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Originally published online as doi:10.1189/jlb.0105049 on March 30, 2005

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(Journal of Leukocyte Biology. 2005;78:37-42.)
© 2005 by Society for Leukocyte Biology

Expression of the common heat-shock protein receptor CD91 is increased on monocytes of exposed yet HIV-1-seronegative subjects

Anthony Kebba*,{dagger},1, Justin Stebbing*, Samantha Rowland*,{dagger}, Rebecca Ingram*,{dagger}, John Agaba{dagger}, Steve Patterson*, Pontiano Kaleebu{dagger}, Nesrina Imami* and Frances Gotch*

* Department of Immunology, Imperial College, Chelsea & Westminster Hospital, London, United Kingdom; and
{dagger} Medical Research Council Programme on AIDS in Uganda, Uganda Virus Research Institute, Entebbe

1 Correspondence: Department of Immunology, Imperial College, Chelsea & Westminster Hospital, 369 Fulham Rd., London SW10 9NH, UK. E-mail: a.kebba{at}ic.ac.uk


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ABSTRACT
 
The significantly higher surface expression of the surface heat-shock protein receptor CD91 on monocytes of human immunodeficiency virus type-1 (HIV-1)-infected, long-term nonprogressors suggests that HIV-1 antigen uptake and cross-presentation mediated by CD91 may contribute to host anti-HIV-1 defenses and play a role in protection against HIV-1 infection. To investigate this further, we performed phenotypic analysis to compare CD91 surface expression on CD14+ monocytes derived from a cohort of HIV-1-exposed seronegative (ESN) subjects, their seropositive (SP) partners, and healthy HIV-1-unexposed seronegative (USN) subjects. The median fluorescent intensity (MFI) of CD91 on CD14+ monocytes was significantly higher in ESN compared with SP (P=0.028) or USN (P=0.007), as well as in SP compared with USN subjects (P=0.018). CD91 MFI was not normalized in SP subjects on highly active antiretroviral therapy (HAART) despite sustainable, undetectable plasma viraemia. Data in three SP subjects experiencing viral rebounds following interruption of HAART showed low CD91 MFI comparable with levels in USN subjects. There was a significant positive correlation between CD91 MFI and CD8+ T cell counts in HAART-naïve SP subjects (r=0.7, P=0.015). Increased surface expression of CD91 on CD14+ monocytes is associated with the apparent HIV-1 resistance that is observed in ESN subjects.

Key Words: CD14+ monocytes • HIV-1 • exposed sero-negative • CD91 • CD14+ monocytes


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INTRODUCTION
 
The pathogenic mechanisms that underlie human immunodeficiency virus type-1 (HIV-1) infection are highly variable and depend on the interplay between numerous host and viral factors, which are likely to determine the rate of clinical progression [1 2 3 4 ]. In untreated individuals, the median time from infection to the development of AIDS is approximately 10 years, although it can develop in 3–6 months [5 , 6 ]. A minority of HIV-infected individuals, termed long-term nonprogressors (LTNP), remains healthy for more than 10 years with no clinical evidence of progression to disease [7 , 8 ]. These cases are characterized by stable or even increasing CD4+ T cell counts and by stronger CD8+ cytotoxic T lymphocyte (CTL) responses against HIV and other viruses other than progressors [9 10 11 12 ]. We have shown previously that such cases have significantly higher levels of CD91, most notably, on their monocytes, in comparison with typical progressors [13 , 14 ], although it remains unclear whether this is a result of constitutive or inducible expression.

Typically, antigen-presenting cells (APCs) can present exogenous antigens on major histocompatibility complex (MHC) class II molecules and endogenously synthesized antigen on MHC class I [15 ]. APCs can also take up exogenous peptides chaperoned by heat shock proteins (HSP), released as a consequence of cell death [16 , 17 ], and represent them through the classical proteosome/transporter-associated antigen processing-dependent, endogenous pathway complexed with their MHC class I molecules [18 ]. HSP cannot activate T cells directly and are able to elicit T cell responses only in the presence of APCs such as monocytes [19 20 21 22 ]. The high efficiency of this process is attributed in all cases to direct binding to, and internalization via, the CD91 molecule (also called {alpha}2-macroglobulin receptor or the low-density lipoprotein-related protein) [19 , 23 24 25 ]. Maintenance of CD8 responses via the antigen entering the class I pathway exogenously via CD91 may explain many features of true LTNP.

