Immunology Today, vol. 6, No. 10, 1985

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Enteric infections and other cofactors in AIDS Douglas L. Archer and Walter H. Glinsmann It is generally accepted that human T-cell lymphotropic virus type III ( H T L V-Ill) is the causative agent of acquired immunodeficiency syndrome (AIDS), but, as yet, there are no clear reasonsfor the different clinical manifestations of AIDS among individuals. In this article Douglas Archer and Walter Glinsmann discuss the history of AIDS and propose a link between H T L V-III infection and gastrointestinal diseaseprocesses with attendant malabsorption. They further propose that maximizing the nutritional status and minimizing the incidence of gastrointestinal infection of individuals infected with H T L V-III may prevent development of thefull-blown AIDS. The acquired immunodeficiency syndrome (AIDS) is an extremely complex collection of immunologic and other abnormalities that results in total loss of immune responsiveness and death by opportunistic infection or neoplasia. Two generalizations as to the cause of AIDS can be derived from the literature: human T-cell lymphotropic virus type III* ( H T L V - I I I ) is the causative agent of AIDS and infection with H T L V - I I I can result in a diverse clinical spectrum ranging from seroconversion only (possibly even reversion to seronegativity), to an asymptomatic carrier state, AIDS-related-complex (ARC), and rarely, full-blown AIDS, dependent on o t h e r ' cofactors'. Analysis of the populations at risk for AIDS would suggest that the nature of the cofactors is variable. The record of AIDS in the United States, particularly in the homosexual male population, provides a historical perspective that suggests the identity of some of the cofactors which may predispose to H T L V - I I I infection and modify its virulence. More important, such a historical perspective provides at least three identifiable intervention points at which the clinical course of the syndrome may be altered so as to avert AIDS.

The first historical period: an enteric epidemic in the US homosexual male population Tile first U S reports of AIDS 1 appeared in J u n e 1981. Given the generally accepted 1-4 year incubation period for H T L V - I I I , the prime suspect causative agent, the AIDS epidemic may actually have started as early as mid1977. Historically, this time period is significant. The first report of a health problem within the homosexual community appeared in 1968 in the form of venereal transmission of amebiasis among men who had not traveled outside New York 2. Several clinical investigators noticed a trend indicating an increased incidence of amebiasis 3'~, giardiasis 5, shigellosis6, and combined infections with these enteric pathogens 7-9 in the ensuing years. The epidemic of these disorders peaked around 1977, the percentage of persons affected by one or more enteric pathogens within the homosexual community *In this article the term H T L V - I I I is used tbr the virus also known as lymphadenopathy-associated virus ( L A V ) and AIDS-related virus ( A R V ) .

Center for Food Safety and Applied Nutrition, Food and Drug Administration, Washington, DC 20204, USA. © 1985,ElsevierSciencePublishersB.V., Amsterdam 0167- 4919/85/$02.00

being equal to that in tropical countries where there is underlying poverty and insanitation. Homosexual communities in major metropolitan areas such as New York, San Francisco, Seattle and Boston all reported similar epidemics at about the same time. It was estimated that 10 000-50 000 men in New York City alone were affected with amebiasis and/or giardiasis 4. Transmission of various enteric pathogens among the homosexual population has been linked both to the degree of promiscuity of the individual and with specific sexual acts 1° which were later linked to H T L V - I I I seropositivity 11.

