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Unraveling the paradoxes of HIV-associated psoriasis: A review of T-cell subsets and cytokine profiles

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Unraveling the paradoxes of HIV-associated psoriasis: A review of T-cell subsets and cytokine profiles
Douglas J Fife MD1, Jeanette M Waller 2, Edward W Jeffes MD PhD3, John YM Koo MD4
Dermatology Online Journal 13 (2): 4

1. UC Irvine Department of Dermatology2. UC Irvine School of Medicine 3. UC Irvine Department of Dermatology, Dermatology Services, Long Beach VA Med Center. 4. UCSF Department of Dermatology, Director, UCSF Psoriasis Day Care Center


HIV-associated psoriasis appears paradoxical, being a T-cell mediated disease in the face of decreasing T-cell counts. Furthermore, psoriasis is generally mediated by type-1 cytokines, whereas in HIV, type-2 cytokines tend to predominate. How can one have psoriasis in the essentially Th2 environment of HIV? The details and pertinent research regarding T cell subsets and cytokine profiles in psoriasis, HIV, and HIV-associated psoriasis were reviewed. It appears that both in the presence and absence of HIV infection, psoriasis is largely mediated by memory CD8 T cells, and that IFN-γ secreted by these cells and others is of key importance. Studying psoriasis in a model such as HIV in which certain elements of the immune system are stripped away or altered may help us better understand the pathogenic mechanisms and potential treatment targets for psoriasis vulgaris.


A clear relationship exists between psoriasis and the profound immunosuppression of HIV infected patients. HIV-associated psoriasis occurs with a prevalence that is similar or increased compared to the general population (Table 1) [1, 2, 3, 4, 5]. Psoriasis often has its initial presentation in advanced HIV infection [4], and it may even be the initial clinical manifestation of HIV infection [6]. Psoriasis tends to become more severe as the HIV infection progresses, and there is even some correlation between low CD4 counts and the severity of psoriasis [6, 7, 8].

Although common, HIV-associated psoriasis is poorly understood, likely because of two main paradoxes it presents: Firstly, although psoriasis worsens with dropping CD4 T-cell counts in HIV, therapies that decrease T-cell count cause psoriasis to improve [9, 10]. Secondly, HIV is typically characterized by a strong Th2 cytokine profile [11], whereas psoriasis vulgaris is characterized by a strong Th1 secretion pattern [12, 13, 14]. A closer look at the disposition of T cell subsets, cytokine profiles, and antigen presentation in HIV and psoriasis provides for better understanding and may clarify these apparent paradoxes.

This article discusses these paradoxes, as well as various theories for the worsening of psoriasis in HIV, including immune dysregulation, an increase in viral and bacterial antigens in the skin, genetic susceptibility, and direct effects of HIV proteins on keratinocytes.

T cells in psoriasis and HIV

T cells can be subdivided into many categories, such as CD4+ (helper/ suppressor) vs. CD8+ (cytotoxic), CD45RA+ (naïve) vs. CD45RO+ (memory), Th1 vs. Th2, and Tc1 vs. Tc2. The balance of these various cell types is significantly disrupted in HIV infection (Fig. 1). An evaluation of CD4+ and CD8+ naïve and memory T cell populations in HIV patients and HIV-negative psoriasis patients may help us to better understand the roles of these cells in HIV-associated psoriasis (Tables 2a, 2b).

Historically, CD4+ T cells were thought to be primarily responsible for driving the immune process leading to psoriasis, while CD8+ T cells were thought to have a suppressor role [12]. In recent years, however, histologic, therapeutic, and genetic evidence have assigned the CD8+ lymphocyte a more prominent, even independent role in the pathogenesis of psoriasis vulgaris.

