., 2005; Saito et al., 2016; Zhou et al., 2021).

Abacavir hypersensitivity.

Abacavir is a nucleoside analog reverse transcriptase inhibitor used as part of cART for treating HIV (Borrás-Blasco et al., 2008; Phillips and Mallal, 2007). Abacavir hypersensitivity is a rare but life-threatening reaction, occurring in approximately 3–5% of people receiving treatment (Borrás-Blasco et al., 2008). It is characterized by fever, skin rash, gastrointestinal disorders, and respiratory symptoms, occurring within 6 weeks of abacavir initiation (Hetherington et al., 2001; Phillips and Mallal, 2007). Abacavir hypersensitivity has been shown to be restricted by the HLA-B*57:01 allele (Norcross et al., 2012; Ostrov et al., 2012) and is mediated by CD8+ T-cell activation and subsequent release of inflammatory cytokines. Lesional skin biopsies from both abacavir hypersensitivity reaction and a positive patch test have shown infiltration of CD8+ T cells (Giorgini et al., 2011; Micozzi et al., 2015; Shear et al., 2008). Genetic screening for the HLA-B*57:01 allele for abacavir hypersensitivity is recommended by the U.S. Food and Drug Administration, European Medicines Agency, and Canada Health in routine clinical practice to reduce the risk of developing the reaction (Mallal et al., 2008; Rauch et al., 2006; Wang et al., 2022; Zucman et al., 2007). However, a major burden with HLA screening for several drugs is that although HLA risk allele is necessary, it is not sufficient for the development of drug hypersensitivity because not all patients carrying the risk alleles develop reactions (Peter et al., 2017). Cardone et al. (2018) developed an HLA-B*57:01–transgenic mouse model that showed the role CD4+ T cells play in mediating tolerance to the altered endogenous peptide repertoire induced by abacavir and proposed a mechanism by which CD4+ T cells suppress DC maturation (Cardone et al., 2018; Phillips and Mallal, 2018), thereby potentially explaining why some HLA-B*57:01 carriers tolerate abacavir.

RESEARCH GAPS

Outside of HIV infection, the pathogeneses of the majority of the inflammatory skin disorders outlined earlier are well immunohistologically characterized. In contrast, there is little evidence of the immunological changes at the site of disease in the context of HIV coinfection. Despite existing evidence on the effect of HIV on mucosal surfaces, there is a need to expand further to skin with distinct epithelial barriers, defining both normal and disease-associated microenvironments. A summary of HIV-associated inflammatory and hypersensitivity skin disorders, their proposed mechanism of HIV dysregulation, and current techniques applied to research areas are described in Table 1, with macroscopic images highlighting these characteristic conditions shown in Figure 2a–i. The majority of data are limited to histopathology and IHC studies, and there is a lack of advanced cutting-edge sites of disease techniques being applied to understand disease pathogenesis in and outside of HIV infection.

Table 1.

HIV-Associated Inflammatory and Hypersensitivity Skin Disorders, Main Immune Effector Cells and Proposed Mechanisms of HIV Immune Dysregulation, and Current Techniques Applied to the Research Area

Skin Disorder	Histological Characteristics	Main Immune Effector(s)	Proposed Mechanism of HIV Dysregulation	Current Techniques Applied to Research Area
Papular pruritic eruptions and eosinophilic folliculitis	PPE: perivascular and interstitial infiltrate of lymphocytes and eosinophils EF: predominant folliculocentric eosinophilic and lymphocytic infiltration	T cells, eosinophils	Exaggerated Th2 response to insect bites (does not occur outside of HIV)	Limited to IHC studies (Afonso et al., 2012; Amerio et al., 2001; McCalmont et al., 1995; Ramos et al., 2005; Resneck et al., 2004; Rosatelli et al., 2000)
Seborrheic dermatitis	Marked hyperkeratosis with confluent parakeratosis, acanthosis, and spongiosis. Yeast forms and exocytosis of lymphocytes also seen	T cells, neutrophils	Exaggerated Th1 and Th2 response to yeast infection (Malassezia species)	Limited to histopathology studies (Cedeno-Laurent et al., 2011; Soeprono et al., 1986)
Atopic-like dermatitis	Acanthosis and spongiosis	Eosinophils, basophils, mast cells, Th2 cells	Exaggerated Th2 cytokine profile, especially increased IL-4, IL-5, and IgE levels	Limited to histopathology studies (Cedeno-Laurent et al., 2011; Singh and Rudikoff, 2003)
Chronic actinic dermatitis	Spongiosis, variable acanthosis with dermal and perivascular lymphocytes	T cells (CD8+)	Exaggerated CTL response	Limited to IHC studies (Hamada et al., 2017; Meola et al., 1997; Pappert et al., 1994; Sidiropoulos et al., 2014)
Psoriasis	Dyskeratotic keratinocytes, irregular acanthosis, perivascular infiltrate of lymphocytes, and macrophages	DCs, KCs, and T cells (Th1, Th17, Th22 cells)	Exaggerated Th1 cytokine profile (does occur outside of HIV)	Limited to IHC (Cedeno-Laurent et al., 2011; Schön and Boehncke, 2005; Smoller et al., 1990) and scRNA-seq studies (outside HIV) (Kim et al., 2021)
Skin manifestations of IRIS	Varies with the type of skin infection or inflammatory disorder	T cells (Th1, CTL)	Exaggerated Th1 responses, and defective Treg activity (number or function) in response to infections or self-antigens	Limited to IHC studies (Nelson et al., 2017)
Maculopapular eruptions	Spongiosis, mild perivascular lymphocytic infiltrate with eosinophils	T cells, LCs, eosinophils	Exaggerated Th1 and Th2 responses	Limited to histopathology studies (Lapins et al., 1996)
Severe cutaneous adverse reactions	DRESS: spongiosis, interface dermatitis, basal vacuolization, lymphocytic & eosinophilic infiltration SJS/TEN: epidermal necrosis, apoptotic keratinocytes, vacuolar interface dermatitis	DRESS: T cells, eosinophils SJS/TEN: T cells, NK, and NK T cells	Exaggerated Th1 and Th2 responses	Limited to IHC (Yang et al., 2014) and scRNA-seq studies (outside HIV) (Kim et al., 2020)
Abacavir hypersensitivity	Perivascular inflammatory infiltrate with eosinophils	APCs, T cells (CD8+)	Exaggerated Th1 responses	Limited to histopathology (Micozzi et al., 2015), IHC (Giorgini et al., 2011), and scRNA-seq studies (Redwood et al., 2019)