The outcome of the first historical period Similarities between symptoms of AIDS and nutritional deficiencies, particularly protein-calorie malnutrition, have been discussed by several groups 12-14. Others have suggested the possible role of parasitic and gastrointestinal infections in predisposing to AIDS or acting in concert with H T L V - I I I to cause the catastrophic loss of immune function t5-18. F r o m the historical perspective of the AIDS epidemic in the US, little has been said about parasitic/gastrointestinal infections except as sequellae to AIDS although, historically, the gastrointestinal infections of epidemic proportion involving ShigeUa, Giardia and Entamoeba preceded introduction of H T L V - I I I . In that case, what role, if any, did these infections have in setting the stage for the AIDS epidemic? There are several overlapping possibilities. First, there is evidence for malabsorption of nutrients and loss of endogenous nutrients during shigellosis, giardiasis 19and amebiasis 2o(reviewed in Ref. 18). Second, damage to the intestinal barrier w o u l d permit greater ease of infection by secondary invaders (including H T L V - I I I if it survives the gastric barrier) and facilitate the influx of microbial and dietary antigens and otherwise normally excluded compounds. Gruskey and. Cooke 2~ demonstrated the increased uptake of normally excluded, antigenic material during gastroenteritis in human infants, and the implications of such an increased uptake have been reviewed 22'23. C h a n d r a 24 demonstrated higher serum antibody titers to a wider variety of food antigens in malnourished children than in healthy controls and suggested that this was partly due to atrophied gut mucosa and reduced secretory immunity. Animals demonstrate the same increased uptake of normally excluded antigenic substances during gastro-

Immunology Today, vol. 6, No. 10, 1985

intestinal infection 2s and malnutrition 26. Finally, enteric infections may result in inflammatory bowel disease (to be discussed later). Numerous symptoms common to AIDS should be manifest as a result of the malnutrition and gut damage (leading to increased invasion of antigens from the gut) mentioned above 14'18. Although mimicry of symptoms does not imply a causal relationship, it m a y indicate a need for further investigation. All three possible results of the first historical period may have set the stage for the introduction of H T L V - I I I . As suggested by Biggar et al. 27, immunologic abnormalities in healthy homosexual men suggest that AIDS arises out of a large pool of susceptible individuals.

The second historical period: introduction of HTLV-III As previously stated, H T L V - I I I was probably introduced into the US homosexual male population around mid-1977. Further support for the approximate time of H T L V - I I I introduction to the US comes from a retrospective study 28of hemophiliac sera collected from 1978 to 1984. Except for a single infant patient who received both factor V I I I and blood transfusions and seroconverted in 1978, the vast majority of hemophilia A patients receiving factor V I I I seroconverted in 1982-1983 and later. Both this study 2° and a similar study in Scotland 29indicate that H T L V - I I I was introduced into the US and from there into Scotland at about the same time as the onset of the AIDS epidemic in each country; the onset of clinical AIDS probably followed the introduction of H T L V - I I I into the U S homosexual population by 1-4 years. Interestingly, none of the 22 H T L V - I I I seropositive, factor V I I I recipients in the US study 2s have contracted AIDS, although several have demonstrated T-lymphocyte abnormalities, lymphadenopathy, and other symptoms of the AIDS prodrome (AIDS-related complex, ARC). This underscores the diversity of clinical symptoms associated with H T L V - I I I infection; they range from seroconversion only (which m a y even revert to negative), to an asymptomatic carrier state, A R C , and rarely, full-blown AIDS 3°. While it is clear that H T L V III precipitates the ultimate collapse of the immune system, it seems equally clear that other 'cofactors' are required for full-blown AIDS 11m. M a n y such cofactors have been discussed (reviewed in Ref. 18), m a n y may play a role(s), and some have just begun to be discovered and discussed. The outcome of the second historical period The outcome of the introduction of H T L V - I I I into the US male homosexual population is the present AIDS epidemic, which has subsequently spread to other populations. The non-homosexual target populations are varied and do not all share identical and identified predispositions. Heterosexual drug addicts, for example, may acquire the virus via shared needles, but again, AIDS does not develop in all those who seroconvert, suggesting other requisite cofactors. Narcotic drugs m a y predispose because of a generally self-abusive lifestyle, as may other infective agents acquired via needle contamination, or depressed immunity as a direct or indirect effect of the drug 32.