Histological evidence reveals that the accumulation of CD8+ memory lymphocytes in the epidermis is linked to both the onset and exacerbation of psoriasis [15]. Multiple studies of psoriatic patients have shown that CD8+ T cell concentrations are increased in the epidermis and papillary dermis of lesional skin compared to uninvolved skin [15, 16, 17, 18, 19]. Analysis of lesional T cells has also demonstrated that the CD8 subpopulation expresses pro-inflammatory cytokines such as IFN-γ and TNF-α more frequently than the CD4 subpopulation [12, 14]. Among the CD8 cells, it is likely that the memory subset is most active in psoriasis; several studies, using both flow cytometry [14] and immunohistochemistry [18, 20], have demonstrated that the memory CD45RO+ T cells are overwhelmingly predominant in psoriatic lesions.

Furthermore, improvement of psoriasis lesions by various therapies including cyclosporine, PUVA, alefacept, and DAB389-IL2, and methotrexate is preceded by a decrease in epidermal T cells (primarily CD8+, CD45R0+) (Table 3) [6, 9, 10, 15, 21, 22, 23, 24, 25, 26, 27]. Genetically, the strong association of psoriasis with several MHC Class I antigens [6, 28, 29, 30, 31] provides additional support for the importance of CD8+ cytotoxic T cells in psoriasis (Table 4). Specifically in the setting of HIV, psoriasis has been strongly linked to MHC Class I antigens HLA-C602 [32, 33, 34] and HLA-B27 [30, 31, 35, 36]. Taken together, the above evidence supports a strong role of the CD8+ T cell, particularly the CD45R0+ memory subtype, in the pathogenesis of psoriasis.

At this point, a closer examination of the T-cell subtypes in HIV may help to provide greater understanding of HIV-associated psoriasis (Fig. 1). HIV progression is characterized by a decrease in the CD4+ T cell count, which leads to a decreased CD4/CD8 T cell ratio. In addition to this relative expansion of the CD8+ T cell population, one also sees either a constant or elevated absolute CD8+ T cell count in HIV patients [30, 37]. The CD8+ T cell count rises initially with HIV infection, and most studies find that a steady, elevated CD8+ cell count can be seen in the peripheral blood of HIV patients until very late in the disease, when CD4+ T cell counts are < 100 [38].

The HIV virus also affects the naïve and memory cell subpopulations differently depending on the T cell type (CD4+ vs. CD8+). The majority of studies show that the virus preferentially infects and replicates in CD45RO+ (memory/effector) CD4+ T cells; whereas in CD8+ T cells, it tends to "prefer" the CD45RA+ (naïve) subtype (Table 4) [29, 30, 31, 38, 39, 40, 41].

The HIV virus's effect on CD8 memory vs. naïve subpopulations is especially pertinent to our discussion of psoriasis. Recent evidence reveals that HIV can infect CD8+ T cells, presumably during a time in their immature state when they transiently express the CD4 molecule in addition to the CD8 molecule [38, 39, 42]. In contrast to what is seen in the CD4+ T cell population, HIV preferentially affects the CD45RA+ (naïve) CD8+ T cells [38, 39]. As the naïve CD45RA+, CD8+ T cell count decreases with HIV disease progression, it contributes to less of the total CD8+ T cell count. In advanced HIV, the memory CD8+ T cell subpopulation comprises over 85-90 percent of the total CD8+ T cell count, compared to 50 percent in healthy controls [38]. And in HIV patients with CD4 count < 200, the memory CD8+ population comprises 80 percent of the total combined (CD4+ and CD8+) T cell count, compared to 15 percent in normal adults [38]. The decrease in the naïve CD8+ subpopulation has been suggested as a possible explanation for the decreased ability of the patients to fight new infections while at the same time suffering from autoimmune diseases such as psoriasis [38, 39, 43, 44, 45, 46].

Some have also proposed that the imbalance of CD4/CD8 ratio itself may lead to immune dysregulation in HIV- associated psoriasis. One possible mechanism suggests that a subset of suppressor CD4+ T cells which normally have an inhibitory effect on the immunologic pathway leading to psoriasis, when depleted, can allow the pathway to proceed unchecked [31]. This hypothesis is supported by an interesting case report of a healthy man with idiopathic CD4 lymphopenia with a long history of widespread psoriasis [47]. Interestingly, his intralesional CD4 counts were similar to normal, healthy patients. Though only one case, it does support the notion of immune dysregulation as one possible mechanism for HIV-associated psoriasis.

