Thomas J. Spira

Seroconversion to Antibodies against Kaposi's Sarcoma–Associated Herpesvirus–Related Latent Nuclear Antigens before the Development of Kaposi's Sarcoma

BACKGROUND If Kaposis sarcoma-associated herpesvirus (KSHV) is the cause of Kaposis sarcoma, serologic evidence of infection should be present in patients before the disease develops. METHODS Using an immunoblot assay for two latent nuclear antigens of KSHV, we tested serum samples from homosexual male patients with the acquired immunodeficiency syndrome (AIDS) with and without Kaposis sarcoma (HIV-infected men with hemophilia), HIV-seronegative blood donors, and HIV-seronegative patients with high titers of antibodies against Epstein-Barr virus (EBV). Serial serum samples obtained from patients with Kaposis sarcoma before the diagnosis of the disease were tested for evidence of seroconversion. RESULTS Of 40 patients with Kaposis sarcoma, 32 (80 percent) were positive for antibodies against KSHV antigens by the immunoblot assay, as compared with only 7 of 40 homosexual men (18 percent) without Kaposis sarcoma immediately before the onset of AIDS. Of 122 blood donors, 22 EBV-infected patients, and 20 HIV-infected men with hemophilia, none were seropositive. When studied by the immunoblot assay over a period of 13 to 103 months, 21 of the 40 patients with Kaposis sarcoma (52 percent) seroconverted 6 to 75 months before the clinical appearance of Kaposis sarcoma. The median duration of antibody seropositivity for KSHV-related latent nuclear antigens before the diagnosis of Kaposis sarcoma was 33 months. CONCLUSIONS In most patients with kaposis sarcoma and AIDS, seroconversion to positivity for antibodies against KSHV-related nuclear antigens occurs before the clinical appearance of Kaposis sarcoma. This supports the hypothesis that Kaposis sarcoma results from infection with KSHV.

Acquired immunodeficiency syndrome (AIDS) associated with transfusions.

Of 2157 patients with the acquired immunodeficiency syndrome (AIDS) whose cases were reported to the Centers for Disease Control by August 22, 1983, 64 (3 per cent) with AIDS and Pneumocystis carinii pneumonia had no recognized risk factors for AIDS. Eighteen of these (28 per cent) had received blood components within five years before the onset of illness. These patients with transfusion-associated AIDS were more likely to be white (P = 0.00008) and older (P = 0.0013) than other patients with no known risk factors. They had received blood 15 to 57 months (median, 27.5) before the diagnosis of AIDS, from 2 to 48 donors (median, 14). At least one high-risk donor was identified by interview or T-cell-subset analysis in each of the seven cases in which investigation of the donors was complete; five of the six high-risk donors identified during interview also had low T-cell helper/suppressor ratios, and four had generalized lymphadenopathy according to history or examination. These findings strengthen the evidence that AIDS may be transmitted in blood.

Tuberculosis atypical mycobacteriosis and the acquired immunodeficiency syndrome among Haitian and non-Haitian patients in South Florida.

To study the association between mycobacterial disease and the acquired immunodeficiency syndrome, we reviewed the records of all cases of tuberculosis and all cases of the syndrome reported in Dade County, Florida, from January 1980 through June 1983. Tuberculosis was diagnosed in 27 of 45 Haitians with the syndrome, but in only 1 of 37 non-Haitians with the syndrome (p less than 0.001). Among the 27 Haitians with the syndrome and tuberculosis, 19 had extrapulmonary tuberculosis, whereas among 286 Haitian patients with tuberculosis without the syndrome, only 56 had extrapulmonary tuberculosis (p less than 0.001). Tuberculosis preceded the syndrome by 1 to 17 months (mean, 6) in 22 patients. In 10 patients with the syndrome and positive sputum cultures who were treated with conventional antituberculosis drugs, the cultures became negative within 1 to 4 months and tuberculosis did not recur. The frequency of disseminated atypical mycobacteriosis or positive sputum cultures for atypical mycobacteria was not significantly different between Haitian (11.3%) and non-Haitian (8.3%) patients with the syndrome.

