serum antibodies to hiv-1 are produced post-measles virus infection: evidence for cross-reactivity...

Serum antibodies to HIV-1 are produced post-measles virus infection: evidencefor cross-reactivity with HLA

P. V. BASKAR, G. D. COLLINS, B. A. DORSEY-COOPER, R. S. PYLE, J. E. NAGEL, D. DWYER*,G. DUNSTON†, C. E. JOHNSON‡, N. KENDIG, E. ISRAEL* D. R. NALIN§ & W. H. ADLER

Laboratory of Immunology, National Institute on Aging, NIH, and*Maryland State Health Department, Baltimore, MD,†Howard University School of Medicine, Washington, DC,‡Case Western Reserve University School of Medicine,

Cleveland OH, and§Merck Research Laboratories, West Point, PA, USA

(Accepted for publication 9 October 1997)

SUMMARY

Convalescent sera obtained from patients who were recently recovered from an acute measles virusinfection were tested for the presence of anti-HIV-1 antibodies by Western blot analysis. While 16%(17/104) of control sera displayed reactive bands to a variety of HIV proteins, 62% (45/73) ofconvalescent sera demonstrated immunoreactive bands corresponding to HIV-1Pol andGag, but notEnv antigens. This cross-reactivity appears to be the result of an active measles infection. No HIV-1immunoblot reactivity (0/10) was observed in sera obtained from young adults several weeks after acombined measles, mumps, and rubella (MMR) vaccination. Interestingly, examination of anti-HLAtyping sera specific for either class I and class II molecules revealed that 46% (19/41) of these seracontained cross-reactive antibodies to HIV-1 proteins. Absorption of measles sera with mixedlymphocyte reaction (MLR)-activated lymphocytes and/or HIV-1 recombinant proteins significantlydecreased or removed the presence of these HIV-1-immunoreactive antibodies. Together, these findingssuggest that the immune response to a natural measles virus infection results in the production ofantibodies to HIV-1 and possibly autoantigens.

Keywords HIV-1 measles indeterminate Western blot

INTRODUCTION

Over the past 10 years, an immunological link has been demon-strated between HIV-1 antigens and cell surface-bound HLAmolecules [1–4]. While the precise mechanisms for this relation-ship are poorly understood, these associations are believed to resultfrom either molecular mimicry between various HIV-1 proteinsand HLA molecules, and/or a physical interaction between thevirus and HLA self proteins. Regardless of the reason, thisassociation has led to the hypothesis that AIDS is, in part, anautoimmune phenomenon in which the immune response to HIV-1may evoke an immune response to self HLA antigens [5–8].

An association between viral and ‘self’ antigens has beenshown to occur in a number of viral infections other than HIV-1[9]. For example, common molecular sequences shared betweenviral proteins and myelin basic protein (MBP) are believed to beresponsible for the autoimmune disease allergic encephalomyelitis(EAE), a multiple sclerosis (MS)-like disease [10]. Molecularsequence analyses have demonstrated that many viral proteins

share similar antigenic epitopes with host cell proteins [11]. Inaddition, upon binding to HLA class II molecules, various viral and‘self’ antigens have also been shown to act as ‘superantigens’,selectively inducing the activation of certain Vb T cell receptor(TCR)-expressing T cell populations, as well as leading to theclonal deletion of these same T cell populations within the thymusand periphery [12–16]. Superantigenic activity has also beensuggested for both HIV-1 and measles virus infections [12,17].Given these various associations, viral infections typically produceboth in vivo and in vitro abnormalities of T cell function.

The widespread use of immunoblotting to study antibody-mediated immune responses to HIV-1 resulted in the discoverythat as many as 30% of individuals, despite being non-reactivewhen screened by ELISA or enzyme immunosorbent assay (EIA)and who are not in a recognized high-risk category for HIV-1infection, have antibodies to HIV-1-associated antigens [18]. Themeaning of these weakly positive or ‘indeterminate’ immunoblotsin apparently healthy, minimal risk individuals is uncertain.Whether an indeterminate immunoblot represents a cross-reactiv-ity between HIV-1-associated antigens and non-HIV-1 antigenshas not been definitively established.