293 AIDS also presents in Haitians recently immigrated to the US. M a n y explanations have been offered, but at least one study showed no differences in immune parameters between symptomless Haitian heterosexual men and women and non-Haitian heterosexual men 33 residing in New York. Another report points out the underlying poverty and malnutrition among many Haitians and suggests a predisposing role of malnutrition and infection in AIDS 3~. Hemophiliacs receiving factor V I I I concentrate and persons receiving blood transfusions are also at greater risk from AIDS. Some studies suggest that factor V I I I alone, or for that matter any large infusion of foreign protein, or bloodborne viruses other than H T L V - I I I cause increased numbers of T8 cytotoxic/suppressor lymphocytes, a condition which m a y facilitate H T L V - I I I infection 35'36.Thus, for many of the high risk groups, an underlying immune status irregularity has been suggested. More important, as previously stated, not all those exposed to or infected with H T L V - I I I have contracted AIDS 28 owing to the diverse clinical spectrum of the disease 3°. This further suggests a cofactor(s) requirement for full-blown AIDS.

Gastrointestinal manifestations of the second historical stage of A I D S in the US Normal healthy sexually active homosexual males, symptomless HTLV-III-infected homosexual males, and A R C and AIDS patients carry a tremendously increased risk of severe intestinal infections by combinations of viruses, bacteria, protozoa and fungi 18'37-39.This may be due in part t o the extreme T-cell dependence of the secretory IgA system, owing to damage incurred during the first historical period. Alternatively, the increased risk of severe infection may result simply from overload of defense systems by constant assault with pathogens, owing to factors related to promiscuity and lifestyle 1°. Such perpetual infections result in malabsorption and malnutrition ~8, colonic inflammation and rectal disorders ~8'4°.Cytomegalovirus ( C M V ) colitis and resultant protracted diarrhea are often an endpoint in A R C and AIDS 41 as well as viral infections by as yet unidentified agents 4°. Some have cited the gastrointestinal infections with their resultant malabsorption, malnutrition and increased systemic antigen load as the 'cofactor ~which, in conjunction with H T L V - I I I , triggers AIDS~8. The third historical period: the present and future Few still question the causal role of H T L V - I I I in AIDS, as evidence for its role is compelling. Unanswered questions remain, however. The diverse clinical spectrum of H T L V - I I I infection is evidence that AIDS need not result; this is strongly suggestive of active cofactors or predisposition. The hallmark of H T L V - I I I infection at its worst is the virtually complete destruction of the T4 + helper/inducer lymphocyte population. I t is clear, however, that when the total spectrum of H T L V III infection is considered, the reversal of the T4/T8 ratio is at first (in the acute phase and in A R C ) due to increases in the T8 + suppressor/cytotoxic population. Increase in the T8 + population is characteristic of many infections, particularly viral infections with C M V and Epstein Barr

