INTERNATIONAL JOURNAL OF LEPROSY^

Volume 59, Number 4Printed in the U.S.A.

Leprosy and AIDS: A Review of the Literature andSpeculations on the Impact of CD4+ Lymphocyte

Depletion on Immunity to Mycobacterium leprae

The cultivatable mycobacteria were thefirst bacteria to be associated with oppor-tunistic infections in individuals infectedwith human immunodcficicncy virus 1(HIV-1). 1,2 Disseminated infection withMycobacterium avium complex strains andan increased incidence of tuberculosis, oftenwith unusual clinical manifestations, werenoted very early in the course of the ac-quired immunodeficiency syndrome (AIDS)epidemic, but infections caused by M. xen-opi, M. kansasii, M. szulgal, Al. asiaticum,M. flave.scens, M. fortuitum, Al. malmoense,M. boris BCG strain, Al. haetnophilum, M.gordonae, and M. marinum have subse-quently been reported. 3-9 Given this level

' Macher, A. M., Kovacs, J. A., Gill, V., Roberts,G. D., Ames, J., Park, C. H. Straus, S., Lane, H. C.,Parillo, J. E., Fauci, A. S. and Masur, H. Bactercmiadue to ,Slycobacterittm avium - intracellzdare in the ac-quired immunodeficiency syndrome. Ann. Intern. Med.99 (1983) 782-785.

Pitchenik, A. E., Cole, D., Russell, B. W., Fischl,M. A., Spira, T. J. and Snider, D. E., Jr. Tuberculosis,atypical mycobacteriosis, and the acquired immuno-deficiency syndrome among Haitian and non-Haitianpatients in South Florida. Ann. Intern. Med. 101 (1984)641-645.

American Thoracic Society. Mycobacterioses andthe acquired immunodeficiency syndrome. Am. Rev.Respir. Dis. 136 (1987) 492-496.

' Ausina, V., Barrio, J., Luquin, M., Sambeat, M.A., Gurgui, M., Verger, G. and Prats, G. Mycobacte-rium xenopi infections in the acquired immunodefi-ciency syndrome. (Letter) Ann. Intern. Med. 109 (1988)927-928.

s Centers for Disease Control. Disseminated Myco-bacterium boris infection from BCG vaccination of apatient with acquired immunodcficicncy syndrome.MMWR 34 (1985) 227-228.

Chan, J., McKitrick, J. C. and Klein, R. S. Myco-bacterium gordonae in the acquired immunodeficiencysyndrome. (Letter) Ann. Intern. Mcd. 101 (1984) 400.

7 Lambertus, M. W. and Mathison, C. E. Mycobac-terium marinunz infection in a patient with crypto-sporidiosis and the acquired immunodeficiency syn-drome. Cutis 42 (1988) 38-40.

8 Rogers, P. L., Walker, R. E., Lane, H. C., Witebsky,F. G., Kovacs, J. A., Parillo, J. E and Masur, H. Dis-seminated Mycobacterium haemophilum infection intwo patients with the acquired immunodeficiency syn-drome. Am. J. Med. 84 (1988) 640-642.

Sherer, R., Sable, R., Sonnenberg, M., Cooper, S.,Spencer, P., Schwimmcr, S., Kocka, F., Muthuswamy,P. and Kallick, C. Disseminated infection with My-

of interest in the interaction of HIV infec-tion with mycobacterial disease, the paucityof reported cases of M. leprae infection inHIV-infected patients is striking. There arean estimated 12 million cases of leprosy inthe world and an unknown, but undoubt-edly large, number of people harboring sub-clinical infection with M. leprae.'° Many ofthese infected individuals reside in regionsof Africa suffering from epidemic rates ofHIV infection.

The interaction of the causative agent ofhuman leprosy, Al. leprae, with the humanimmune system has fascinated immunolo-gists for decades. The concept of a clinicaldisease spectrum derived from the variableindividual response to the infecting organ-ism, and which is reflected in the immu-nohistology of the skin lesions, is well es-tablished." , 12 Research on leprosy duringthe past decade has focused on various as-pects of the immune response to M. leprae,but the specific determinants of protectiveimmunity and of the clinical type of leprosywhich develops in any single patient remainobscure. It is possible that the study of pa-tients co-infected with HIV and Al. lepraewill provide valuable information on therole played by the CD4+ lymphocyte in thehost-parasite interaction.

