The Cause of AIDS?

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malignancies and one of which, feline leukaemia virus, known to cause immunosuppression in cats.7 Of particular interest was HTLV-1, a retrovirus associated was

The Cause of AIDS?

possibility that the acquired immunodeficiency syndrome (AIDS) might be caused by a virus arose at an early stage. The tell-tale epidemiological pattern of a disease that affected promiscuous homosexuals, drug addicts, haemophiliacs, and occasionally their sexual partners or children bore a striking resemblance to hepatitis B. Indeed, the analogy was so close that some suggested that hepatitis B virus itself (or an associated virus) might be implicated, 1,2 although this now seems unlikely. From first principles, the AIDS agent might be expected to be novel (or previously unrecognised), transmissible by blood and other body fluids but of low infectivity, and unaffected by conventional antimicrobial agents. In addition, it should be oncogenic, or at least lymphotropic. Amongst candidate viruses, cytomegalovirus (CMV) and Epstein Barr virus (EBV) were of potential interest. CMV is itself immunosuppressive3 and is likely to be implicated in the pathogenesis of Kaposi’s sarcoma.4 But CMV is ubiquitous, and restriction endonuclease analysis of isolates from AIDS patients did not suggest the emergence of a single "killer strain".5 Clearly, CMV itself could not be the cause of AIDS. EBV, too, is probably an oncogenic virus but it infects B rather than T lymphocytes. The high EBV titres in most AIDS patients are probably an effect, rather than a cause, of the breakdown in immune regulation that THE

characterises this disease.6 Attention thus turned to the retroviruses-RNA tumour viruses that had long been linked with animal 1. McDonald MI, Hamilton JD, Durack DT. Hepatitis B surface antigen could harbour the infective agent of AIDS. Lancet 1983; ii. 882-84. 2. Ravenholt RT. Role of hepatitis B virus in acquired immunodeficiency syndrome. Lancet 1983, ii: 885-86. 3. Hamilton JR, Overall JC, Glasgow LA. Synergistic effect on mortality in mice with murine cytomegalovirus and Pseudomonas aeruginosa, Staphylococcus aureus, or Candida albicans infections. Infect Immun 1976; 14: 982-89. 4. Giraldo G, Beth E, Huang E-S. Kaposi’s sarcoma and its relationship to cytomegalovirus (CMV). III. CMV, DNA and CMV early antigens in Kaposi’s sarcoma. IntJ Cancer 1980; 26: 23-29 5. Detels R. Epidemiologic perspectives, pp 214-216. In: Gottlieb MS, moderator. The acquired immune deficiency syndrome. Ann Intern Med 1983; 99: 208-20. 6. Lane HC, Masur H, Edgar LC, Whalen G, Rook AH, Fauci AS. Abnormalities of B-cell activation and immunoregulation in patients with the acquired immune deficiency syndrome N Engl J Med 1983; 309: 453-58.

with certain types of human leukaemia.8 The first suggestion that this might be a fruitful line of inquiry came from studies of simian AIDS (SAIDS), a condition that has some similarity with the human disease. By means of a filterable agent present in tissue extracts, SAIDS was transmitted to healthy monkeys. Subsequently, a type D retrovirus was isolated from an affected animal, grown in tissue culture, and then given to healthy recipients which became ill with SAIDS some weeks later.9 lo Could HTLV-I be the cause of AIDS? Antibody to a membrane-associated antigen of the virus was found in 25% of patients with AIDS, but rarely in the general population or disease-free controls.]]i DNA probes identified HTLV-II in lymphocytes of AIDS patients,12 and in one case, infectious virus was isolated. 13 But why were so many AIDS patients seronegative, and, more importantly, why was AIDS virtually unknown in areas, such as Japan, where seropositivity for HTLV-1 is widespread? It is against this background that one must set recent reports of the identification of AIDS patients of a human type C retrovirus related to, although antigenically distinct from, HTLV-I. Soon after the first accounts of AIDS came descriptions of an apparently related syndrome of generalised lymphadenopathy. (The article at the front of this issue illustrates the progression of this syndrome in 8 of 42 patients to true AIDS, though not all those in this series seem to be going downhill.) French workers isolated "lymphadenopathy associated virus" (LAV) from a homosexual patient with this "prodromal AIDS",14 and subsequently found the same or similar viruses ("immune deficiency associated virus",IDAV) in cases of fully developed AIDS from several of the risk groups. 15 Gallo and his associates at the National Institutes of Health then reported the successful isolation of a lymphotropic retrovirus from 48 AIDS patients but none of 115 healthy controls.]6By means of a human neoplastic T-cell line that was permissive for the growth of the agent they were able to produce M, Hardy WD Jr, Cotter SM, Jakowski RM, Sliski A Naturally occurring persistent feline oncornavirus infection in the absence of disease. Infect Immun 1975; 11: 470-75 8. Editorial. Gallo on T-cell leukaemia-lymphoma virus Lancet 1982; ii: 1083. 9. Gravell M, London WT, Hamilton RS, et al Transmission of simian AIDS with type D retrovirus isolate. Lancet 1983, i: 334-35 10. Marx PA, Maul DH, Osborn KG, et al. Simian AIDS. isolation of atype D retrovirus and transmission of the disease. Science 1984; 223: 1083-86. 11. Essex M, McLane MF, Lee TH, et al. Antibodies to cell membrane antigens associated with human T-cell leukemia virus in patients with AIDS. Science 1983; 220: 859-62. 12. Gelmann EP, Popovic M, Blayney D, et al. Proviral DNA of aretrovirus, human T-cell leukemia virus, in two patients with AIDS. Science 1983; 220: 862-65. 13. Gallo RC, Sarin PS, Gelmann EP, et al. Isolation of human T-cell leukemia virus in acquired immune deficiency syndrome (AIDS) Science 1983; 220: 865-67. 14 Barre-Sinoussi F, Chermann JC, Rey F, et al Isolation ofa T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS). Science 7. Essex

