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During 1985 and 1986, the authors measured antibodies to human T-lymphotropic virus type I (HTLV-I) in a cohort of 13,260 Jamaicans from all parts of the island who applied for food-handling licenses. HTLV-I seroprevalence was strongly age and sex dependent, rising from 1.7% (10-19 years) to 9.1% (greater than or equal to 70 years) in men and from 1.9% (10-19 years) to 17.4% (greater than or equal to 70 years) in women. In a logistic regression analysis, women were more likely to be seropositive than were men, and farmers, laborers, and the unemployed were more likely to be HTLV-I seropositive than were those reporting student or professional occupations. In men, African ethnicity was associated with HTLV-I seropositivity in the univariate analysis but was not a risk factor after adjustment for age and sex. There was a trend toward higher age-stratified HTLV-I seroprevalence among younger women who reported more pregnancies, but older multigravidas had lower rates of HTLV-I seropositivity. Persons born outside Jamaica had significantly lower seroprevalence than did those born in Jamaica, but they were of slightly different ethnic and occupational compositions than those born in Jamaica.

A series of colchicine and isocolchicine derivatives were evaluated as inhibitors of HIV replication in H9 lymphocytes. Colchicine showed only very slight inhibition in the absence of toxicity, as measured by the therapeutic index (IC50/EC50). None of the derivatives inhibited HIV replication in the absence of toxicity.

Nine tannins, including gallo- and ellagitannins, were evaluated as potential inhibitors of HIV replication. 1,3,4-Tri-O-galloylquinic acid [1], 3,5-di-O-galloyl-shikimic acid [2], 3,4,5-tri-O-galloylshikimic acid [3], punicalin [6], and punicalagin [7] inhibited HIV replication in infected H9 lymphocytes with little cytotoxicity. Two compounds, punicalin and punicacortein C [8], inhibited purified HIV reverse transcriptase with ID50 of 8 and 5 microM, respectively. Further studies with H9 lymphocytes indicated that chebulagic acid [5] and punicalin did not inactivate virus directly. However, 1,3,4-tri-O-galloylquinic acid and 3,5-di-O-galloylshikimic acid were more effective inhibitors under those conditions. All tannins appear to inhibit virus-cell interactions. Thus, inspite of their anti-RT activity, the mechanism by which tannins inhibit HIV may not be associated with this enzyme.

Tropical spastic paraparesis or human T-lymphotropic virus type I (HTLV-I)-associated myelopathy is a degenerative encephalomyelopathy with pyramidal tract dysfunction affecting the lower extremities. It is associated with HTLV-I infection and found primarily in the Caribbean region and in southwestern Japan. Five cases of tropical spastic paraparesis (or HTLV-I-associated myelopathy) in Hawaii are reported. All five patients were born in Hawaii; four are women. Each of the patients has parents who were from HTLV-I-endemic areas of Japan. Two of these patients had serum antibodies to HTLV-I. Five of six of the spouses and children of the seropositive patients were also seropositive. Viral cultures of lymphocytes from both seropositive patients and two of the three seropositive children were positive for HTLV-I. None of the five patients had a history of antecedent blood transfusion, multiple sexual partners, or intravenous drug use. There is no evidence of adult T-cell leukemia or lymphoma in any of the patients or their families. Given the increasing seroprevalence of HTLV-I in the United States, clinicians need to be alert to new cases of this disorder.

The carbocyclic analogue of 3-deazaadenosine (3-deaza-C-Ado) has been synthesized and found to have antiviral activity in cell culture against herpes simplex virus type 1, vaccinia virus, and HL-23 C-type virus. It is relatively noncytotoxic at effective antiviral concentrations and is not subject to deamination or phosphorylation. It acts as a competitive inhibitor of S-adenosyl-L-homocysteine hydrolase, is at best a poor substrate, and does not inactivate the enzyme significantly. 3-Deaza-C-Ado may cause a selective inhibition of the methylation of the polynucleotide 5' cap of viral mRNA via higher cellular concentrations of S-adenosyl-L-homocysteine, resulting from the inhibition of S-adenosylhomocysteine hydrolase in infected cells, since increases in the intracellular level of S-adenosylhomocysteine, but no effects on DNA or RNA synthesis, were observed after incubation of these cells with it.