Taken together, the expansion of the CD8+ memory T subset appears to be largely responsible for the paradoxical exacerbation of psoriasis in the immunocompromised state of HIV infection.

The opposing cytokine profiles of HIV and psoriasis

Cytokines produced by T cells are generally categorized into two types (Fig. 2a). Generally speaking, type 1 cytokines negatively regulate the production of type 2 cytokines, and vice versa. Psoriasis is typically recognized as being mediated by T cells that secrete type 1 cytokines [12-14, 48-50] whereas HIV is generally thought to cause a shift towards a Th2 cytokine profile [11, 51, 52].

The cytokine profile in psoriasis

Type 1 cytokines IFN-γ and TNF-α and their receptors are present in psoriatic epidermis [17], but absent or very low levels of type-2 cytokines such as IL-4 and IL-10 are found in psoriatic lesions [13, 50]. The paucity of plasma cells and B cells in psoriatic lesions also reflects the lack of type-2 cytokines in the lesions of these patients (Table 6) [44, 52]. When T cells extracted from psoriatic lesions are examined by mRNA PCR, they also show a trend toward type 1 cytokine production [53]. Immunohistochemical [50], flow cytometric, and cell culture [48] analysis of T-cells from psoriatic skin [12, 14] also reveal a strong type 1 predominance.

Treatment of psoriasis results in a decreased expression of type 1 cytokines by both peripheral blood and lesional T-cells that correlates with clearing of the lesions, as shown in studies of UVB light therapy [54], fumarate therapy [55], and alefacept [56]. The importance of type-1 cytokines in promoting the psoriatic phenotype is further evidenced by the improvement in psoriatic lesions when type-2 cytokines IL-10 [57, 58] and IL-4 [59] are administered to patients to downregulate type-1 cytokines IFN-γ and TNF-α. Of the type 1 cytokines, significant evidence suggests IFN-γ as the key contributor to keratinocyte hyperproliferation in psoriasis [13, 26, 60, 61].

The cytokine profile in HIV infection

Clerici and Shearer were the first to apply the model of type 1 and type 2 cytokines to HIV infection in humans. In 1993 and 1994 they presented evidence that peripheral blood T cells from HIV patients have an increased production of the type-2 cytokines IL-4-6 and IL-10 [51, 62]. They also showed decreased production of Type-1 cytokines IL-2 and IFN-γ as the HIV infection progressed. They suggested that the switch from type 1 cytokine production to type 2 cytokine production was indicative of overall prognosis; those patients with higher type-1 responses leading to cell-mediated immunity had significantly lower rates of seroconversion and, for those infected, a slower progression towards AIDS. Multiple subsequent studies confirmed a decrease in IL-2 and stable or increasing levels of IL-4, IL-5, and IL-10 in the peripheral blood of HIV-infected individuals [11, 63, 64].

Downstream products of Th2 stimulation provide further evidence of the tendency toward a type 2 cytokine production in HIV. Because type-2 cytokines promote humoral immunity, one would expect to see elevated plasma cell levels and hypergamma-globulinemia in HIV patients; this hypothesis has been confirmed in several studies [11, 44, 65]. Correspondingly, this cytokine shift further compromises cell medicated immunity, paralleling the increase in intracellular opportunistic infections that occur with HIV progression [4, 8].

Although many consider the type 1 to type 2 cytokine shift to be a key feature in the progression of HIV [1, 52, 62], the exacerbation and occurrence of type-1 cytokine-mediated diseases such as psoriasis implies that cytokine profiles in HIV should not be oversimplified.

Although it has been repeatedly demonstrated that IL-2 production decreases and IL-4 and IL-10 production increases, there may not be a true or complete Th1-Th2 shift in HIV infection. Particularly with respect to IFN-γ, an important type 1 cytokine, several authors have shown an increase in production in HIV-infected individuals, particularly when examining CD8+ memory cells [11, 64, 65, 66, 67]. Some have proposed that while there may be a true Th1 to Th2 cytokine profile shift within the CD4 population, there may be an increased subpopulation of activated CD8+ T cells resulting in increased IFN-γ [11].