Kaposi's sarcoma-associated herpesvirus infection prior to onset of Kaposi's sarcoma

Objectives:Kaposis sarcoma-associated herpesvirus (KSHV), a newly discovered human gammaherpesvirus, is found in the majority of KS lesions from patients with and without AIDS. Peripheral blood mononuclear cells (PBMC) were examined for KSHV DNA to determine whether viral infection precedes onset of this neoplasm. Design:Randomized and blinded case–control study of prospectively collected PBMC samples from ongoing cohort studies. Methods:Paired PBMC drawn before and after KS onset from 21 AIDS-KS patients were compared to paired PBMC from 23 high-risk HIV-infected homo-/bisexual patients who did not develop KS and to a single PBMC sample from 19 low-risk, HIV-infected hemophiliac patients. Extracted DNA samples were amplified by polymerase chain reaction (PCR) using two non-overlapping nested primer sets to control for potential PCR contamination. Results:In all comparisons, patients who went on to develop KS were significantly more likely to show evidence of KSHV infection prior to onset of KS than either control group. Of PBMC samples from AIDS-KS patients drawn prior to KS, 52% were positive for KSHV DNA whereas both high- and low-risk control groups had lower rates of PBMC infection (9–13%). KSHV infection can precede KS onset by up to 21 months among AIDS-KS patients. Conclusions:AIDS-KS patients are significantly more likely to show evidence of KSHV infection in PBMC prior to KS onset than control HIV-infected patients. Because identical PBMC samples from cases and controls were examined blindly, these results are not caused by a bias in tissue sampling. Homo-/bisexual and hemophiliac AIDS patients who do not develop KS appear to have a low prevalence of infection. These findings indicate that KSHV infection is specifically associated with the subsequent development of KS in AIDS patients.

Opportunistic Infections and Kaposi's Sarcoma Among Haitians: Evidence of a New Acquired Immunodeficiency State

Twenty Haitian patients, hospitalized from 1 April 1980 to 20 June 1982, had Pneumocystis carinii pneumonia, central nervous system toxoplasmosis, esophageal candidiasis, cryptococcosis, disseminated cytomegalovirus, progressive herpes simplex virus, chronic enteric coccidiosis, or invasive Kaposis sarcoma. Ten patients died. Opportunistic infections were frequently multiple and were recurrent in three patients. In seven patients disseminated tuberculosis preceded the other infections by 2 to 15 months. There was no evidence of an underlying immunosuppressive disease, and no history of homosexuality or intravenous drug abuse. At least three patients probably acquired the syndrome in Haiti. Lymphadenopathy was common. Seventeen patients tested had anergy, and 18 had lymphopenia. Monoclonal antibody analysis of peripheral-blood T-cell subsets done on 11 patients showed a marked decrease in T-helper cells and an inversion of the normal ratio of T-helper cells to T-suppressor cells. This syndrome among heterosexual Haitians is strikingly similar to the syndrome of immunodeficiency described recently among American homosexuals.

National Case-Control Study of Kaposi's Sarcoma and Pneumocystis carinii Pneumonia in Homosexual Men: Part 1, Epidemiologic Results

To identify risk factors for the occurrence of Kaposis sarcoma and Pneumocystis carinii pneumonia in homosexual men, we conducted a case-control study in New York City, San Francisco, Los Angeles, and Atlanta. Fifty patients (cases) (39 with Kaposis sarcoma, 8 with pneumocystis pneumonia, and 3 with both) and 120 matched homosexual male controls (from sexually transmitted disease clinics and private medical practices) participated in the study. The variable most strongly associated with illness was a larger number of male sex partners per year (median, 61 for patients; 27 and 25 for clinic and private practice controls, respectively). Compared with controls, cases were also more likely to have been exposed to feces during sex, have had syphilis and non-B hepatitis, have been treated for enteric parasites, and have used various illicit substances. Certain aspects of a lifestyle shared by a subgroup of the male homosexual population are associated with an increased risk of Kaposis sarcoma and pneumocystis pneumonia.