Various purine and pyrimidine analogs and methotrexate were tested to determine whether they induce morphologic and functional myeloid differentiation in HL-60, a human promyelocytic leukemia cell line. Functional maturity was assessed by nitro blue tetrazolium reduction assays. 3-Deazauridine caused nearly all of the cells to differentiate during 6 days of treatment. Pyrazofurin, virazole, puromycin aminonucleoside, and the tricyclic nucleoside 3-amino-1,5-dihydro-5-methyl-1-beta-D-ribofuranosyl-1,4,5,6,8-pentaazaacenaphthylene induced maturation in 44-64% of the cells, whereas 5-azacytidine, 5-bromo-2'-deoxyuridine, 5-iodo-2' deoxyuridine, thymidine, and the antimetabolite methotrexate induced maturation in 28-36% of the cells. In terms of effective concentration, the most potent inducer was methotrexate (10-8 M). The predominant cell types after treatment with all of these compounds were the metamyelocyte and banded neutrophilic granulocyte.

Four new tetragalloylquinic acids, 3,5-di-O-galloyl-4-O-digalloylquinic acid, 3,4-di-O-galloyl-5-O-digalloylquinic acid, 3-O-digalloyl-4,5-di-O-galloylquinic acid, and 1,3,4,5-tetra-O-galloylquinic acid, were isolated and characterized from a commercial tannic acid as a new class of human immunodeficiency virus (HIV) reverse transcriptase (RT) inhibitor. Compounds 2, 3, and 4 inhibit HIV RT activity 90, 89, and 84% at 100 microM and 73, 70, and 63% at 30 microM, respectively. Compounds 2-5 also inhibit the HIV growth in cells in the range of 61-70% with low cytotoxicity at 25 microM. The HIV cell growth inhibitory effects of these compounds at 25 microM and 6.25 microM (44-57%) are comparable to their effects against the HIV RT at 30 microM and 10 microM, respectively. The inhibitory effect of 3 against DNA polymerases indicates that the selective antiviral action of 3 is determined by more than its action with HIV RT.

We studied 56 asymptomatic homosexual male volunteers in Pittsburgh for 1 1/2 yr for relationships between cytomegalovirus (CMV) and human T-lymphotropic virus type III (HTLV-III) infections. CMV was most frequently isolated from semen (8%) as compared with throat washings (5.9%) and urine (0%) on initial testing of CMV-seropositive subjects. Other viruses commonly isolated from immunosuppressed patients (herpes simplex virus, adenovirus) were rarely detected in this cohort. Seropositivity to HTLV-III was significantly associated with isolation of CMV from semen in our asymptomatic cohort (odds ratio = 9.5, p = .008). These results suggest that HTLV-III infection is associated with selective, temporal activation of CMV in the genital tract of asymptomatic homosexual men.

A new DNA polymerase and DNase activity were identified from cells infected with human B-lymphotropic herpesvirus (HBLV). DNA polymerase associated with HBLV infection was similar in its sensitivity to inhibition by ppi analogs as other herpesvirus-specific DNA polymerases but was dissimilar in its inhibition by certain nucleoside triphosphates.

A serological survey of 250 outpatients in rural Zaire showed that the prevalence of antibody against HTLV-I, HTLV-II, and HTLV-III, as detected by enzyme-linked immunosorbent assay, correlated strongly with level of antibodies against Plasmodium falciparum. The age curve for the prevalence of antibody against these retroviruses and high titres of antibodies against P falciparum were similar. Tests with control sera obtained from HTLV-III seropositive homosexual men and American subjects repeatedly infected with malaria who had high antibody titres against P falciparum indicated that there was no cross-reactivity between P falciparum and these retroviruses. Immune-complex levels, but not IgG, IgM, or IgE levels, also correlated strongly with seropositivity in the ELISA HTLV-I and HTLV-III assay, although immune-complex-positive control samples were negative. Possible explanations include coincidental distribution paralleling malaria; similar mode of transmission; virus activation and/or enhanced antibody production due to the effect of malaria on the immune system; and false-positive reactivity in the ELISA assay due to cross-reactive antibodies or other unknown factors.