Leprosy and HIV infection—a review of the literature

A literature search performed a decadeinto the HIV epidemic (May 1991) on con-current leprosy and HIV infection uncov-

cobacterium kansasii in the acquired immunodeficien-cy syndrome. Ann. Intern. Mcd. 105 (1986) 710-712.

'" Bloom, B. R. and Godal, T. Selective primaryhealth care: strategics for control of disease in the de-veloping world. V. Leprosy. Rev. Infect. Dis. 5 (1983)765-780.

" Ridley, D. S. and Jopling, W. H. Classification ofleprosy according to immunity; a five-group system.Int. J. Lepr. 34 (1966) 255-273.

' 2 Sansonetti, P. and Lagrange, P. H. The immu-nology of leprosy: speculations on the leprosy spec-trum. Rev. Infect. Dis. 3 (1981) 422-469 (274 ref.).

639

640^ International Journal of Leprosy^ 1991

ered four case reports, 13- ' 5 three publishedepidemiologic surveys,' - ' 8 abstracts of anadditional epidemiologic study," an edi-torial,'" and two studies in a primate modelsystem. , ' ,„

Case studies. The first case reported wasthat of a 43-year-old homosexual with his-tologically diagnosed borderline tubercu-loid leprosy.' 5 He received dapsone and clo-fazimine with an excellent clinical responsebut subsequently developed Kaposi's sar-coma and pulmonary tuberculosis, and waspositive for HIV. The leprosy never re-curred.

'' Janssen, F., Wallach, D., Khuong, M. A., Pennec,J., Pradinaud, R., Said, G. and Cottenot, F. Associationdo maladie de Hansen et d'infection par le virus del'immunodeficience humaine: deux observations. PresseMed. 17 (1988) 1652-1653.

" Kennedy, C., Chin A Lien, R. A. M., Stolz, E.,van Joost, T. and Naafs, B. Leprosy and human im-munodeficiency virus infection. A closer look at thelesions. Int. J. Dermatol. 29 (1990) 139-140.

" Lamfers, E. J. P., Bastiaans, A. H., Mravunac, M.and Rampen, F. H. J. Leprosy in the acquired im-munodeficiency syndrome. Ann. Intern. Med. 107(1987) 111-112.

Leonard, G., Sangare, A., Verdier, M., Sassou-Guesseau, E., Petit, G., Milan, J., M'Boup, S., ley, J.-L., Dumas, J.-L., Hugen, J., N'Gaporo, I. and Denis,F. Prevalence of HIV infection among patients withleprosy in African countries and Yemen. J. Acquir.Immune Defic. Syndr. 3 (1990) 1109-1113.

"7 Meeran, K. Prevalence of HIV infection amongpatients with leprosy and tuberculosis in rural Zambia.Br. Med. J. 298 (1989) 364-365.

Tekle-Haimanot, R., Frommel, D., Tadesse, T.,Verdier, M., Abebe, M. and Denis, F. A survey ofHTLV-I and HIVs in Ethiopian leprosy patients. AIDS5(1991) 108-110.

Pean, C., Pape, J. W., Deschamps, M.-M.,Dambreville, M. and Johnson, W. D., Jr. Natural his-tory of M. leprae and HIV co-infection. (Abstract) In:Proceedings of the V International Conkrence on AIDS;the Scientific and Social Challenge, Montreal, June4-9, 1989. Ottawa: International Development Re-search Centre, 1989, p. 427.

2° Turk, J. L. and Rees, R. J. W. AIDS and leprosy.(Editorial) Lepr. Rev. 59 (1988) 193-194.

2 ) Baskin, G. B., Gormus, B. J., Martin, L. N., Mur-phey-Corb, M., Walsh, G. P. and Meyers, W. M. Pa-thology of dual Mycobacterium leprae and simian im-munodeficiency virus infection in rhesus monkeys. Int.J. Lcpr. 58 (1990) 358-364.