These data suggest that HIV-1 antigen uptake and cross-presentation via CD91-mediated endocytosis may be contributory mechanisms underlying a host anti-HIV-1 defense. This hypothesis is supported by the discovery of specific incorporation of HSP into the coat of HIV-1 [26 ], a feature not shared by many other viruses, and the recent finding of efficient class I and class II processing of HIV-1 Gag-p24 peptides complexed to HSP gp96 [27 ]. To test this hypothesis further, we have extrapolated the above observations in LTNP to a cohort of apparently HIV-1-resistant individuals (in whom repeated and known sexual exposure does not result in established HIV-1 infection) in Entebbe, Uganda. We compared the surface expression of CD91 in these individuals with that from seropositive (SP) subjects and HIV-1-unexposed seronegative (USN) subjects.


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MATERIALS AND METHODS
 
Patients
We have established a cohort of HIV-1 serodiscordant couples at the Medical Research Council Program on AIDS (Entebbe, Uganda) The exposed seronegative (ESN) partners are known to be sexually exposed to HIV-1, as seen from histories of frequent unprotected sex during periods of known serodiscordance, including the occurrence of pregnancies. Also included in the cohort are USN subjects who acted as controls. Nonexposure to HIV-1 in these controls was determined using the following criteria: no history of sexually transmitted diseases; abstaining from sex or if sexually active, had only one HIV-1-seronegative partner; and were HIV-1-seronegative at time of enrollment. CD4+ T cell counts, HIV-1 infection status, and plasma viral load (pVL) were determined as described previously and extensively [28 ].

Results were available for 21 ESN (comprising 11 males, 10 females; mean age, 39.1±6.8 years), six USN (five males, one female; mean age, 26.8±3.8 years), and 23 SP (11 females, 12 males; mean age, 37.0±8.2 years). Eleven of the 21 SP were highly active antiretroviral therapy (HAART)-experienced at the time of sample withdrawal.

Flow cytometry of peripheral blood mononuclear cells (PBMC)
Cryopreserved PBMC were thawed and prepared for assaying as described previously, and all samples were stored, collected, and analyzed in an identical manner [11 ]. Cell suspensions (containing ≥5x105 PBMC) were stained with anti-CD14-peridinin chlorophyll protein (PharMingen, Oxford, UK) and anti-CD91-fluorescein isothiocyanate (FITC; anti-{alpha}2-macroglobulin {alpha}-chain, Biomac, Leipzig, Germany) or anti-immunoglobulin G1-FITC (PharMingen), as described previously [13 , 14 ]. The only modification was the use of fluorescein-activated cell sorter wash containing 1x phosphate-buffered saline, 2 mM EDTA, 1 mg/ml NaN3, and 2% fetal bovine serum. The same settings were used for all acquisitions. At least 100,000 events were acquired in the live gate and analyzed on a FACSCalibur using CellQuest® software (Becton Dickinson, San Jose, CA). Positive staining for CD91 was determined by comparison with the appropriate isotype-matched control in all experiments.

Statistical analysis
The main hypothesis in our protocol was to examine differences in the mean flourescence intensity (MFI) staining (or percent population stained) between monocytes of PBMC derived from ESN and other control groups. Comparisons of the CD91 MFI between different groups were performed using the Mann-Whitney U nonparametric test. The Pearson correlation coefficient (r) was used to investigate correlations (P value calculated following regression analysis) between CD91 MFI and absolute CD4+,CD8+ counts or pVL.


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RESULTS
 
We suggest that higher surface expression of CD91 on monocytes of ESN, as a result of exposure to HIV in their partners or constitutively increased levels, confers some protection from infection with HIV. Because of the previous finding that higher expression of CD91 is associated with LTNP [13 ], we suggest that constitutive, increased expression may help mediate resistance.