The prevalence of antibodies against HTLV-III and -I was studied among populations of 6 distinctly different regions of Kenya, an equatorial African country in which AIDS has rarely been observed. Overall, 21% of subjects had ELISA reactions suggesting the presence of antibody against HTLV-III. The frequency of HTLV-III antibodies was highest among the Turkana people (50%) and lowest among the Masai (8%). Prevalence increased with age but was not related to sex. The pattern of ELISA-detected antibody against HTLV-I was similar. The specificity of these antibodies was supported by Western blot analysis of a subset of sera with high and low ELISA ratios, in which 66% and 73% of those with ELISA ratios considered positive (= greater than 5.0 in this study) also had a profile of bands consistent with HTLV-III and HTLV-I respectively. The antibodies detected were not cross-reactive between HTLV-III and HTLV-I on Western blot analysis. In a series of subjects with various parasitic and infectious diseases, patients with idiopathic splenomegaly and with schistosomiasis had a high proportion of antibodies against both HTLV-III and HTLV-I. This survey shows that reactivity in the ELISA HTLV-III and HTLV-I assays are common among Kenyans but vary considerably by region.

Seven cases of acquired immunodeficiency syndrome (AIDS) and AIDS-related complex (ARC) associated with human T-cell leukemia (lymphotropic) virus (HTLV)-III infection were documented in married males whose family members consented to medical evaluation. Five spouses also had evidence of HTLV-III infection documented by isolation of virus and by detection of serum antibody directed against viral structural proteins. Three of the five HTLV-positive spouses also had clinical evidence of ARC. The remaining four spouses were clinically healthy. Eleven children (between 14 months and 13 years of age) were also evaluated for evidence of disease and exposure to HTLV-III. Only one 14-month-old child was seropositive for antibody to HTLV-III. These data support the opinion that close household contact to patients with ARC or AIDS is not an efficient mechanism for virus transmission, while demonstrating that HTLV-III can be transmitted by repeated heterosexual contact.

Homosexual men were studied for associations among human T-lymphotropic virus type III (HTLV-III) infection, Epstein-Barr virus (EBV) infection, and T cell abnormalities. The presence of IgG antibody to EBV capsid antigen and antibody to EBV early antigen was significantly associated with augmented counts of suppressor T cells in healthy HTLV-III-seronegative men. HTLV-III-seropositive asymptomatic subjects had significantly enhanced titers of antibody to EBV and lower ratios of helper to suppressor T cells compared with HTLV-III-seronegative homosexual men. Of three men who seroconverted to HTLV-III, two had a greater than fourfold increase in titer of IgG antibody to EBV capsid antigen after seroconversion. These results suggest that the interaction of HTLV-III and EBV and their immunologic perturbations are significant in the natural history of this retrovirus infection in homosexual men.

Four mouse hybridomas secreting monoclonal antibodies specific for p24, the major core antigen of the human T-cell leukemia virus type III (HTLV-III), have been developed, and their specificities have been partially characterized. These antibodies specifically recognized p24 of HTLV-III in extracts of HTLV-III and in HTLV-III-producing cells. No epitopes cross-reactive with HTLV-I and -II were detected with these antibodies. These hybridomas will be extremely valuable reagents in identifying expression of HTLV-III in infected cultures and in cells or tissues from patients with suspected immunodeficiency syndrome.