" Gormus, B. J., Murphey-Corb, M., Martin, L. N.,Zhang, J., Baskin, G. B., Trygg, C. B., Walsh, G. P.and Meyers, W. M. Interactions between simian im-munodeficiency virus and Mycobacterium leprae in ex-perimentally inoculated rhesus monkeys. J. Infect. Dis.160 (1989) 405-413.

The next case was a 28-year-old male fromMartinique." He had received triple ther-apy (dapsone, rifampin, clofazimine) forlepromatous disease, complicated by ery-thema nodosum leprosum (ENL), from 1976through May 1985, with negative bacterialindices on skin biopsy from 1978 through1986. In February 1987 he developed a re-active polyarthritis (believed secondary tochlamydial infection) but was found to havea 1+ bacterial index (BI), suggesting a re-lapse of his leprosy. He was also found tobe HIV positive and to have chronic gen-eralized lymphadenopathy.

The same authors reported a 27-year-oldmale who had been treated for "cutaneousleprosy" from 1978 through 1982. He pre-sented in 1987 with a sensorimotor poly-neuropathy and palpable nerve trunks. Askin biopsy showed a "tuberculoid infil-trate" and histologic changes suggestive ofa reversal reaction. At the same time, hewas found to have positive serology to HIV,candidal esophagitis, and a CD4/CD8 ratioof 0.3.

The final case was a 35-year-old, HIV-positive woman with an anesthetic maculeclinically consistent with BT/BB leprosy."The histopathology of the lesion, however,was more typical of downgrading BL dis-ease. The cutaneous granulomas had a lym-phocyte:histiocytc ratio of 3:1 and half ofthe lymphocytes were CD4+. The most un-usual abnormalities were the absence of nat-ural killer (NK) cells and interleukin-2 re-ceptor positive cells in the granulomas andthe lack of HLA-Dr expression by epider-mal keratinocytes. Clincially, the patient hadmoderately advanced HIV disease (periph-eral blood CD4 count was 300 with a CD4/CD8 ratio of 0.6), but her skin lesions re-sponded rapidly to dapsone, rifampin andclofazimine.

There is little insight to be gained fromthe first two cases. In one the leprosy neverrecurred, and the evidence for recurrence inthe second was limited to a BI of 1+ onskin biopsy. An occasional low positive BIis hardly unusual in lepromatous patients,even after years of therapy, and does not initself imply relapse. The third case raisesseveral interesting points. The first is thatthe patient relapsed with a histologic pictureof tuberculoid disease despite having a re-versed CD4/CD8 ratio and advanced HIV

59, 4^ Editorials^ 641

disease. The second is that there was his-tologic evidence of a reversal or upgradingreaction. The final case demonstrated a dis-cordance between the clinical and histologicstaging. It is intriguing that CD4+ lympho-cytes were well represented in the granulo-mas despite the deficiency in circulatingCD4+ cells. The authors speculate, though,that functional defects in these CD4+ cellscould have been responsible for the atypicalaspects of the immunohistology which werenoted above. All of the cases with clinicalleprosy responded promptly to convention-al therapeutic regimens.

Epidemiologic studies. A small studyconducted in Zambia reported that 6 of 18(33%) of newly diagnosed leprosy patientshad antibodies to HIV, which was similarto the prevalence of seropositivity found insuspected tuberculosis cases (21/47, 45%)but significantly greater than that found insurgical patients (2/39, 5%) or blood donors(4/55, 7%) at the same hospita1. 17 No detailsconcerning the type of leprosy present in thepatients was given, other than the commentthat most had serious symptoms "such asparalysis or neuritis." This study suffers fromits small size, potential bias in patient se-lection (those with mild cutaneous diseasewere presumably not seen at the hospital),and failure to confirm HIV seropositivityby immunoblotting. 23 Nonetheless, it doesraise the possibility that co-infection withHIV could accelerate the development ofclinical leprosy, or promote the develop-ment of significant neurologic disease in un-treated patients infected with Al. leprae. Thisstudy is also noteworthy in that it focusedon newly diagnosed leprosy patients withactive disease. It would be anticipated thatthe effects of HIV-induced immuno-suppression on leprosy would be most ev-ident in this population.