The present study demonstrates that within the sera of patients

Clin Exp Immunol 1998;111:251–256

251q 1998 Blackwell Science

Correspondence: Padma Baskar PhD, Laboratory of Immunology,National Institute on Aging, NIH, 4940 Eastern Avenue, Baltimore, MD21224, USA.

with HIV-1 or measles virus infections, there are cross-reactiveantibodies to both viral and self antigens that can be detected on ananti-HIV-1 immunoblot. Using convalescent sera from patientsrecovering from recent measles virus infections, indeterminateimmunoblot reactivity was removed by absorption with specificHIV-1-gag proteins. Similarly, in sera obtained from AIDSpatients, HIV-1 and autoreactive antibodies were removed byabsorption with lymphoid cells. Furthermore, several HLAtyping sera were shown to contain HIV-1-reactive antibodies thatcould be absorbed by purified HIV-1 proteins. Together, theseresults suggest that sera obtained from AIDS and convalescingmeasles patients contain both autoreactive and HIV-1-reactiveantibodies that may contribute to viral disease pathology.

PATIENTS AND METHODS

SeraMeasles convalescent sera were collected in the State of Mary-land (n¼ 73) and Lima, Peru (n¼ 4). Pre-immunization and multi-ple post-immunization sera were obtained from young adults(n¼ 10; ages 23–32 years) in Cleveland, Ohio, who had beenvaccinated with a live measles, mumps, rubella vaccine (M-M-RII; Merck & Co., Inc., West Point, PA). Normal, control sera(n¼ 104) were obtained from non-HIV-infected people living inthe Washington, DC area. Sera from HIV-infected individuals(n¼ 3) were obtained from patients within our clinical population.This study was approved by the Institutional Review Board (IRB)of the Francis Scott Key Medical Center that oversees all clinicalresearch protocols of the Gerontology Research Center, NIA, NIH.In all cases, the collection and use of the sera also had IRBapproval at the institution where the sera originated. All serawere anonymously labelled during the studies performed at theNIA. Sera were collected under sterile conditions and stored at¹208C.

Anti-HLA typing seraTwo different sources of anti-HLA typing antisera were utilized inthe current studies. These various sera were commercially obtainedfrom either Pel Freeze Clinical Systems (Brown Deer, WI) or theHoward University Genetics Laboratory (Washington, DC).

Anti-HIV-1 Western blotsWestern blot (WB) analyses were performed using the NovapathImmunoblot Assay Kit (BioRad Labs, Richmond, CA) accordingto the manufacturer’s instructions. The kit is manufactured fromHIV-1 propagated in the T lymphocyte cell line HUT-78. Thepartially purified virus is inactivated and disrupted with SDS andspecific HIV-1 proteins separated by gel electrophoresis in thepresence of SDS. Separated proteins are transferred by electro-blotting onto nitrocellulose. All serum specimens, whether fromHIVþ persons, anti-HLA sera or from patients recovering frommeasles virus infection, were run using the same procedure. Insome cases, sera were run at several dilutions to appreciate betterthe effects of absorption with lymphoid cells. None of the indivi-duals whose sera resulted in an indeterminate anti-HIV-1 immuno-blot banding pattern were HIV-EIA- or ELISA-positive.

Absorption of sera to remove anti-measles virus antibodyOne hundred microlitres of convalescent serum from each of 10patients who had recently had measles were added to one vial ofmeasles virus live vaccine (ATTENUVAX; Merck & Co.) that had

been reconstituted with 500ml of sterile water. The reconstitutedvaccine contained not less than 1000 tissue culture infectious doses(TCID)50 and approximately 25mg of neomycin. This vaccine isproduced in chick embryo cell culture and contains no preserva-tives or other viral proteins, but does contain small amounts ofsorbitol and hydrolysed gelatin as stabilizers. The serum–virusmixture was incubated at 378C for 3 h, overnight at 48C, and thenwas dialysed against distilled water for 24 h at 48C. Each samplewas then reduced in volume to 90ml by vacuum centrifugation(DNA Speed-Vac; Savant Instruments, Farmingdale, NY). Acontrol was run for each sample (the same protocol but withoutthe addition of the ATTENUVAX). WB were run using 30ml ofeach serum sample. The absorbed sera were also re-examined fortheir anti-measles virus antibody activity.