The genus Dipodomys (kangaroo rats) exhibits major interspecies variations in the proportions of highly reiterated satellite DNA sequences in the genome as well as in the chromosome number and the proportions of uni-armed and bi-armed chromosomes. For nearly all of the approximately 22 species of the genus and several subspecies, liver DNA was distributed in neutral CsCl buoyant density gradients into four fractions; principal DNA (1.698 g/ml), intermediate-density DNA (1.702 G/ML), MS satellite (1.707 g/ml) and HS (heavy satellites (1.713 g/ml). The total nuclear DNA content of diploid liver cells measured in eleven species by quantitative cytophotometry, ranged from 6.9 to 10.9 pg. These data were correlated with known features of the karotypes of individual species. The salient findings were: (1) that interspecies variations in diploid chromosome number cluster at 52-54, 60-64 and 70-72 (2) that high total nuclear DNA was associated with high chromosome number, and with relatively large amounts of satellite DNA (3) that a high ratio of HS satellites to intermediate-density DNA was generally correlated with a predominance of metacentric and submetacentric chromosomes (high fundamental number). The relationships of satellite DNA to karyotype structure reveal a new level of hierarchy in the genome that appears capable of exerting global control over environmental adaptation and the evolution of new species. This mechanism is consistent with recent hypotheses that changes in the macro-structure of the genome are more important than point mutations in facilitating the rapid phases of animal evolution.

We screened inpatient and outpatient parenteral drug users with no clinical evidence of AIDS for immunodeficiency and antibodies to HTLV-III by ELISA. Among 20 outpatient drug users, 5 (25%) were seropositive. Three of these (and 2 who were seronegative) had low T-cell ratios. Over 6 months, 1 seropositive patient with a low ratio developed oral thrush and weight loss. We also studied 13 parenteral drug users hospitalized for conditions other than AIDS. Eight had low T-cell ratios, and at least 6 of these developed AIDS or ARC within 4 months. Serum from 8 of 13 inpatients was available for HTLV-III testing: 6/8 were seropositive and 3 of these 6 were among those developing AIDS or ARC. Abnormal T-cell ratios among all patients were associated with abnormal HTLV-III serology (p = .02). Of the 7 patients who developed AIDS or ARC, 4 were tested for both antibodies and T-cell ratios: all 4 were seropositive and had low ratios. A low ratio (p = .0004), a positive ELISA (p = .014), and abnormalities of both tests (p = .001) were associated with the development of AIDS or ARC. Of the 26 patients without AIDS or ARC, 3 were lost to follow-up and 23 did not develop AIDS or ARC. Six of these 26 had abnormal ratios. Of the 21 patients who did not develop AIDS or ARC and who were tested for HTLV antibodies, 2 were lost to follow-up. Seven of 21 were seropositive and 2/21 were both seropositive and had a low ratio. One of these 2 seropositive patients with low ratios also had lymphadenopathy, but he was lost to follow-up. The other had no adenopathy and remained well until her death from trauma a year later. This study found two populations with very different risks. Six of 13 hospitalized parenteral drug users and only 1 of 20 healthy outpatients developed AIDS or ARC.

The third member of the family of T cell leukemia viruses (HTLV III) has been proposed as the primary etiologic agent of the acquired immunodeficiency syndrome (AIDS). A high risk of AIDS has been reported among patients with hemophilia, particularly those with factor VIII deficiency who receive commercial clotting factor concentrates. In a prevalence survey conducted between September 1982 and April 1984, initial serum samples from 74% of hemophiliacs who had ever been treated with commercial factor VIII concentrate, 90% of those frequently treated with factor VIII concentrate, and 50% of those treated with both factor VIII and factor IX concentrates had antibodies reactive against antigens of HTLV III, compared with none of the hemophiliacs treated only with factor IX concentrate or volunteer donor plasma or cryoprecipitate. Two of the seropositive patients have developed AIDS-related illnesses, and a third patient died of bacterial pneumonia. One initially seronegative patient developed antibodies against HTLV III during the study and is currently well. The predominant antibody specificities appear directed against p24 and p41, the presumed core and envelope antigens of HTLV III, suggesting that factor VIII concentrate may transmit the p24 and p41 antigens of HTLV III. However, the presence of infectious retroviruses in clotting factor concentrates and the effectiveness of screening and viral neutralization procedures remain to be determined.