1983; 220: 868-70. 15. Vilmer E, Barre-Sinoussi F, Rouzioux C, et al Isolation of new lymphotropic retrovirus from two siblings with haemophilia B, one with AIDS. Lancet 1984; i: 753-57. 16. Gallo RC, Salahuddin SZ, Popovic M, et al. Frequent detection and isolation of cytopathic retroviruses (HTLV-III) from patients with AIDS and at risk for AIDS. Science 1984; 224: 500-02.

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the virus. 17 Not only did this provide sensitive in-vitro detection system, but it also allowed them to carry out a detailed antigenic analysis. This revealed that the new agent, HTLV-III, although clearly a member of the HTLV-retrovirus family, could be readily distinguished from the two strains originally implicated as causing leukaemia.18 It will clearly be important to establish quickly whether the French and American viruses are indeed identical. Both have the morphological appearances of retroviruses and possess a magnesium-dependent reverse transcriptase. Significantly, they have a selective tropism for T-helper lymphocytes, although the extent to which they are cytopathic for these cells under normal circumstances is not yet clear. Seroepidemiological studies have shown that antibody to these agents is virtually absent in the general population, but that anti-LAV antibody is present in 75% of patients with prodromal AIDS and in 38% of cases with fully developed disease.19 For HTLV-111, the figures are 79% and 88% respectively20-a disturbing

large quantities of a

more worrying, although in a is the extent of seropositivity in different sense, symptomless homosexuals: 18% are LAV positive, and 35% have antibody to HTLV-III. Of course, the finding that a rather unusual virus is present more often in AIDS patients than in healthy controls is no proof of causality; it is possible that these viruses are simply passengers-yet another opportunist infection to which these patients are susceptible. Nevertheless, their independent observation in two laboratories, the fact that they have been identified in many of the risk groups (and only rarely in controls), and longitudinal observations suggesting that seroconversion may precede clinical illnessl9 will all, if confirmed, lend credence to our prejudice that viruses such as these are likely to be the guilty party. Whether infection with this virus is sufficient alone to cause the disease remains to be seen; co-factors (genetic suscepti-

discrepancy. Perhaps

bility,21 immunosuppression by

CMV3

or

semen 22)

may well be important, and these questions can only be answered by large-scale prospective studies. If these viruses are indeed involved in the pathogenesis of AIDS, the discovery represents a major advance. But our optimism should be guarded; tracking-down of the "AIDS agent" will be the beginning, not the end of the story. 17.

Popovic M, Sarngadharan MG, Read E, Gallo RC Detection, isolation and continuous production of cytopathic retroviruses (HTLV-III) from patients with AIDS and pre AIDs. Science 1984, 224: 497-500.

Schupbach J, Popovic M, Gilden RV, Gond MA, Sarngadharan MG, Gallo RC. Serological analysis of a subgroup of human T-lymphotropic retroviruses (HTLV-III) associated with AIDs. Science 1984; 224: 503-05. 19. Brun-Vezinet F, Rouzioux C, Barre-Sinoussi F, et al Detection of IgG antibodies to lymphadenopathy associated virus (LAV) by ELISA, in patients with acquired immunodeficiency syndrome or lymphadenopathy syndrome. Lancet (in press). 20. Sarngadharan MG, Popovic M, Bruch L, Schupbach J, Gallo RC. Antibodies reactive with human T-lymphotropic retroviruses (HTLV-III) in the serum of patients with

18.