Removal of WB reactivity by absorption with HIV-1 recombinantproteinsRecombinant HIV-1 p18 and p24 proteins produced in a baculo-virus expression system were obtained from Intracel (Cambridge,MA). One hundred microlitres of either measles convalescentsera or anti-HLA antisera were added to 100 mg of recombinantprotein and incubated at 378C for 3 h and then overnight at 48C.Each sample was reduced to 100ml by vacuum centrifugation. Acontrol was done for each sample without the addition of recom-binant protein. The absorbed sera were examined for immunoblotreactivity.

Removal of the IgG fraction from measles convalescent serumConvalescent serum samples from three different patients recentlyrecovered from measles were treated to remove the IgG fraction.HiTrap Protein G Affinity Columns (Pharmacia LKB Biotech-nology, Piscataway, NJ) were washed with three volumes ofdeionized water and equilibrated with two volumes of startingbuffer (20 mM Na phosphate pH 7·0). A 400-ml serum sample wasapplied to each column and run in with 5 volumes of startingbuffer. Column bound IgG was eluted in one fraction withthree volumes of a buffer containing 0·1M glycine HCl pH 9·0.The eluted fraction from each column was dialysed against 6lof dH2O for 24 h at 48C, followed by vacuum centrifugation toreduce the volume to 200ml. Twenty microlitres of a 1M Tris–HClbuffer pH 9·0 were added to each 200-ml sample to preserveactivity.

Absorption of anti-measles virus and anti-HIV-1 sera withlymphoid cellsAbsorption with different types of cells was tested for their effecton the WB patterns. Cells used for absorption were: (i) densitygradient-separated non-activated peripheral blood mononuclearcells (PBMC) from three HIV¹ donors; and (ii) 3-day-old mixedlymphocyte cultures in which there was an increase in the expres-sion of HLA class II antigens. These activated cells were createdby culturing PBMC at a final density of 2·5×106/ml in 30 ml ofmedia (RPMI 1640 with 10% fetal calf-serum (FCS), 5×10-5

M

2-mercaptoethanol (2-ME) and 100mg/ml gentamicin) at 378C in a5% CO2 atmosphere for 3 days. For absorption of the sera, variousnumbers of cells were centrifuged into pellets and then resus-pended in 0·1 ml of added serum and incubated at 48C for 24 h.After incubation, the serum was separated from the cells bycentrifugation at 3000g for 10 min and analysed for bands on theanti-HIV-1 immunoblot.

252 P. V. Baskaret al.

q 1998 Blackwell Science Ltd,Clinical and Experimental Immunology, 111:251–256

RESULTS

During a survey seeking possible causes for indeterminate HIV-1WB, we noted that approximately half of the individuals who hadrecently recovered from a measles infection exhibited indeter-minate HIV-1 immunoblots. The most prevalent HIV-1-specificbands were p18, p24, gp41 and p55. We followed up theseobservations by testing sera isolated from Peruvian indian children(n¼ 4) and children and college age adults living within theMaryland area (n¼ 73), all of whom had recently recoveredfrom measles virus infections. All of the Peruvian children and45 out of 73 (62%) of the Maryland residents produced specificimmunoblot bands characteristic of indeterminate HIV-1 WB(Fig. 1). Overall, 96 bands with 14 different molecular weightswere detected. The most common and dense of these bands wereassociated with the p24 and p65 HIV-1 antigens. Passage of threerepresentative convalescent sera through anti-IgG affinity columnsremoved the HIV-1 immunoblot-reactive bands, while blottingwith the eluate fraction derived from these columns producedsimilar bands as non-passaged sera. These results strongly suggestthat band reactivity observed using measles convalescent sera wasdue to serum IgG. The above also strongly suggest that activemeasles virus infections result in the production of antibodies thatare cross-reactive with HIV-1 proteins. However, it was unclearwhether an active infection is a prerequisite for the production ofthese cross-reactive antibodies. To this end, post-immunizationsera derived from 10 young adult donors recently immunized witha live measles, mumps and rubella vaccine (ATTENUVAX) werealso examined using the HIV-1 immunoblots, and failed to produceany immunoreactive bands. Despite this lack of reactivity, vacci-nation resulted in a several fold increase in anti-measles virusantibody titres. Interestingly, absorption of several convalescentmeasles sera with the measles virus vaccine strain (Enders’attenuated Edmonston strain) resulted in the removal of antibodiesreactive to the measles virus but not to HIV-1 antigens. In contrast,absorption of convalescent measles sera with baculovirus-derived