A much larger study conducted in theIvory Coast, Congo, Senegal and Yemenfound that the prevalence of antibodies toHIV-1 and HIV-2 was identical in leprosypatients and controls in each of the coun-tries, although the rates differed betweencountries (from 0% HIV-1 seropositivity

23 Miller, R. A., Collier, A. C., Buchanan, T. M. andHandsfield, H. H. Seroepidemiologic screening for an-tibodies to LAV/HTLV-III in Sri Lanka, 1980-1982.N. Engl. J. Med. 313 (1985) 1352-1353.

among both patients and controls in Yemento 3.8% in patients and 5.2% in controls inthe Congo). 16 All positive HIV serologieswere confirmed by immunoblot. The prev-alence of HIV-1 infection among patientswith lepromatous (3.6%) and tuberculoid(3.7%) leprosy was identical. A similarly de-signed study conducted in Ethiopia by someof the same investigators' 8 found antibodiesto HIV-1 in 3.2% of the leprosy patientsand 2.5% of controls (not significantly dif-ferent). Of the 8 seropositive leprosy pa-tients, 3 had multibacillary disease, 3 hadpaucibacillary disease, and 2 had indeter-minate leprosy. None were clinically in re-action.

The final study was performed in Haitibetween 1985 and 1988.' 9 The HIV sero-positivity rate was comparable for the 200tuberculoid and 75 lepromatous patientsstudied (overall 18/275, 6.5%). New lesionsdeveloped during therapy in 4 of 14 (29%)seropositive tuberculoid patients, 0 of 4seropositive lepromatous patients, and2 of 257 (0.8%) seronegative patients. Thepatients who developed new lesions also be-came anergic to lepromin. The tuberculoidpatients, even those without new leprosylesions, were very likely to develop an HIV-associated illness during the follow-up pe-riod.

Summary of case reports and epidemio-logic studies. No firm conclusions can bedrawn from the limited data available atthis time, but several patterns seem to beemerging. Concurrent HIV infection ap-pears to result in anergy to lepromin. Re-lapses ofleprosy, particularly of tuberculoidleprosy, may be more common in co-in-fected individuals. There is also the sugges-tion that concurrent tuberculoid leprosy canaccelerate the progression of HIV-relateddisease, and that HIV co-infection may pro-mote the development of clinical leprosy,or at least of severe neurologic complica-tions of leprosy. There is no data indicatingthat concurrent HIV infection has any effecton the clinical classification (e.g., tubercu-loid or lepromatous) of the leprosy whichis present, either at the time of initial pre-sentation or at relapse. Finally, there hasbeen one case each of reversal and down-grading reactions in co-infected patients buterythema nodosum leprosum (ENL) has notbeen reported.

642^ International Journal of Leprosy^ 1991

Primate model of co-infection with HIVand M. leprae. In the course of a study onexperimental primate leprosy, five rhesusmonkeys were inadvertently inoculated withbacilli harvested from a donor asympto-matically co-infected with simian immu-nodeficiency virus (SIV). 21,22 Four of thefive animals seroconverted to SIV and three(75%) developed clinical leprosy. Only 21%of the SIV seronegativc monkeys receivinga comparable inoculum developed leprosy.All three animals with SIV and clinical lep-rosy developed other opportunistic infec-tions consistent with advanced SIV infec-tion and were humanely killed. At necropsy,two had evidence of borderline lepromatousdisease and one had indeterminate diseasewith only scant numbers of bacilli. The oneSIV-positive animal that did not developleprosy also remained clinically free of SI V-related complications. Diminished or ab-sent lepromin skin-test responses were seenin the SIV-positive animals that developedleprosy.

Of particular note was one animal thatappeared to be resistant to Al. leprae, havingremained healthy while developing astrongly positive skin test response to lep-romin and a humoral response to phenolicglycolipid-I (PGL-I) typical of resistant an-imals. This animal was reinoculated withbacilli unknowingly contaminated with SI Vand 48 months later developed borderlinelepromatous leprosy. The authors conclud-ed that co-infection with SIV and Al. lepraeincreases the susceptibility of the monkeysto leprosy despite an antibody response usu-ally associated with resistance and, in at leastone instance, an active cellular immune re-sponse as reflected by a positive leprominskin test. It might also be argued that activeinfection with Al. leprae led to acceleratedSIV disease, since the only SIV-positive an-imal without clinical leprosy failed to showevidence of progressive immunodeficiency.