The emergence of HIV/AIDS in the Americas and beyond

HIV-1 group M subtype B was the first HIV discovered and is the predominant variant of AIDS virus in most countries outside of sub-Saharan Africa. However, the circumstances of its origin and emergence remain unresolved. Here we propose a geographic sequence and time line for the origin of subtype B and the emergence of pandemic HIV/AIDS out of Africa. Using HIV-1 gene sequences recovered from archival samples from some of the earliest known Haitian AIDS patients, we find that subtype B likely moved from Africa to Haiti in or around 1966 (1962–1970) and then spread there for some years before successfully dispersing elsewhere. A “pandemic” clade, encompassing the vast majority of non-Haitian subtype B infections in the United States and elsewhere around the world, subsequently emerged after a single migration of the virus out of Haiti in or around 1969 (1966–1972). Haiti appears to have the oldest HIV/AIDS epidemic outside sub-Saharan Africa and the most genetically diverse subtype B epidemic, which might present challenges for HIV-1 vaccine design and testing. The emergence of the pandemic variant of subtype B was an important turning point in the history of AIDS, but its spread was likely driven by ecological rather than evolutionary factors. Our results suggest that HIV-1 circulated cryptically in the United States for ≈12 years before the recognition of AIDS in 1981.

Acquired immune deficiency in Haitians;: opportunistic infections in previously healthy Haitian immigrants.

We describe acquired immune deficiency manifested by opportunistic infections in 10 previously healthy heterosexual Haitian men. The opportunistic pathogens included Toxoplasma gondii (in four patients), Cryptococcus neoformans (in one), Pneumocystis carinii (in four patients), and Candida albicans (in three). Six of the patients also had Mycobacterium tuberculosis. Immunologic studies of three patients showed a decrease in the numbers and activity of helper T cells, with normal or increased populations of suppressor T cells. Serologic markers for previous infections from hepatitis A, cytomegalovirus, and herpes simplex virus were detected in several patients. Six of the patients died despite specific antimicrobial therapy. The clinical and immunologic findings in these 10 Haitians are similar to those reported in drug addicts and homosexuals with the acquired immune-deficiency syndrome.

ACQUIRED IMMUNODEFICIENCY SYNDROME WITH SEVERE GASTROINTESTINAL MANIFESTATIONS IN HAITI

29 patients (19 males and 10 females) in Haiti were diagnosed as having acquired immunodeficiency syndrome. Their clinical presentation was characterised by unexplained chronic diarrhoea, prolonged fever, extreme weight loss, anorexia, and severe infections. The infectious agents included: Candida albicans (27 patients), Mycobacterium tuberculosis (7 patients), Cryptosporidium (11 patients), Pneumocystis carinii (2 patients), cytomegalovirus (4 patients), and herpes virus (3 patients). In 1 woman Kaposis sarcoma developed during the course of her disease. Immunological studies of 20 patients revealed profound cell-mediated immune deficiency with cutaneous anergy, marked decrease in the number of T helper cells, and impairment of lymphocyte proliferation. 18 patients died.

National Case-Control Study of Kaposi's Sarcoma and Pneumocystis carinii Pneumonia in Homosexual Men: Part 2, Laboratory Results

The Centers for Disease Control conducted a case-control study to investigate an outbreak of Kaposis sarcoma and Pneumocystis carinii pneumonia in homosexual men. The occurrence of these diseases was found to be associated with certain aspects of lifestyle, including a greater number of male sex partners per year, exposure to feces during sex, history of syphilis and non-B hepatitis, treatment for enteric parasites, and use of various illicit substances. Laboratory studies reflected both this lifestyle and the probable underlying cause of the Kaposis sarcoma and P. carinii pneumonia--cellular immune deficiency. Patients were found to have lymphopenia, specifically a deficiency of the T-helper subpopulation, resulting in a reversal of the T-helper to T-suppressor ratio. Levels of IgG and IgA were increased. When compared with controls, patients were also found to have significantly higher titers of antibody to Epstein-Barr virus and cytomegalovirus, a higher prevalence of antibody to hepatitis A virus and Treponema pallidum, a lower prevalence of antibody to varicella zoster virus, and a higher frequency of isolation of cytomegalovirus.