recombinant HIV-1 p18 and p24 proteins specifically removed theHIV-1 immunoblot-reactive bands present within convalescentmeasles sera (Table 1).

Absorption of convalescent measles sera with either resting oractivated lymphoid (mixed lymphocyte reaction (MLR)) cellsremoved most of the HIV-1 immunoblot-reactive antibodies fromthe immunoreactive sera (Fig. 2, Table 2). Absorption of a stronglypositive control serum provided with the HIV-1 immunoblot kit aswell as sera derived from a paediatric AIDS patient with MLR-activated lymphocytes failed to affect immunoblot band intensity.However, absorption of two HIV-1þ sera that produced weakerbands on HIV-1 immunoblots with MLR-activated lymphocytesdemonstrated a slight decrease in some band intensities. Based onthese absorption studies, these results suggest that HIV-1 cross-reactive antibodies present in the convalescent sera obtained from

Measles virus and HIV-1 Western blots 253


Fig. 1.Representative HIV-1 immunoblot using sera obtained from variousgroups of individuals, some who had had a recent measles infection. Lanes1, 2, and 3, sera from children and young adults from Maryland; lanes 4 and5, sera samples from individuals who had had a measles infection but whowere further in the post-recovery period; lanes 6, 7, and 8, sera samplesfrom Peruvian children who had had a measles infection.

Table 1. Removal of Western blot reactivity of measles sera withrecombinant HIV-1 protein

Sera Sera Sera

Antigen 1 1 2 2 3 3specificity before after before after before after

p18 0 0 0 0 þ 0p24 þ 0 þ 0 0 0

Table shows results using community-acquired measles convalescentsera.

0.2

0

De

nsi

ty (

AU

)

2 4 6 8 10 12

0.4

0.6

0.8

0

Cells used for absorption (x 106)

Fig. 2. Changes seen in the density of the p18 band on an HIV-1 Westernblot after absorption of a serum from an HIV-1-infected person with non-activated normal lymphocytes or mixed lymphocyte reaction (MLR)-activated lymphocytes. There were 37% DRþ cells in the MLR-activatedculture and<1% in the non-activated lymphocytes. As seen in this figure,the density of the band changed when the activated (DRþ) cells were usedfor absorption, while little change occurred when non-activated cells wereused.W, Non-activated cells;X, activated cells 37% DRþ.

measles patients possess autoreactive antibodies that react withor bind to molecules on the surface of human lymphocytes(Fig. 3).

While it is unclear which lymphocyte surface molecules arereactive with HIV-1 antigens and HLA, previous studies havesuggested an immunoreactive association between HIV-1 antigens

and HLA molecules [5]. To examine this question, we tested 41different HLA typing sera derived from multiparous women onimmunoblots for possible cross-reactivity with various HIV-1proteins. The HIV-1 blot immunoreactivity of the anti-HLA anti-sera failed to display an indiscriminate binding pattern on theHIV-1 immunoblots, but did, in many cases, yield specific andreproducible bands on the immunoblots. Curiously, HLA typingsera with the same putative specificity often produced dissimilarHIV-1 immunoblot band patterns (Table 3). Overall, about 2/3 ofall the typing sera displayed some reactivity withPol and Envregion antigens, with the most common and strongest reactionsbeing to theGag antigens p24 and p55. The above results demon-strate that naturally derived HLA-reactive antisera possess HIV-1-specific antibodies that may be due to cross-reactive epitopesbetween HIV-1 and various HLA molecules.

