Clinical and immunological findings in HTLV-III infection.

Clinical, immunological, microbiological, virological, and lifestyle parameters were followed in 200 homosexual men living in Finland. The subjects were seen at 3- to 6-month intervals starting in summer 1983. Human T-cell lymphotropic virus III (HTLV-III) antibodies detected by enzyme immunoassay and confirmed by Western blotting were seen in 18 (9%) of the cases. Initially two cases had acquired immunodeficiency syndrome, three had acquired immunodeficiency syndrome-related complex, three had lymphadenopathy syndrome, and ten were asymptomatic. During the follow-up two asymptomatic cases developed lymphadenopathy syndrome and three developed enlarged lymph nodes. Immunological studies revealed decreased T-helper cell values and/or T-helper/suppressor ratios in all clinical categories, the findings being more severe and progressive in the symptomatic cases. The finding most clearly distinguishing HTLV-III antibody positive cases from the antibody negative ones was a decreased response to a specific recall antigen, purified protein derivative of tuberculoprotein. Responses to mitogens phytohemagglutinin and pokeweed mitogen were also decreased, but to a lesser extent. The primary immunological defect associated with helper T-cell infection by HTLV-III thus seems to be loss of antigen specific immune responses. It is suggested that this is the result of previous antigenic stimulation of HTLV-III infected T-helper cells and that the cellular destruction is associated with initial mitotic activity.

Immunosuppression in homosexual men seronegative for HTLV-III.

Clinical, microbiological, and lifestyle patterns in homosexual men showing in vitro immunological abnormalities were studied and related to the susceptibility to human T-lymphotropic virus type III (HTLV-III) infection. In a cohort of male homosexual volunteers in Finland, 90% were HTLV-III antibody negative. Ten % of the HTLV-III negative cases showed decreased T-helper/suppressor cell ratios, mostly due to elevated numbers of T-suppressor cells. In this immunosuppressed group, more signs of diarrhea, intestinal giardiasis, genital warts, and hepatitis B were observed than in the other HTLV-III antibody-negative study subjects. The type of sexual practice was not associated with the in vitro immune abnormalities. During a follow-up of up to 16 months, 4 initially HTLV-III antibody negative cases showed seroconversion. Three of these had inverted T-helper/suppressor cell ratios prior to the seroconversion. It is concluded that persons showing in vitro immunosuppression are more susceptible to HTLV-III infection when being exposed to the virus or else alteration in T-cell subsets signals a pre-antibody-positive or early phase of HTLV-III infection.

Serological responses to mycoplasmas in HIV-infected and non-infected individuals.

OBJECTIVE: To assess the frequency of mycoplasma infections in HIV-antibody-positive and -negative individuals by studying the serological responses against mycoplasmas, especially Mycoplasma fermentans and M. pirum. DESIGN: An enzyme-linked immunosorbent assay (ELISA) was used to measure immunoglobulin G (IgG) class antibody concentrations against six mycoplasma species in sera of HIV-positive and HIV-negative individuals. METHODS: Serum samples were obtained from 30 HIV-positive individuals (10 asymptomatics, 10 with lymphadenopathy syndrome and 10 with AIDS), 10 HIV-negative partners of HIV-positive individuals and 40 HIV-negative blood donors. Antibodies to M. fermentans strains incognitus and PG18, M. pirum, M. genitalium, M. pneumoniae and M. hominis were assessed by immunoblot or ELISA. Absorbance values were taken as a semiquantitative measurement for antibody concentration and an arbitrary cut-off value (0.8) was set to establish seroprevalence. RESULTS: There was no significant difference in the mean IgG concentrations of any of the six mycoplasmas between HIV-positive and HIV-negative groups. Antibody concentrations were also similar in different clinical phases of HIV infection. Antibody concentrations to different mycoplasma strains were compared with each other to reveal eventual cross-reactions caused by shared antigens; the strongest correlation (r = 0.836) was found between M. fermentans strains incognitus and M. pirum antibody concentrations. The correlation between M. fermentans strains incognitus and PG18 was also significant but weaker (r = 0.522). No shared antigens between M. fermentans strain incognitus and M. pirum were demonstrated by immunoblot. CONCLUSIONS: Antibodies against M. fermentans type strain PG18, strain incognitus and against M. pirum are detected infrequently and their presence does not correlate with HIV infection per se or with the clinical stage of HIV infection.

Antibodies to recombinant HIV-1 nef protein detected in HIV-1 infection as well as in nonrisk individuals.