Role of CD4+ lymphocytes inimmune response to M. leprae

The cellular immune response in leprosyis extraordinarily complicated, involvingseveral lymphocyte subpopulations as wellas other cell types. 24-26 CD4+ lymphocytes

Modlin, R. L., Melancon-Kaplan, J., Young, S. M.M., Pirmez, C., Kino, H., Convit, J., Rca, T. H. and

have been linked to classical delayed-hy-persensitivity reactions' and to immunegranuloma formation. 12- 27 CD4+ lympho-cytes also have been postulated to be in-volved in protective immunity to M. lepraeand in the immune interactions that deter-mine what form of leprosy will develop inan individual destined to develop clinicaldisease, 28, 29 although other cell popula-tions, in particular CD8+ (suppressor-Tcells) lymphocytes, almost certainly play arole as wel1. 29-31

The involvement of CD4+ lymphocytesin ENL and reversal reactions is controver-sial. There is indirect evidence consistentwith increased CD4+ lymphocyte activityin ENL. 32 ' 33 Reversal reactions have longbeen attributed to an upgrading of the cel-lular immune response, specifically theCD4+ lymphocyte response, analogous toa systemic delayed-hypersensitivity reac-

Bloom, B. R. Learning from lesions: patterns of tissueinflammation in leprosy. Proc. Natl. Acad. Sci. U.S.A.85 (1988) 1213-1217.

Modlin, R. L., Pirmez, C., Holman, F. M., Tori-gian, V., Uyemura, K., Rea, T. H., Bloom, B. R. andBrenner, M. B. Lymphocytes bearing antigen-specific

T-cell receptors accumulate in human infectiousdisease lesions. (Letter) Nature 339 (1989) 544-548.

2" Smith, P. D., Ohura, K., Masur, H., Lane, H. C.,Fauci, A. S. and Wahl, S. M. Monocyte function in theacquired immune deficiency syndrome: defective che-motaxis. J. Clin. Invest. 74 (1984) 2121-2128.

" Kirkpatrick, C. H. Delayed hypersensitivity. In:Immunological Diseases. 4th ed., Samter, M., ed. Bos-ton: Little, Brown and Company, 1988, pp. 261-277.

" Bloom, B. R. Learning from leprosy: a perspectiveon immunology and the Third World. J. Immunol. 137(1986) i—x.

2' Bloom, B. R. and Mehra, V. Immunological un-responsiveness in leprosy. Immunol. Rev. 80 (1984)5-28.

`" Mehra, V., Convit, J., Rubinstein, A. and Bloom,B. R. Activated suppressor T cells in leprosy. J. Im-munol. 129 (1982) 1946-1951.

Modlin, R. L., Mehra, V., Wong, L., Fujimiya, Y.,Chang, W.-C., Horwitz, D. A., Bloom, B. R., Rea, T.H. and Pattengale, P. K. Suppressor T lymphocytesfrom lepromatous leprosy skin lesions. J. Immunol.137 (1986) 2831-2834.

" Miller, R. A., Shen, Y.-Y., Rca, T. H. and Har-nisch, J. P. Treatment of chronic erythema nodosumleprosum with cyclosporine A produced clinical andimmunohistologic remission. Int. J. Lcpr. 55 (1987)441-449.

Uyemura, K., Dixon, J. F. P., Wong, L., Rca, T.H. and Modlin, R. L. Effect of cyclosporine A in ery-thema nodosum leprosum. J. Immunol. 137 (1986)3620-3623.

59,4^ Editorials^ 643

tion.' 2 ' 34 However, thalidomide, which actsthrough suppression of helper T-cell activ-ity, has no effect on reversal reactions. 35 . 36

Correlation of observations in co-infectedindividuals and populations withpredictions: consistencies and surprises

Many of the published observations onco-infections have been in agreement withthe postulated roles of CD4+ lymphocytesin the host response to M. leprac. In par-ticular, the immunohistologic findings in thecase reported by Kennedy, et al.," the in-creased prevalence of clinical disease inco-infected primates, 22 and the apparentlyuniversal lepromin anergy in HIV/SIV-in-fected leprosy cases fit with predictions. Thelack of reported cases of ENL among mul-tibacillary leprosy patients with HIV infec-tion and the occurrence of at least one caseof reversal reaction in a co-infected patientare also consistent with involvement ofCD4+ lymphocytes in ENL but not in re-versal reactions, although it is hazardous togeneralize given the small number of cases.