DISCUSSION

Sera from up to 30% of individuals in non-risk categories forHIV-1 produce one or more bands on anti-HIV-1 immunoblots[18,19]. While the causes of these indeterminate immunoblotpatterns are generally unknown, similar results have been reportedusing sera obtained from patients with malaria [20–22] andleishmaniasis [23]. Polyclonal B cell activation has also beenshown to produce anti-HIV-1 antibodies in HIV-1¹ individuals[24]. One suggestion as to the origin of indeterminate HIV-1immunoblot reactivity is that it is due to antibodies producedfollowing exposure to defective human immunodeficiency virusesor to distantly related animal retroviruses [25]. In the present study,we show that measles virus infection produces antibodies thatcross-react with HIV-1 antigens. Following ‘natural’ measles virusinfections, children and young adults develop circulating IgGantibodies that result in specific immunoblot reactivity on HIV-1immunoblots. However, due to the limited availability of freshlyisolated measles patient sera, only 73 Maryland and four Peruvianindian samples were provided by the Maryland State Health Depart-ment for these studies. Thus, this small and non-age-matchedsample number has prevented a direct comparison between thevarious donors for environmental, physiological and genetic simi-larities that may account for the differences observed within ourassays. In contrast, individuals ‘vaccinated’ with the live measles,mumps and rubella vaccine failed to produce HIV-1-reactive anti-bodies. This discrepancy may be due to differences in the ability ofwild-type and vaccine strains of measles virus to infect cells. Wild-type measles virus has previously been shown to infect hostleucocytes, particularly monocytes [26] quite effectively, whilevaccine strain virus failed to infect any leucocytic population [27–31]. Therefore, it also seems quite possible that the route of viralentry, the level of virus exposure, and the effects of viral load onimmune cells may contribute to the development of HIV-1 cross-reactive antibodies.

There are a number of similarities between HIV-1 and measlesvirus infections. Both viruses cause significant immune suppression,infect CD4þ lymphocytes, CNS tissue and monocytes/macrophagesbothin vivoandin vitro [31–36]. Our results also demonstrate thatinfections due to either of these viruses result in the appearance ofcross-reactive serum antibodies which produce immunoreactivebands on an HIV-1 immunoblot. The HIV-1-reactive antibodiespresent in the sera may not be entirely specific for viral antigens,as absorption experiments suggest additional reactivity to self-antigens. These antibodies may be generated through the sharing of



Table 2. Changes in Western blot reactivity following absorption withresting or mixed lymphocyte reaction (MLR)-activated human lymphocytes

Absorption with resting Absorption with activatedlymphocytes, sera* lymphocytes‡, sera

HIV antigenspecificity 1 2 3 4 1 2 3 4

p18 0† 0 0 0 þ 0 0 0p24 0 0 0 0 þ 0 0 0p32 0 0 0 0 þ þ 0 0p39 þ þ 0 0 þ þ 0 0p41 0 0 0 0 0 þ 0 0p51 0 þ 0 0 þ þ 0 0p55 0 0 0 0 þ þ 0 þ

p65 0 0 0 0 0 þ 0 þ

p120 0 þ 0 0 þ þ 0 0p160 0 þ 0 0 þ þ 0 0

* Sera 1 and 2 were from adults who were HIVþ but had not progressedto AIDS. Serum 3 was from a paediatric AIDS patient born to an HIV-infected mother. Serum 4 was the positive control serum supplied in theBioRad Novapath Immunoblot Assay Kit.

† 0, No effect;þ, > 10% decrease in band density.‡ Resting lymphocytes contained<1% DRþ T cells. Activated lym-

phocytes contained 37% DRþ T cells.

0.5

0

De

nsi

ty (

AU

)

2

0.6

0.7

0.8

0.9

1

4 6 8 10 12

0.4

Cells used for absorption (106)

gp41

p32

p24

gp43

Fig. 3. Changes seen in various HIV-1 bands on an HIV-1 Western blotwhen the serum from an HIV-1-infected patient was absorbed usingvariable numbers of mixed lymphocyte reaction (MLR)-activated normallymphocytes. This figure complements the data presented in Fig. 2 andshows that the density of some of the bands on the Western blot changewhile others do not when the serum from an HIV-1-infected person isabsorbed with activated lymphoid cells.