Antibodies to the human immunodeficiency virus (HIV) regulatory gene nef (negative factor) product are claimed to be characteristic of early and latent HIV infection. We looked for anti-nef antibodies in individuals infected with HIV or at risk for HIV, in blood donors, and in patients with diverse dermatological disorders. In HIV-infected patients, antibodies to recombinant nef protein were seen by Western blot assay in 29 of 54 (54%) individuals at any time during a prospective follow-up. Except for a decline in the level prior to ARC and AIDS, the occurrence of antibodies did not significantly correlate with any pattern of disease progression in 22 patients followed for up to 4 years. Among the 141 HIV risk group members, negative in recombinant HIV ELISA tests, anti-nef antibodies were detected in 7 (5%) individuals. However, an anti-nef antibody response was also seen in 5 of 93 (5%) nonrisk dermatological patients and in 4 of 37 (11%) healthy blood donors. Solitary HIV gag protein antibody responses were most frequent (7%) in the group of individuals at risk for HIV but the majority of anti-nef positive sera did not react with HIV gag proteins. The relatively frequent occurrence of indistinguishable anti-nef antibody responses in nonrisk individuals suggests that immunological cross-reaction between nef and some cellular regulatory protein may occur.

Helper T-cell recognition of HIV-1 Tat synthetic peptides.

The regulatory proteins coded by the human immunodeficiency virus, (HIV)-1 genome are expressed by the infected cells before the initiation of the synthesis of structural proteins and thus immune response directed against these proteins could destroy infected cells before the release of infectious virions. The evaluation of T-lymphocyte responses toward Tat, one of the main HIV-1 regulatory proteins, is therefore of interest. We selected a group of HIV-infected patients with retained response to the recall antigen purified protein derivative and tested their CD4+ helper T-cell response toward recombinant Tat and toward 12 soluble synthetic partially overlapping 15-16-mer Tat peptides in a proliferation assay. Three peptides (amino acids 17-32, 33-48, and 65-80) were significantly recognized by the helper T-cells from infected individuals but not by the nine HIV-1-negative control persons. Nine of the 14 patients (64%) responded to at least one of these Tat peptides. Of the identified immunodominant peptides containing T-cell epitopes, one (aa 65-80) was recognized in association with human leukocyte antigens DR-2 allele, while the others appeared to be promiscuous and were equally recognized in association with several DR molecules. The identified immunogenic peptides were analyzed for the predicted presence of T-cell antigenic sites by several algorithms and positive correlation was detected for each peptide. Our results thus indicate that Tat protein can induce a cell-mediated immune response and identify three peptides containing T-cell epitopes that may be of importance in vaccine development.

Intrathecal humoral immunologic response in neurologically symptomatic and asymptomatic patients with human immunodeficiency virus infection.

We analyzed the intrathecal humoral immunologic response in 42 human immunodeficiency virus (HIV)-infected patients. Eighteen patients had clinical neurologic abnormalities, while the remaining 24 patients were neurologically symptom-free. Nine of the neurologically symptomatic patients at early infection had slight neurologic dysfunction; in nine other subjects at late infection, the neurologic impairment was moderate or severe. When compared with symptom-free patients, neurologically symptomatic patients had increased intra-blood-brain barrier (BBB) HIV-specific IgG (p less than 0.001) and total IgG synthesis (p less than 0.01) with oligoclonal bands (OCBs) in the CSF and/or serum (11/18 versus 3/24). At early stages of the infection, neurologically symptomatic patients showed increased total intrathecal IgG synthesis (9/9) coincident with OCBs in the CSF and serum (7/9) and slight mononuclear pleocytosis (7/9), but less frequent HIV-specific IgG production within the CNS (6/9). In advanced infection, the number of neurologically symptomatic patients with intrathecal HIV-specific IgG synthesis (8/9) was higher, while the number of those with increased total intra-BBB IgG synthesis (5/9; p less than 0.01), OCBs (4/9), and increased CSF leukocyte count (1/9; p less than 0.001) was lower than at early infection. Our data suggest humoral intra-BBB immunoactivation at early stages of HIV infection followed by declining B cell response within the CNS at advanced infection.

CSF protein and cellular profiles in various stages of HIV infection related to neurological manifestations.