Stored donor and recipient sera from prospective studies of post-transfusion hepatitis were analysed for the presence of human T-cell lymphotropic virus type-III/lymphadenopathy associated virus (HTLV-III/LAV) antibodies as determined by enzyme-linked immunosorbent assays (ELISA). Of 3961 donor samples given to 461 patients, only 2 (0.05%) contained specific HTLV-III/LAV antibodies as determined by an avidin-biotin-enhanced western blot tech nique. Anti-HTLV-III/LAV was measured before and 3 and 6 months after transfusion in 295 recipients of anti-HTLV-III-negative blood, 7 recipients of ELISA-positive blood which was western blot negative, and 2 recipients of ELISA-positive blood confirmed as specific by western blot. Only the last 2 recipients became infected with HTLV-III/LAV, as assessed by antibody seroconversion (p less than 0.0001). Serocon version occurred early (6 and 8 weeks after transfusion) and was characterised first by antibody to p24 and later by antibody to p41. AIDS has not developed in either patient, but one has a T4/T8 ratio of 0.4 and impaired mitogen responses; the second patient has no evidence of immune dysfunction 4 years after exposure. This study confirms that HTLV-III/LAV infection can be transmitted by blood transfusion and supports the advisability of anti-HTLV-III/LAV testing of all blood donors. It also confirms the validity of western blot testing for HTLV-III/LAV specificity and suggests that ELISA-positive, western-blot-negative blood may not be infectious.

The aim of this study was to compare the sensitivity of chromatin from representative cellular stages of spermiogenesis to a single-strandeded nuclease after heat denaturation. Thermal denaturation of chromatin was assayed in situ in fixed round, elongating and elongated spermatids and in testicular sperm from mice. Production of single-stranded deoxyribonucleic acid (DNA) at elevated temperatures was monitored by digesting chromatin with endonuclease specific for single-stranded DNA (S1 nuclease), staining the residual DNA with gallocyanin-chrome alum (GAC) and measuring the stain content by absorption cytophotometry. Changes in GCA staining were minimal over the temperature range of 22-90 degrees C in each cell type not exposed to nuclease. Staining of undigested cells decreased progressively with advancing cell maturity. Nuclease had no effect on the GCA content of round spermatids below 60 degrees C, but above this temperature there was a progressive decrease in GCA-stainable chromatin. Both round and elongating spermatid stages showed a significantly greater sensitivity to nuclease digestion than did more mature stages; sperm showed no effects of nuclease action below 80 degrees C. Progressive chromatin condensation and a concomitant decrease in the number of available DNA phosphate groups during spermiogenic cell maturation may be responsible for the observed decline in sensitivity to nuclease and decreased GCA staining. Thermal denaturation of round spermatids labeled with 3H-thymidine produced no change in autoradiographic mean nuclear grain counts, indicating no loss of thymidine-labeled DNA from the slides during denaturation. When round spermatids and sperm were hydrolyzed with hot tricholoroacetic acid before staining, both nuclear GCA content and autoradiograph grain count were partially reduced, indicating incomplete DNA removal. Almost complete loss of Feulgen-stainable material occurred in these cells and may be due to depurination and elimination of Feulgren-reactant aldehyde groups.

A cohort of homosexual men at high risk of the acquired immunodeficiency syndrome (AIDS) was monitored to examine the relation between lifestyle, clinical conditions, T-lymphocyte subsets, and antibody to the AIDS-associated human retrovirus, human T-cell leukaemia virus III (HTLV-III). HTLV-III antibodies were present in 35 (53%) of the 66 subjects tested in June, 1982. 4 of the seronegative subjects had HTLV-III antibodies when re-tested one year later, a seroconversion rate of 1.2% per month. In the HTLV-III seropositive subjects, AIDS developed at a rate of 6.9% per year (minimum incidence of AIDS = 4.6% per year) and other clinical signs of immunodeficiency (lesser AIDS) at 13.1% per year. All 6 of the AIDS cases and at least 8 of the 10 lesser AIDS cases had detectable HTLV-III antibodies 1 week to 21 months before diagnosis. Of 24 other subjects with stable lymphadenopathy, 19 (79%) had or acquired HTLV-III antibodies. Lower helper T-cell counts were very closely related to HTLV-III seropositivity (r = -0.53, p = 0.0001), even in the 26 healthy subjects with no clinical abnormalities (r = -0.37, p = 0.07). In both univariate and multivariate analyses, the lifestyle risk factors for HTLV-III seropositivity were large number of homosexual partners (p less than or equal to 0.03) and receptive anal intercourse (p less than or equal to 0.03), with an apparent synergistic interaction between these two activities (chi 2 = 8.71, p = 0.003). These data suggest that frequent receptive anal intercourse with many homosexual partners predisposes to HTLV-III infection with the consequent emergence of lymphadenopathy and the various manifestations of lesser and fully fledged AIDS.