Others suggest that the cytokine shift is actually an effect of the differential disposition of memory and naïve T-cell subsets in HIV, as naïve subsets produce primarily IL-2, while the memory subsets produce IL-4, IL-10, and IFN-γ. Thus the expanded population of memory CD8+ cells produces higher levels of IL-4, IL-10, and IFN-γ, whereas the decreased IL-2 may be explained by the depletion of naïve subsets [38].

Thus, the notion of a complete Th1 to Th2 cytokine shift in HIV may be an oversimplification. The decrease in IL2 and increases in IL4, IL10, and constant or elevated IFN-γ suggests a unique cytokine pattern in HIV, which does not fit neatly into the Th1 vs. Th2 classification scheme (Table 6).

In summary, psoriasis in healthy individuals has been described as being mediated by type-1 cytokines, notably IFN-γ and TNF-α, with low levels of type-2 cytokines IL4 and IL10. HIV is traditionally thought to involve a shift from type 1 to type 2 cytokine profile with decreased IL2 and increased IL4 and IL10. Critical to understanding of psoriasis in HIV patients, however, is the fact that activated CD8+ cells produce increased levels of IFN-γ compared to healthy controls [30, 66, 68, 69]. Furthermore, because other type 1 cytokines are reduced in HIV, IFN-γ becomes a more likely candidate key factor driving the psoriatic phenotype.

PART 3. HLA-DR: A link between IFN-γ and Psoriasis, especially in HIV?

HLA-DR, an MHC class-II antigen, is generally found on antigen presenting cells of the immune system, such as B lymphocytes and monocytes. When expressed on T lymphocytes it is essentially a marker of activation [14, 70]. In normal human epidermis, HLA-DR expression is limited to Langerhans cells and acrosyringial epithelium [71]. During inflammation, however, its expression can be induced in cells that normally have little to do with immune function. Most notably, skin lesions from over 38 dermatoses, all associated with dermal lymphocytic infiltrates, have been reported to contain HLA-DR+ keratinocytes [72]. Psoriasis is included in this category of diseases; it is postulated that in actively inflamed psoriatic lesions, keratinocytes are induced by IFN-γ to synthesize and express HLA-DR [73]. Injection of IFN-γ into normal, non-psoriatic human keratinocytes as well as into lesional skin has been shown to induce HLA-DR expression by keratinocytes [74]. Furthermore, keratinocytes of non-lesional skin in normal psoriatic patients are not exposed to increased levels of IFN-γ and do not express HLA-DR [75].

It is thought that the keratinocyte expression of HLA-DR in promotes the further accumulation of leukocytes within psoriatic plaque [76, 77, 78]. A number of effective therapies for psoriasis, including fumaric acid therapy, cyclosporine, corticosteroids, methotrexate, anthralin, retinoids, and PUVA result both in growth inhibition of hyperproliferative cells and in the down regulation of keratinocytic HLA-DR expression. Many suspect that this down regulation of aberrant HLA-DR expression may itself play a key role in the mechanism of effectiveness of these treatments [23, 79].

A plausible role for keratinocyte HLA-DR expression in the pathogenesis of psoriasis could involve interaction with microbial superantigens [80]. Exacerbation of psoriasis in normal patients is strongly associated with bacterial infection, especially by staphylococcal and streptococcal bacteria. Streptococcal pyrogenic exotoxins and staphylococcal enterotoxins can act as superantigens, thereby potently and polyclonally stimulating TCR VB+, CD4+ T cells and macrophages via binding to their MHC Class II molecules [81, 82, 83]. Superantigens have also been shown both in vitro and in vivo to stimulate production of TNF-α in HLA-DR+ human keratinocytes, even in the absence of T-cells [80, 84-86]. Furthermore, testing with a TSST-1 superantigen mutant specifically incapable of binding HLA-DR failed to induce lesions, indicating that the superantigens interacted directly with HLA-DR on the keratinocytes [80].