CSF protein and cellular profiles were studied in 28 HIV-infected patients. Twenty of them had neurological complaints, but only 6 patients had objective neurological deficits such as dementia, ocular motility disorders or polyneuropathy. The serum/CSF HIV antibody ratio was on average lowest in acquired immunodeficiency syndrome (AIDS) (4 patients) and highest or almost normal in lymphadenopathy syndrome (LAS) (11) and asymptomatic seropositivity (ASX) (7), while it varied between these extremes in AIDS-related complex (ARC) (6). However, low values of the ratio were also found in the HIV-infected patients free of neurological symptoms and even in one ASX patient. The CSF IgG index was elevated in all these 4 general stages of HIV infection without any significant differences between them. The CSF/serum albumin ratio was slightly increased in patients with neurological deficits, but this ratio showed no association with any other clinical factor analysed. CSF leucocytes were increased in the early stages of the disease, but later the cellular reaction subsided. HIV was isolated from post mortem brain tissue of two AIDS patients and from the CSF of one of them. The results suggest increased intrathecal virus-specific IgG synthesis, not only in patients with neurological deficits and at advanced stages of infection, but also in neurologically symptom-free subjects and at early infection. The lack of correlation between the increased virus-specific IgG synthesis within the CNS and the presence of neurological symptoms suggests that neurologically "silent" areas of brain white matter are often affected in HIV infection.

Mild brain atrophy in early HIV infection: the lack of association with cognitive deficits and HIV-specific intrathecal immune response.

Brain MRI and/or CT were performed on 72 HIV-infected patients at various stages of the disease, and on 34 controls. The neuroradiological findings were related to duration of the infection, neurological symptoms, and cognitive abnormalities as well as to immunological findings in the CSF and blood. All types of brain atrophy were more severe and more frequent in HIV-infected subjects than in controls. Patients with neurological symptoms, those with advanced HIV infection, and patients with a duration of HIV infection of more than 4 years showed the most severe and most frequent neuroradiological abnormalities, including central and cortical atrophy, brain stem atrophy, and cerebellar atrophy. Subjects with cognitive defects exhibited more severe central atrophy than cognitively intact patients. However, slight brain atrophy and/or parenchymal lesions were found in 57% of cognitively intact HIV-seropositive individuals. Patients with brain atrophy and those with radiologically normal brain, both showed increased intrathecal synthesis of total IgG, and intrathecal HIV-antibody synthesis. However, a declined general immune response and a lowered CSF leukocyte count were seen predominantly in patients with brain atrophy. The results suggest that subcortical, neurologically "silent" areas of brain white matter are an early target of HIV infection.

B-cell epitopes in HIV-1 Tat and Rev proteins colocalize with T-cell epitopes and with functional domains.

We describe the characterization of the B-cell epitopes of HIV-1 regulatory proteins Tat and Rev. The prevalence of antibodies to these proteins among human immunodeficiency virus (HIV)-1-infected individuals was examined by enzyme-linked immunosorbent assay (ELISA) and by Western blotting. The Tat and Rev antibody-positive sera were selected for epitope mapping performed with partially overlapping synthetic peptides bound to polyethylene pins. Eighteen and twelve percent of HIV-infected individuals had antibodies against Tat or Rev, respectively. In Tat, four epitopic regions were identified, situated within amino acids 6-10 (PRLEP), 21-37 (ACTNCYCKKCCFHCQVC), 39-58 (ITKALGISYGRKKRRQRRRA) and 74-82 (TSQSRGDPT). The most frequently recognized epitopic regions were located in the middle of the protein. In Rev, the two most frequently recognized epitopic regions were near the amino terminus of the protein within amino acids 12-20 (LIRTVRLIK) and 38-49 (RRNRRRRWRERQ). A third epitope was mapped around amino acids 55-62 (ISERILGT) and a fourth around amino acids 78-83 (LERLTU). To analyze the specificity of Tat and Rev epitopes, soluble synthetic peptides representing the identified epitopes were used in an ELISA assay, and the recognition of most epitopes was shown to be specific for HIV-1-infected individuals. In addition, many of the Tat and Rev epitopes were shown to overlap with regions having functional activity or with regions previously identified as T-cell epitopes.

EEG in early HIV-1 infection is characterized by anterior dysrhythmicity of low maximal amplitude.

We analyzed the EEGs of 67 HIV-1-infected patients at various stages of the disease and of 35 HIV-1-seronegative controls. The most common EEG abnormality in HIV-1 infection was an increased amount of generalized episodic or persistent, predominantly anterior slow activity, associated with a low level of maximal amplitude. When compared to the controls, a lower maximal amplitude of dominant background activity (p less than 0.001), and more marked generalized (p less than 0.01) and anterior (p less than 0.001) disturbances were already seen in early stages of HIV-1 infection. EEG abnormalities were more severe in patients with advanced HIV-1 infection than in those at early infection (p less than 0.001 to p less than 0.05). The presence of a more marked, posteriorly (p less than 0.01) accentuated, generalized slow activity (p = 0.02) was found more often in patients with T-helper cell counts lower than 0.4 x 10(9) (p = 0.05) than in those with higher numbers of T-helper cells. No clear associations were found between the severity of EEG abnormalities and the duration of HIV-1 infection. Our results suggest that EEG is a sensitive method in detecting subclinical functional cerebral disturbances caused by HIV-1.