We observed that the CD91 MFI on CD14+ monocytes was significantly higher in ESN compared with SP or USN. We also observed a significantly higher CD91 MFI in cells derived from SP compared with USN subjects (Fig. 1a ). Intracouple comparisons demonstrated that in 14/18 (77.8%) couples, CD91 MFI was, on average, 1.7 times higher in the ESN compared with their SP partner. In only four/18 (22.2%) couples was the CD91 MFI higher (on average 1.4x) in the SP than in the ESN partner. These data suggest an association between high CD91 surface expression on CD14+ monocytes and apparent HIV-1 resistance (Fig. 2 ).



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  		Figure 1. Comparison of CD91 MFI on CD14+ monocytes among the different groups of subjects in the cohort. Comparison of CD91 MFI on CD14+ monocytes is made amongst (a) SP (•), ESN (o), and USN ({diamondsuit}) subjects and (b) among HAART-naïve ({blacktriangleup}) and HAART-experienced ({blacktriangledown}) SP subjects and USN ({diamondsuit}) subjects. Only HAART-experienced SP subjects maintaining therapy at the time of sample withdrawal were included. Shown are the median and range. Comparison of medians was performed using the Mann-Whitney nonparametric test at two-tailed significance. Statistically significant differences are shown in boldface.



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  		Figure 2. Dot-plots comparing CD91 MFI on CD14+ monocytes of ESN and SP partners of the same couple. Comparison of CD91 MFI on CD14+ monocytes between ESN and SP partners of the same couple. Each couple was assigned a number shown above each dot-plot. In couples 2, 3, 4, 7, 9, 10, 12, and 14 (labeled), the ESN partner was female and the SP partner male, and in couples 17, 19, 20, 23, 24, 25, 26, 28, 29, and 30, the ESN partner was male and the SP partner female. Results were available for the couples shown.

In this small study, there was lack of normalization of CD91 MFI to levels observed in USN in eight SP subjects on HAART, despite sustaining undetectable pVLs (Fig. 1b) . Intriguing preliminary data in three SP subjects experiencing pVL rebounds following interruption of HAART showed CD91 MFI levels not significantly different from USN subjects (difference between medians, P=0.606), a finding that requires confirmation in a larger cohort. The sudden rise in viraemia, which inevitably accompanies treatment interruption, may result in increased binding to CD91 and decreased expression of this molecule. It has been observed previously that CD91 MFI is reduced subsequent to exposure of monocytes to HIV-1 in vitro [13 ], a likely consequence of HSP in the viral coat competing with fluorescent antibody for CD91 receptor binding. Here, we hypothesize that in such cases, levels of CD91 become elevated with time as viral set-points are reached.

The positive correlation between CD91 MFI and CD8+ T cell counts in HAART-naïve SP subjects (Fig. 3 ) provides additional evidence to suggest a role for CD91 receptor-mediated uptake of antigen in enhancing human leukocyte antigen class 1-restricted T cell responses. We have previously demonstrated HIV-1-specific CD8+ CTL in SP individuals in our cohort [28 , 29 ] and have also shown a positive correlation between CD8+ T cell counts and the breadth and magnitude of responses (unpublished observations). As we suggest that the observed up-regulation of CD91 is associated with protection from HIV-1 infection, it should also logically be associated with robust HIV-1-specific CD8+ CTLs in ESNs, and we have previously demonstrated the presence of distinct interferon-{gamma} (IFN-{gamma}) responses in ESN in our cohort [28 ]. When we compared six/18 ESN with HIV-1-specific IFN-{gamma} responses and 12/18 ESN without detectable responses. CD91 MFI, although higher among the former, was not significantly different in the two groups.



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  		Figure 3. CD91 MFI on CD14+ monocytes of HAART-naïve SP subjects as a function of autologous, absolute CD8+ T cell counts. Correlation was made between CD91 MFI on CD14+ monocytes and autologous CD8+ T cell counts of HAART-naïve SP subjects. Pearson’s correlation coefficient at two-tailed significance is shown in boldface. Pearson’s correlation coefficient for ESN subjects was –0.3 (P=0.257) and for USN subjects, was 0.5 (P=0.305).