On the other hand, the absence of clinicalevidence of downgrading, or of a shift incase distribution toward the lepromatouspole, is surprising. None of the epidemio-logic surveys published to date has found abias toward HIV scropositivity among mul-tibacillary patients. It is also unexpected thatthe patients with tuberculoid disease whorelapsed after becoming HIV seropositiverelapsed with tuberculoid rather than mul-tibacillary disease (although it is possiblethat the clinical/histologic discordance seenin one patient' 4 may actually be a commonphenomenon in this patient population, andthat the "tuberculoid" relapses might havehad multibacillary histology). Finally, ifHIV-associated immunosuppression is as-sociated with an increased incidence of clin-ical progression among patients with sub-

Harboe, M. The immunology of leprosy. In: Lep-rosy. Hastings, R. C., ed. New York: Churchill Liv-ingstone, 1985, pp. 53-87.

Jacobson, R. R. Treatment. In: Leprosy. Hastings,R. C., ed. New York: Churchill Livingstone, 1985, pp.193-222.

Moncada, B., Baranda, M. L., Gonzales-Amaro,R., Urbina, R. and Loredo, C. E. Thalidomide—effecton T cell subsets as a possible mechanism of action.Int. J. Lepr. 53 (1985) 201-205.

clinical leprosy, one would predict anincreasing incidence of leprosy in HIV-en-demic areas, with the "excess" cases testingHIV positive. Only one of the epidemio-logic studies' 7 provides any support for thishypothesis.

SummaryThe potent effects of HIV infection on the

human immune system, the complexity ofthe host-parasite interaction in leprosy, andthe paucity of current information on thenatural history of co-infected patients makesthis area a fertile ground for clinical andimmunologic investigation. Several studieshave now validated the prediction that thereexists a large cohort of patients, particularlyin Africa, who are concurrently infected withHIV and M. leprac. Sparse but tantalizingevidence suggests that infection with HIVmay increase the incidence of leprosy amongindividuals with subclinical infection withM. leprae, either through shortening the in-cubation period or by increasing diseasepenetrance. Similarly, active mycobacterialdisease may accelerate the course of HIVdisease, as has been postulated to occur dur-ing concurrent infections with certain otherviral and bacterial pathogens in HIV-posi-tive patients. A subtle and complex inter-play between HIV and leprosy may thusresult which will impact the observed epi-demiology of both illnesses in regions whereboth are prevalent. Possible effects of theHIV epidemic on leprosy control programshave been outlined by the World HealthOrganization and in an editorial by Turkand Rees. 2° , 37

The published experience provides fewguidelines for the clinical care of co-infectedpatients. The initial response to conven-tional therapeutic regimens appears to beexcellent, but no follow-up data have beenincluded. The possible absence of ENL inthese patients would simplify care for mul-tibacillary disease, if this observation isconfirmed in larger field studies. On the oth-er hand, short-course treatment regimens,particularly the 6- to 12-month regimensrecommended for selected cases of pauci-

Abstract of a Special Meeting on "Interrelationsof Tropical Diseases and HIV infection, UNDF-WorldBank-WHO, Kenya, 1987." Lepr. Rev. 59 (1988) 277.TDR/GPA/TD-HI V/87.3.

644^ International Journal of Leprosy^ 1991

bacillary disease, may be associated withunacceptable failure rates in HIV-positiveindividuals. The answers to these questionscan only be provided by further work onthe epidemiology, clinical manifestations,response to therapy, and immunologic re-sponses of patients co-infected with M. lep-rae and HIV.

—Richard A. Miller, M.D.Division of Infectious DiseasesDepartment of Medicine

Seattle Veterans AdministrationMedical Center and the

University of WashingtonSeattle, Washington, U.S.A.

Reprint requests to: Dr. Richard A. Mil-ler, Medical Service (111-1D), Seattle VAMedical Center, 1660 South ColumbianWay, Seattle, Washington 98101, U.S.A.