Febrile pharyngitis as the primary sign of HIV infection in a cluster of cases linked by sexual contact.

Three cases of febrile pharyngitis were recorded retrospectively in a cluster of 5 men and 1 woman linked by sexual contact to a human immunodeficiency virus (HIV) carrier. In all 3 patients, a progression into clinical HIV disease was noted during an observation period of 20-25 months. The febrile pharyngitis developed similarly in each patient after an incubation time of 3-5 weeks. High fever of sudden onset and a sore bright red throat were accompanied by extreme lethargy and, in 2/3 patients, a morbilliform rash. The acute illness lasted 4-7 days and was followed by mild lymphadenopathy. All 3 patients were HIV seropositive 17-19 months later, when they first entered the study. By contrast, those 2 cases who did not fall ill, continued to be seronegative for 19-39 months after the exposure. Seroconversion of HIV could retrospectively be demonstrated in 1 of the 3 patients 2 weeks after the onset of the febrile illness. A simultaneous lack of rise in the EBV and CMV titres suggests HIV as the causative agent for this febrile mononucleosis-like pharyngitis.

Sexually transmitted diseases and the use of condoms in a cohort of homosexual men followed since 1983 in Finland.

High rates of sexually transmitted diseases (STDs) were recorded among 235 homosexually active men at the start of a prospective follow-up study in June 1983 in Finland. The vast majority (88.5%) reported at least one STD, the most common of them being pubic lice (64.7%) followed by gonorrhoea (42.9%) and non-gonococcal urethritis (26.4%). Those 31 (13.2%) who were seropositive for HIV at the end of the study, had experienced more episodes of STDs than the seronegative individuals (p = 0.0027). Nine HIV seroconversions were noted during the follow-up of 5-40 months, all in individuals who had practised "unsafe" sex. The study participants were repeatedly given detailed advice for avoiding HIV infection, and a tendency towards "safer" sexual practises resulting in a decrease in incidence of most STDs, was noted during the course of the study. However, further spread of HIV is to be expected because 57% of the men still reported practising and sex at the end of the follow-up, and 42% of them without condoms.

PIP: 235 homosexual men participated in a prospective study conducted in Helsinki, Finland, in 1983-86 aimed at identifying associations between sexually transmitted diseases (STDs), condom use, and human immunodeficiency virus (HIV) infection. The mean observation time was 22.7 months and the average age of study participants was 35.3 years. Of the 235 men, 27 (12%) gave no history of previous STD at the 1st examination. The remainder reported at least 1 STD, the most common being pubic lice (65%), gonorrhea (43%), and nongonococcal urethritis (26%). The 31 men (13%) who were seropositive for HIV infection at the end of the study had experienced significantly more STD episodes than seronegative subjects. All 9 of the seroconversions considered to have taken place during the study period involved men whose sexual behavior included unprotected receptive or insertive intercourse into the mouth or rectum. No HIV infection emerged among the men who practiced safe sex practices--monogamous sex with an HIV seronegative partner, no mucosal contact during sex, or the consistent use of condoms during anal sex. There was a weak association between HIV and hepatitis B infection, but a strong link between HIV and the prevalence of hepatitis B c antibodies. The statistically significant association observed in this sample between HIV seropositivity and heavy exposure to STDs may either reflect an enhanced probability of encountering HIV along with other pathogens or the role of other STDs as cofactors in HIV infection. The decreasing incidence of STDs observed during the follow-up period reflects counseling about risk reduction that was provided as part of the study. By the end of the study period, almost half the men had stopped practicing anal sex and almost 1/3 were using condoms. However, further spread of HIV can be expected in Finland given the fact that 57% of study subjects were still practicing anal sex at the end of the follow-up, the majority of them without condoms.

Dermatologic findings related to human immunodeficiency virus infection in high-risk individuals.

A variety of dermatologic disorders have been associated with human immunodeficiency virus (HIV) infection. This prospective study reports the frequency of mucocutaneous findings in 237 individuals at high risk for HIV infection, 33 of whom were HIV seropositive, during a follow-up of 5 to 36 months; 12.1% of the study population, all of them HIV seronegative, were devoid of any pathologic changes of the skin or mucous membranes, whereas all HIV-seropositive individuals exhibited one or several pathologic conditions during the observation period. Oral candidiasis, seborrheic and infectious eczematoid dermatitis, and acquired ichthyosis were among the most frequently encountered dermatologic disorders among the HIV-seropositive individuals, and a worsening of the skin symptoms accompanied the clinical deterioration of the patients.