There were no significant correlations (Table 1 ) between CD91 MFI in SP subjects and CD4+ T cell counts or pVL; in ESN subjects and pVL of their HAART-naïve SP partner (used as a surrogate for genital viral load); and in ESN and their risk to become HIV-1-infected (determined using parameters that included condom use, frequency of sex, and CD4+ T cell counts and pVL of SP partner).


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  		Table 1. CD91 MFI As A Function of CD4+, CD8+ T Cell Counts or pVL among Different Categories of Study Subjects


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DISCUSSION
 
Massively increased numbers of CD91-positive, dermal dendritic cells have now been shown to parallel the development of new, chronic-relapsing, inflammatory skin lesions in psoriasis, whereas other innate receptor levels (Toll-like receptors) were unchanged (O. Boyman, C. Conrad, C. Dudli, Kielhorn, B. J. Nickoloff, F. O. Nestle, submitted work). Thus, mechanisms that in one disease (HIV) may facilitate protection, may lead to a state of immunity via a common mechanism in another. Stimulation of CD91 leads to full activation of p38 mitogen-activated protein kinase signaling, which in turn, leads to production of nuclear factor-{kappa}B (p65 subunit nuclear translocation) and subsequent generation of tumor necrosis factor {alpha} by APCs [30 ]. The broader importance of this large cell-surface dimmer is suggested by the finding of increased levels on monocytes of those individuals with metastatic melanoma, who have prolonged survival [31 ].

Our results suggest an association between apparent HIV-1 resistance and high CD91 surface expression on CD14+ monocytes. Even if CD14+ monocytes are unable to provide costimulatory signals needed to initiate primary antigen-specific T cell responses [18 , 21 ], they can be precursors of dendritic cells, which are more efficient stimulators [22 ]. Furthermore, higher surface expression of CD91 surface expression on these monocytes in ESN indicates they have been significantly aroused to sample their extracellular milieu, which on occasion, may contain HIV-1 during repeated exposures. This requires further exploration in this setting.

High levels of CD91 on monocytes may lead to enhanced cross-presentation of HIV antigens by these cells and consequent enhanced stimulation of the activated anti-HIV CTLs. This observation may explain the preservation of CD8+ CTL responses that have been consistently observed in LTNP [9 10 11 12 ]. Recently, LTNP have been found to maintain expression of high levels of perforin on their CD8+ T cells [12 ], and these cells secrete {alpha}-defensins in response to stimulation [32 ]. As data have also demonstrated that CD91 mediates internalization of {alpha}-defensins in a specific, dose-dependent manner [33 ], the response to secreted {alpha}-defensins from stimulated CD8+ T cells in LTNP [32 ] may be enhanced further by CD91 overexpression in these individuals.

Correlative evidence for down-regulation of a CD91-mediated pathway of immune activation as a mechanism of immune escape exists. Thus, levels of a CD91 ligand, {alpha}2-macroglobulin, are elevated in animal models of cancer [34 ] and during recovery of animals from autoimmune encephalitis [35 ]. Elevation of tissue/serum HSP, such as gp96 and/or {alpha}2-macroglobulin, and CD91 expression may thus be seen as two faces of a host-pathogen interaction. Up-regulation of CD91 may therefore represent a useful therapeutic and perhaps preventive strategy against HIV.


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ACKNOWLEDGEMENTS
 
This study was supported by Wellcome Trust Grant Number 059437. We acknowledge all study participants without whom this study would not have been possible; all staff at the recruitment sites (the Joint Clinical Research Centre, the AIDS Information Centre, and The AIDS Support Organization in Kampala and Entebbe); the microbiology and serology laboratories of the Medical Research Council Program on AIDS in Uganda, Entebbe; and Drs. R. Downing, S. Balinandi, and S. Balinda of the Centres for Disease Control–Uganda.

Received January 25, 2005; revised March 3, 2005; accepted March 6, 2005.


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