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Virus (EBV). Preventing the destruction of the T4 + population by immunostimulation (e.g., interleukin 2, gamma interferon), or by immunoprophylaxis (vaccine to HTLV-III) may well prevent AIDS, but the other major cellular manifestation of the disease process, namely an increase in the T8 + population, should not be treated lightly or overlooked. A recent report suggests that a subpopulation of T8 + cells, the T8Leu7-bearing population, expands in ARC, and if expansion progresses far enough, AIDS may result 42. Expansion of this T8Leu7-bearing subpopulation ofT8 ÷ cells was not observed during CMV, herpes simplex, or EBV infections 42. The authors suggest either that H T L V - I I I , in addition to destroying T4 ÷ cells, may be responsible for expansion of the TSLeu7 + subset, or that expansion of this subset makes the host more permissive for the effects of HTLV-II142. It appears that as lymphopenia progresses in the course of AIDS, the T8Leu7 + subpopulation remains constant in number, it is extremely imrnunosuppressive, and although it possesses the natural killer cell marker, it may be deficient in its killing ability 42. Curiously, the suppression of immunoglobulin synthesis in patients with mild Crohn's disease is due to a T-cell subpopulation expressing the Leu2aHNK-1 ÷ phenotype ~3 which is equivalent to the T8Leu7 + subpopulation that expands in A R C and as AIDS progresses. The Crohn's disease study further showed that the percentage of T4 + cells decreased, N K activity of HNK-1bearing cells was diminished, and the Leu2aHNK-1 + cells may have been activated or stimulated in the gastrointestinal tract 43.James et al. 43 suggest that the increase in suppressor cell activity (demonstrable in vitro) in Crohn's disease is accompanied (in vivo) by an increase in function of cells that block the suppression. In mice, such cells are termed contrasuppressor cells; they can be found in the gastrointestinal tract, among other places. Lehner et al. 44 have recently described a human contrasuppressor cell that expresses the T8 antigen, binds Vicia viUosa lectin, and in addition to countering T8 + suppressor cell activity, functions as an antigen-presenting cell (to T4 + cells) as well. The fate of this cell type during the progression of AIDS is unknown. A similar T8Leu7 + subset has been observed in patients with other humoral immunodeficiencies and predisposition to infection, and again, natural killing ability was impaire& 5. The stimulus for its expansion is uncertain, but there may be a role for immune complexes, at least in the appearance of this subset o f T 8 ÷ ceils in inflammatory bowel disease 46. Recently, immune complexes were found in progressively greater amounts in groups of healthy homosexual men, A R C patients and AIDS patients 47. Small IgGcontaining immune complexes are present in the sera of patients with ulcerative colitis or Crohn' s disease 48. These immune complexes are reportedly responsible, because of non-specific deposition (with complement) on platelets, for the thrombocytopenic purpura often observed in sexually active homosexual men and AIDS patmnts 49. There is ample evidence that inflammatory bowel processes are present in both the first and second historical periods of the AIDS story. There is also ample opportunity for immune complex formation or influx of

Immunology Today, vol. 6, No. 10, 1985

other antigenic or otherwise stimulatory substances during pathogen-induced inflammatory processes in the bowel, as well as evidence of malabsorption and malnutrition 5°. O f further interest are studies in nude mice, showing that inflammatory bowel disease, accompanied by lymphoma, cellular hyperplasia and lymphadenopathy, was caused in these congenitally athymic animals by injection of a factor which passes a 0.2/am triter and was derived from colon tissue of humans with Crohn's disease 51. Thus, an understanding of the role of the T8 ÷ lymphocyte in the entire spectrum of disease leading to AIDS and the possible participation of the bowel in the process provides another avenue of approach for prevention of full-blown AIDS. The clinical evidence suggests a role for intestinal pathogens and bowel dysfunction in predisposition to AIDS (first historical period), as a possible trigger mechanism or cofactor for H T L V - I I I infections (second historical period), and in the pathogenic process of AIDS itself (third historical period). Considerable hope can be derived from the variety of intervention points in which the progression to full-blown AIDS may be altered by prevention/cure of bowel infections, nutritional support, and immunologic modulation by drugs and/or recombinant IL-2 or interferons. Attempts at nutritional support have begun, in the form of total parenteral feeding for AIDS patients with severe diarrhea a n d malabsorption, but all ultimately succumbed to opportunistic infection or neoplasia 52. The first historical period of the AIDS saga in the US should also serve as a warning to health professionals that in any circumstances in which general sanitation deteriorates, the public is at risk for an agent such as H T L V - I I I , or another as yet unrecognized agent. Recent evidence suggests that a large group of high-risk homosexual men remain uninfected with, and susceptible to, HTLV-II153. Perhaps the aforementioned intervention points in the progression to AIDS may help these persons avoid AIDS, or lessen their likelihood of acquiring AIDS. []

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Enteric infections and other cofactors in AIDS.

It is generally accepted that human T-cell lymphotropic virus type III (HTL VIII) is the causative agent of acquired immunodeficiency syndrome (AIDS),...
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