AIDS. Science 1984; 224: 506-08. AE, Laubenstein LJ, Rubinstein P, et al. Disseminated Kaposi’s sarcoma in homosexual men. Ann Intern Med 1982; 96: 693-700. 22 Sonnabend J, Witkin SS, Purtilo DT. Acquired immunodeficiency syndrome, opportunistic infections, and malignancies in male homosexuals. A hypothesis of etiologic factors in pathogenesis. JAMA 1983, 249: 2370-74.

21 Friedman-Kien

Management of Gastro-oesophageal Reflux IT is fortunate that most people with gastrooesophageal reflux have only mild and intermittent symptoms, because the condition is very common. In one survey of hospital employees, 7% had heartburn every day and 36% had it at least once a month.’ Clearly, many people with reflux do not seek medical help and either tolerate their discomfort or rely on proprietary antacids. The principal barrier to reflux is the oesophageal sphincter,2>3 which probably increases its tone in response to raised intragastric pressure or episodes of reflux.4-7 In subjects with reflux, poor tone leads to sphincteric incompetence, but other abnormalities may be present besides. Normally, the oesophagus is efficiently cleared of errant gastric juice by swallow/distension-induced peristaltic waves and in some patients with reflux this defence mechanism may be faulty.8 Gastric emptying may likewise be delayed,9 so that post-prandial reflux has more time to happen. The pylorus may be incompetent, allowing regurgitation of bile and duodenal contents into the stomach and, potentially, the oesophagus: duodenogastric reflux was found in 52 of 59 patients with heartburn but in only 4 of 21 control subjects.’o The concentration of bile in the stomach is often greater than normal in patients with oesophagitis." Even in the absence of gastric acid and pepsin-eg, in patients with achlorhydria-gastro-oesophageal reflux of bile can cause severe oesophageal damage. 12 Gastrooesophageal 3 reflux does not always cause oesophagitis" and, clearly, the resistance of the oesophageal mucosa must be important in determining individual susceptibility to damage. This resistance may, like gastric mucosal cytoprotection, be

prostaglandin-mediated. Treatment of reflux is most likely to be effective in the long term if the patient has bad habits which he is willing to correct. Cigarette smoking facilitates reflux 1. Nebel OT, Fornes MF, Castell DO Symptomatic gastro-esophageal reflux incidence and precipitating factors. Am JDig Dis 1976; 21: 953-56. 2. Fisher RS, Malmud LS, Roberts GS, Lobis IF. The lower esophageal sphincter asa barrier to gastroesophageal reflux Gastroenterology 1977; 72: 19-22. 3 Dent J, Dodds WJ, Friedman RH, et al Mechanisms of gastro-esophageal reflux in recumbent asymptomatic human subjects J Clin Invest 1980, 65: 256-67. 4. Lind JF, Warrian WG, Wankling WS. Response of the gastro-esophageal junctional zone to increases in abdominal pressure Can JSurg 1966, 9: 32-38. 5. Cohen S, Harris LD. Does hiatus hernia affect competence of the gastroesophageal sphincter? N Engl J Med 1971; 284: 1053-56 6 Dodds WJ, Hogan WJ, Miller WN, Stef JJ, Arndofer RC, Lydon SB. Effect of increased intra abdominal pressure on lower esophageal sphincter pressure. AmJ Dig Dis 1975, 20: 298-308. 7. Ahtaridis G, Snape WJ, Cohen S Lower esophageal sphincter pressure as an index of gastroesophageal acid reflux Dig Dis Sci 1981; 26: 993-98. 8. Stanciu C, Bennett JR Oesophageal acid clearing one factorin the production of reflux oesophagitis. Gut 1974, 15: 852-57. 9. McCallum RW, Berkowitz DM, Lerner E. Gastric emptying in patients with gastroesophageal reflux. Gastroenterology 1981, 80: 285-91. 10. Gillison EW, Capper WM, Airth GR, Gibson MJ, Bradford I. Hiatus hernia and heartburn. Gut 1969; 10: 609-13 11. Crumplin MK H, Stol DW, Murphy GM, Collis JL The pattern of bile salt reflux and acid secretion in sliding hiatus hernia Br J Surg 1974; 61: 611-16 12. Orlando RC, Bozymski EM. Heartburn in pernicious anaemia—a consequence of bile reflux. N Engl J Med 1973; 289: 522-23. 13. DeMeester TR, Wang CI, Wernely JA, et al. Technique, indications and clinical use of 24 hour esophageal pH monitoring. J Thorac Cardiovasc Surg 1980; 79: 656-70.