The above information provides a very plausible explanation for the worsening of psoriasis in HIV patients, regardless of the paucity of CD4+ T cells (Fig. 3). Specifically, HIV patients have high circulating levels of IFN-γ secondary to disease-induced expansion of the memory CD8+ population. Particularly in the setting of HIV, IFN-γ induces human keratinocytes to aberrantly express HLA-DR [75, 87]. Because HIV patients are susceptible to infection by streptococcus and staphylococcus, in addition to many other usual and opportunistic pathogens, they may be exposed to these and other superantigens chronically or at high levels [7]. Accordingly, many have shown that infections with staphylococcus or streptococcus are closely linked to increases in psoriatic flares of HIV positive patients [7, 6, 35 , 43, 88, 80, 90, 91, 92, 93].

Interestingly, it was recently proposed that the HIV virus's own gp120 envelope protein itself acts as a superantigen, capable of stimulating B cells, CD4+ T cells, and basophils [94, 95, 96]. Whether gp120 is capable of stimulating HLA-DR+ keratinocytes in the manner that other superantigens do has apparently not been studied to date. However, if gp120 can indeed act as a superantigen to stimulate HLA-DR+ keratinocytes, this could provide a likely mechanism for the HIV virus itself inducing psoriasis in previously non-psoriatic patients.

Other possible mechanisms for HIV-induced psoriasis

Some have proposed that the presence of the HIV virus itself in skin keratinocytes and Langerhans cells of HIV patients [96, 97] may play a more direct role. It has been postulated that HIV tat gene, or other portions of the HIV genome, may directly stimulate epidermal and endothelial proliferation [28, 31]. This is supported by transgenic mice studies in which mice containing intact copies of proviral HIV DNA produced a clinical and histological phenotype similar to psoriasis skin lesions [98], the finding of proviral DNA in dermal dendritic and Langerhans cells [98, 99], and in the improvement of psoriasis with antiretroviral therapy [5, 43, 92, 99, 100, 101, 102].

Namazi et al. have suggested that HIV-induced nitric oxide production by macrophages, increased release of Substance P in the skin of HIV-infected individuals, and reduction of the Langerhans' cells in the skin of HIV patients may be other factors in HIV-associated psoriasis [19].

One finding that seems to confound the above discussion is the multiple reports of psoriasis improving in the late stages of AIDS [30, 35, 103]. If the virus itself were responsible, we would expect psoriasis to worsen late in the course. This finding, however, does not eliminate the possibility of HIV acting as a costimulatory factor through antigenic presentation.


The exacerbation of psoriasis in the setting of HIV forces us to reevaluate our understanding of the immune processes active in its pathogenesis. Careful analysis reveals that psoriasis is largely mediated by CD45RO+, memory CD8+ T cells, the same population of cells that is both relatively and absolutely expanded in HIV infection. Although psoriasis is characterized by the type 1 cytokines IL2, TNF-α, and IFN-γ, with the latter predominating, IFN-γ produced by CD8+ T cells in HIV may also be the main perpetrator of psoriasis in that setting.

The mechanistic connection between IFN-γ and psoriasis in HIV is uncertain, although is possible that IFN-γ induces keratinocytes to aberrantly express HLA-DR, thus predisposing the keratinocytes to polyclonal activation by superantigens and typical antigens, likely in excess in the setting of HIV. Once activated, these keratinocytes produce TNF-α and other cytokines that perpetuate the psoriatic phenotype. Furthermore, the findings of the HIV virus itself in skin cells of infected individuals implies numerous possibilities for an alternative or additional, more direct role of the virus in inducing psoriatic flares.

Studying psoriasis in the setting of HIV may help to clarify the basic pathogenic mechanisms of psoriasis vulgaris, assigning prominent roles to CD8+ memory T cells and IFN-γ in the pathogenesis of both HIV-associated psoriasis and psoriasis vulgaris. This information may be of great clinical importance in an era where specific targeting of disease mediators is possible.


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