Abbreviations: APC, antigen-presenting cell; CTL, cytotoxic T lymphocyte; DC, dendritic cell; DRESS, drug reaction with eosinophilia and systemic symptoms; EF, eosinophilic folliculitis; IHC, immunohistochemistry; IRIS, immune reconstitution inflammatory syndrome; PPE, papular pruritic eruption; scRNA-seq, single-cell RNA sequencing; SJS/TEN, Stevens–Johnson syndrome/toxic epidermal necrolysis; Th, T helper; Treg, regulatory T.

Figure 2. Montage of images highlighting the inflammatory and hypersensitivity skin disorders associated with HIV.

(a) PPE presents with an itchy and symmetric papular eruption involving predominantly the extremities and trunk, sparing the palms and soles. Apparent secondary changes include excoriations, ulceration, postinflammatory hyperpigmentation or hypopigmentation, and scarring. (b) EF is characterized by an erythematous papulopustular eruption on the face, neck, upper chest, and back. (c) SD is characterized by dry, flaky, or greasy scales in areas of large and active sebaceous glands such as the scalp, eyebrows, beard area, nasolabial folds, and upper chest. It can progress to result in erythroderma (involving >90% of body surface area) or exfoliative dermatitis. (d) AD presents as erythematous scaly papules and plaques. (e) CAD is characterized by pruritic eczematous or lichenified or even infiltrated patches and plaques that are initially limited to sun-exposed areas, although in severe cases, other areas may be involved and become erythrodermic. (f) Psoriasis is characterized by excessively rapid KC proliferation, and common presentations include plaque, erythrodermic, inverse psoriasis, and reactive arthritis-like psoriasis syndrome. (g) Skin manifestations of IRIS present as a temporary worsening of several infections and inflammatory skin disorders due to the restoration of immunity by cART. (g) The image shows a flare up of molluscum contagiosum after the initiation of cART. (h) MPE is characterized by flat macules and papules on a background of erythema. (i) DRESS (left) has diverse cutaneous lesions, often starting as a symmetrical MPE that may progress to coalescent erythema, infiltrated plaques, purpura, exfoliative dermatitis, and facial edema. The rash is accompanied by fever; internal organ involvement (i.e., hepatitis); and hematologic alterations such as eosinophilia, leukocytosis, and/or lymphocytosis. SJS/TEN (right) is characterized by confluent erythematous macules and atypical target lesions on which blisters occur, leading to skin detachment. This detachment also affects the mucosa and reveals subepithelial erosions that are often hemorrhagic. Images (in a, b, d, f, g, and h) were adapted from the study by Oladokun et al. (2018a). Images (in c, e, and i) were obtained from participants in our IMARI-Africa study on the provision of written informed consent (study approved by the University of Cape Town Research Ethics Committee, reference number R031/2018). The authors affirm that human research participants provided informed consent for the publication of the images in Figure 2. AD, atopic-like dermatitis; CAD, chronic actinic dermatitis; cART, combinational antiretroviral therapy; DRESS, drug reaction with eosinophilia and systemic symptoms; EF, eosinophilic folliculitis; IMARI-Africa, Immune-mediated Adverse Drug Reactions in Africa; IRIS, immune reconstitution inflammatory syndrome; KC, keratinocyte; MPE, maculopapular eruption; PPE, papular pruritic eruption; SD, seborrheic dermatitis; SJS/TEN, Stevens–Johnson syndrome/toxic epidermal necrolysis.