amino acid homologies between the virus and host [1,10] orthrough the cytokine-modulating properties of the viruses andtheir products [37]. In addition, studies by Arthuret al. [38] havesuggested the newly budding HIV-1 viruses possess host-derivedcell surface molecules, such as HLA-DR andb2-microglobulin ontheir capsid surface. Also, studies by Orentas & Hildreth [39],using a MoAb-based capture assay, have demonstrated class I andII MHC proteins associated with both HIV-1 and simian immuno-deficiency virus (SIV) [39]. Perhaps these viral-associated hostmolecules result in new epitope(s) formation, leading to the gen-eration of autoreactive antibodies. Immunoblot analysis of the serafrom HIV and measles patients with purified HLA molecules arecurrently under investigation. HIV-1 is associated with a widerange of autoimmune phenomena that are correlated with the lossof CD4þ cells and disease progression [7,8,40].

Furthermore, HLA typing sera also gave a positive reaction onHIV-1 immunoblots used in our studies. Sera from HIV-1-infectedindividuals at different stages of the illness react with both MHCclass I molecules and class II-derived peptides. MoAbs to gp41-derived sequences cross-react with MHC class II-derived peptidesand recognize native class II molecules [1,5]. As these HLA-reactive antibodies are generally obtained from multiparousfemales who have generated them during previous pregnancies,this cross-reactivity is not completely unexpected. As previouslyreported, indeterminate HIV-1 immunoblots may be attributable tothe presence of HLA antigens on the immunoblot [1]. Unlike thereport of Drabick & Baker [41], the NovaBlot HIV-1 immunoblotstrips displayed no 43–45-kD bands and only occasional 56-kDbands that may represent class I and class II molecules, respec-tively. The MHC specificities we observed were generally associ-ated with putative HIV-1gag andpol proteins rather than HIV-1envantigens.

Though our study did not directly demonstrate ‘molecularmimicry’ between HLA and HIV-1, it does support and extend

the previous studies published by other laboratories. If molecularmimicry between HIV-1 and HLA class II antigens exists, thissimilarity may lead to the generation of autoantibodies in HIV-1-infected individuals resulting in increased immune suppression andmodulation [1,5].

In conclusion, viral infections provoke complicated immuneresponses. Understanding these responses can lead to more effica-cious vaccine strategies and a better understanding of the patho-genesis of viral induced illness. The association of HIV-1 andtissue histocompatibility antigens is especially interesting con-sidering recent provocative experimental evidence suggestingthat a tissue antigen response can be protective for HIV-1 diseaseand that treating this response in an infected person can prolongtheir disease-free period [42].

ACKNOWLEDGMENTS

The authors thank Drs Diane Griffin and Brian Ward for providingconvalescent measles sera, Dr Armead Johnson who provided the HLAspecificities of the typing sera, Ms Suzanne Strutt and the late Ms CharlotteAdler who prepared the figures, and Dr Dennis D. Taub for critical reviewand advice relating to the manuscript.

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Measles virus and HIV-1 Western blots 255


Table 3. Anti-HLA typing sera specificities and reactivity with the HIV-1 Western blot (WB)

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A10, 32 p24 DR10 p65, p160A10, 11 p24, p55, p65 DR10 p24, p55, p65, p160A10 p18, p24 DR10 p18, p24, p55, p65, p160A10 p24, p55 DR10 p51, p55, p65, p160A2, 28, B12 p24, p55 DR11 p32A2, 28 p55 DR11 p24A28 p24 DR4, 5 (11) p24A25, 32, Cw4 p18 DR11 p24, p55A25, 26 p24, p65 DR11 p24, p55, p160B5 p160 DR9 p24, p32, p51, p55, p65, p160B5,18,35 p55 DR9 p32, p65B5 p55 DQ2 p32B7 p24 DR4, 7 p18, p24, p160A24 p24 DR5 p24, p55A30 p18,p24,p41,p160 DR3 p24B22 p24 DR1 p65B35 p160 DR1, 6 p24, p55

DR5, 8 p18, p24, p55, p160

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serum antibodies to hiv-1 are produced post-measles virus infection: evidence for cross-reactivity...

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