A human retrovirus--human T cell lymphotropic virus-III (HTLV-III)--has recently emerged as the probable cause of acquired immunodeficiency syndrome (AIDS). In May 1984, 250 outpatients at a hospital in a remote area of eastern Zaire were surveyed for AIDS type illnesses and the prevalence of antibodies against HTLV-III determined by an enzyme linked immunosorbent assay using disrupted whole HTLV-III virus as the antigen. No clinical cases of AIDS were diagnosed among these patients. Overall, 31 (12.4%) had clearly positive ratios (greater than or equal to 5.0) and a further 30 (12.0%) had borderline ratios (3.0- less than 5.0). Western blots of serum samples from subjects with antibodies yielded bands consistent with HTLV-III as found in American patients with AIDS and members of groups at risk of AIDS. The prevalence of antibody was highest in childhood (p = 0.02); among adults prevalence rose slightly with age. HTLV-III antibodies were more common among the uneducated (p = 0.006), agricultural workers (p = 0.03), and rural residents (p = 0.006), but the Western blot bands were generally weak in this group. By contrast, one urban resident had strong bands. The relatively high prevalence of antibodies among the rural poor in this area of Zaire suggests that HTLV-III or a closely related, cross reactive virus may be endemic in the region. A different natural history of infection, perhaps in childhood, may also explain the findings.

Using blood samples collected since 1978, we investigated the epidemiology of human T-cell lymphotropic virus type III (HTLV-III), the etiologic agent of the acquired immunodeficiency syndrome, in a group of 378 homosexually active men who have resided in New York City since the acquired immunodeficiency syndrome epidemic began. The anti-HTLV-III prevalence was 6.6% in sera from 1978 or 1979, and the subsequent annual incidence of seroconversion among susceptible men ranged between 5.5% and 10.6%. The highest incidences were in recent years, even though these men reported a decrease in their sexual activity during this time. These data demonstrate the continuing risk of HTLV-III infections in the homosexual population studied and emphasize the need for more effective prevention of transmission. The year during which antibody was first present was the only factor identified that was associated with altered cell-mediated immunity in antibody-positive men. Men who became antibody positive in 1981 or earlier currently had significantly lower OKT4/OKT8 ratios than did those who seroconverted more recently. Further follow-up will be necessary to establish the reasons for this association.

The third member of the human T-cell leukemia (lymphotropic) retrovirus family (HTLV-III) is a newly discovered retrovirus that has been closely associated with the acquired immunodeficiency syndrome (AIDS). In our application of an enzyme-linked immunosorbent assay (ELISA) for HTLV-III antibodies, 72 (82%) of 88 patients with AIDS were positive, 14 (16%) were borderline, and two (2%) were negative. In contrast, only 1% of 297 volunteer blood donors were positive, 6% were borderline, and 93% were negative, demonstrating that this ELISA for HTLV-III antibodies is highly specific and sensitive for AIDS (excluding borderline results, 98.6% and 97.3%, respectively). Among persons at high risk for AIDS, 8% had borderline results, with positive and negative results readily distinguished as bimodal distributions that paralleled the temporal and geographic trends in AIDS. None of the 188 laboratory and health care employees working with patients with AIDS or their specimens were positive for HTLV-III antibodies, indicating that current precautions for health care workers appear adequate. This ELISA for HTLV-III antibodies will be a useful screening test among blood donors and populations at risk for AIDS, will aid in the diagnosis of suspected AIDS, and will help in defining the spectrum of diseases that are etiologically related to HTLV-III.