TECHNICAL APPROACHES

Expanded immunohistochemistry and multiplex fluorescent microscopy

Basic immunohistochemistry has been invaluable in the early definition of inflammatory skin disorders, helping to identify the main culprit immune cell populations and some of the molecules they produce/express that may be mediating disease. Expanding immunostaining targets is improving disease characterization and will ensure all possible mediators of disease at the site of disease are uncovered. This includes expanding target immune cell populations (both innate and adaptive) and their associated cytokines, chemokines, and cell surface receptors. Furthermore, defining these in and outside of HIV infection would provide great insight into the role of HIV in disease progression. It must be noted that the identification of certain immune cell populations such as T_RM cells remains a challenge owing to their phenotypic heterogeneity and expression of multiple surface markers, precluding the use of standard triple colocalization immunofluorescence approaches (Schunkert et al., 2021). Recent advances in multiplex immunofluorescence microscopy imaging aid in overcoming this barrier (Phillips et al., 2021; Willemsen et al., 2022).

Single-cell immune approaches: move from bulk transcriptomic approaches to single-cell analyses

Single-cell RNA sequencing (scRNA-seq) presents another powerful technique that has been applied to characterize the transcriptome of immune and nonimmune cell populations from lesional and nonlesional skin in inflammatory and hypersensitivity conditions. Transcriptomic changes at the site of disease not only provide insights into the current understanding of disease pathogenic mechanisms but also help to identify key pathogenic T-cell populations, overexpressed genes, and altered cellular pathways; all of which can be translated to clinical implementation of personalized medicine (Shalek and Benson, 2017). In skin lesions of psoriasis, this technique has been used to elucidate gene expression profiles of pathogenic versus regulatory immune cell subsets compared with that in normal skin and define personalized and targeted treatment approaches (Kim et al., 2021). Furthermore, in skin lesions of DRESS, pathway analyses have been applied to identify the Jak–signal transducer and activator of transcription pathways as potential therapeutic targets (Kim et al., 2020). Understanding the transcriptomic profile of normal skin in and outside HIV infection will give more insight into the immune cells and gene expression profiles at the steady state. Further profiling of HIV-infected diseased skin will help to characterize disease-causing cell populations.

Spatial transcriptomics

Despite recent advances in scRNA-seq in identifying isolated cell subpopulations in tissue, the inability to capture the spatial localization of cells within the site of disease tissue has been a major limitation. This spatial information is crucial in understanding the intracellular communication underlying normal and diseased skin (Longo et al., 2021; Rao et al., 2021). Spatial transcriptomics addresses this challenge by physically mapping gene sets expressed in specific cell subsets in the actual tissue, shedding light on the niches enriched for distinct gene sets. This technique is increasingly being utilized in characterizing other skin disorders such as cancer (Ma et al., 2021), but to our knowledge, it has not previously been applied in characterizing inflammatory and hypersensitivity skin disorders outlined in this review. Therefore, integrating the scRNA-seq approach together with a physically mapped-out transcriptomic atlas of normal skin in and outside of HIV will further supplement the nature and local distribution of transcriptomic changes observed in diseased skin.

CONCLUSIONS AND FUTURE DIRECTIONS

It is well-established that HIV infection increases the risk of developing varying inflammatory skin disorders. Several HIV-driven immunological changes have been proposed and described systemically and at the level of the skin. The homeostatic function of both immune (innate and adaptive) and nonimmune cell subsets residing in the skin is altered during HIV infection, and this local immune dysregulation is the main driver for the onset of inflammatory skin disorders. The direct mechanistic pathway of HIV at the site of disease in developing specific skin disorders remains elusive, and there are limited research approaches being applied at the site of disease to investigate this. Future research efforts need to focus on applying these more advanced single-cell and spatial transcriptomic approaches, in addition to expanded immunohistochemistry and multiplex approaches, to better understand the specific changes in the skin immunity that drive inflammatory and hypersensitivity disorders, with the potential to develop novel biomarkers and intervention strategies.

Abbreviations:

AD

atopic dermatitis

APC

antigen-presenting cell

CAD

chronic actinic dermatitis

cART

combinational antiretroviral therapy

CLA

cutaneous lymphocyte antigen

DC

dendritic cell

DRESS

drug reaction with eosinophilia and systemic symptoms

EF

eosinophilic folliculitis

HSV

herpes simplex virus

IHC

immunohistochemistry

ILC

innate lymphoid cell

IRIS

immune reconstitution inflammatory syndrome

KC

keratinocyte

LC

Langerhans cell

MPE

maculopapular eruption

NVP

nevirapine

PPE

papular pruritic eruption

SCAR

severe cutaneous adverse reaction

scRNA

single-cell RNA sequencing

SD

seborrheic dermatitis

SJS

Stevens–Johnson syndrome

T_eff

effector T cell

T_EM

effector memory T

TEN

toxic epidermal necrolysis

Th

T helper

Treg

regulatory T cell

T_RM

tissueresident memory