Activation of the complement system in human immunodeficiency virus infection: relevance of the classical pathway to pathogenesis and disease severity

In vitro studies implicate classical and alternative complement pathway activation in the pathogenesis of human immunodeficiency virus (HIV) infection. To ascertain their importance in vivo, activation fragments of the classical (C4d), alternative (Ba), and common (C3d) pathways were measured and fragment to parent molecule ratios derived in 74 HIV-infected individuals and related to circulating immune complex (CIC) levels, Centers for Disease Control (CDC) stage, and beta 2-microglobulin, neopterin, and CD4-positive (CD4+) lymphocyte levels. All fragments and ratios were significantly higher in patients (P less than .01) than controls. C4 conversion indices (C4d and C4d to C4) increased linearly with increasing CDC stage (P less than .001), while CD4+ lymphocytes decreased linearly (P less than .001). C4d, C3d, C4d to C4, and C3d to C3 correlated with increasing CIC and beta 2-microglobulin, and C4d and C4d to C4 correlated with decreasing CD4+ lymphocytes (P less than .05). The relationship of classical complement pathway activation to disease progression and CD4+ lymphocytes suggests its involvement in the pathogenesis of HIV infection.     

Immunological predictors of survival in HIV type 2-infected rural villagers in Guinea-Bissau

We investigated the association between beta2-microglobulin, neopterin, serum levels of soluble urokinase-type plasminogen activator receptor (suPAR), CD4 count, and plasma viremia with survival in 133 HIV-2-infected villagers and 160 controls living in rural Guinea-Bissau. Subjects were recruited in 1991 and visited at home every 3-6 months until 1998. Median beta2-microglobulin, neopterin, and suPAR were significantly higher and CD4% significantly lower among HIV-2-infected individuals than controls. Thirty-one HIV-2-infected individuals died and 7 were lost to follow-up. beta2-Microglobulin, CD4%, and plasma viral load were associated independently with survival in multivariate analyses. Neopterin and suPAR did not reach statistical significance. These findings suggest that immune activation is central to the pathogenesis of HIV. They also have important implications for resource-poor settings where CD4 count and plasma viral load are unaffordable.     

Beta 2-microglobulin levels in drug users: the influence of risk behaviour.

beta 2-microglobulin (beta 2M) levels were measured in 217 Edinburgh drug users to assess their usefulness as a marker for HIV-related disease. Eighty HIV-seronegative drug injectors had significantly higher levels than 100 HIV-seronegative blood-donor controls. Amongst 137 asymptomatic HIV-seropositive drug users, those who were defined as continued drug users had significantly higher beta 2M levels and percentages of CD3+ T lymphocytes with DR Class II expression than non-injecting drug users. beta 2M levels correlated with the percentage of activated DR+ CD3+ T lymphocytes. These findings indicate that changes in beta 2M levels may reflect differences in drug-injecting behaviour and are not influenced solely by HIV status or progression. These changes in beta 2M probably represent differing degrees of immunostimulation resulting from the antigenic challenges afforded by continued or frequent drug injection. It is important to establish normal ranges for beta 2M from HIV-seronegative controls who are matched with respect to risk group and behaviour. All these factors should be taken into account if beta 2M is to be used as a marker of HIV progression.     

Immunological comparison of HIV-1-, HIV-2- and dually-reactive women delivering in Abidjan, C?te d'Ivoire.

OBJECTIVES: To compare the basic immunological changes induced by HIV-1 and HIV-2 infection and to assess the immune status of subjects serologically reactive to both HIV-1 and HIV-2 (dually-reactive). DESIGN: Immune parameters were studied cross-sectionally in women delivering in Abidjan, C?te d'Ivoire, West Africa, where HIV-1 and HIV-2 are endemic. In this area, a significant number of sera from infected individuals are reactive to both HIV-1 and HIV-2. SUBJECTS AND METHODS: Two hundred and twenty-eight women delivering in a major maternity clinic were screened for HIV-1 and HIV-2 using an enzyme-linked immunosorbent assay. Seropositivity was confirmed by Western blot. The immune parameters studied were CD4+ and CD8+ lymphocyte subsets, immunoglobulin (Ig) serum levels, neopterin and beta 2-microglobulin (beta 2M) serum levels. RESULTS: Similar but less pronounced immune changes were present in HIV-2-reactive subjects compared with HIV-1- and dually-reactive subjects. The observed differences between the HIV-seropositive groups could not be explained by differences in age or disease stage but paralleled differences in the frequency of persistent generalized lymphadenopathy (PGL). The intermediate immune profile of HIV-2-reactives (between seronegatives and HIV-1- and dually-reactives) was most clearly reflected by the number of CD8+ lymphocytes, the CD4:CD8 ratio and the IgG serum level. Median neopterin and beta 2M levels, though significantly increased in all HIV-seropositive groups, did not differ significantly between HIV-2-, HIV-1- and dually-reactives. CONCLUSIONS: HIV-2 infection is associated with typical HIV-related immunological changes. Immunologically, dually-reactives resemble HIV-1-reactives more closely than HIV-2-reactive subjects.     

Immune activation markers and AIDS prognosis.

Four assays for serum levels of cellular products of immune activation were examined as prognostic markers for AIDS in a prospective study of asymptomatic HIV-seropositive homosexual men. Baseline serum values of beta 2-microglobulin (beta 2M), neopterin, soluble CD8 (sCD8), and soluble interleukin-2 receptor (sIL-2R) for 185 men were examined univariately and multivariately as predictors of AIDS during 36 months of follow-up. Thirty-three cases of AIDS (18%) were diagnosed during the follow-up period. All four assays correlated highly with each other (r = 0.48-0.63), and all four were good univariate predictors of AIDS and comparable to CD4 lymphocyte count. beta 2M, neopterin, and sCD8 predicted AIDS independently of both CD4 count and HIV p24 antigen or p24 antibody in multivariate analysis. Within the range of CD4 count 200-499 x 10(6) cells/l, an immune activation marker used in combination with an assay for p24 antigen identifies those at 3-6% risk of AIDS over 36 months (low risk on both assays) and those at 63-86% risk (high risk on both assays). These results can be used to guide physicians and patients making decisions about treating asymptomatic HIV infection with zidovudine in individuals with CD4 lymphocyte count of 200-499 x 10(6) cells/l.     

Prognostic value of an elevated CD8 lymphocyte count in HIV infection. Results of a prospective study of 152 asymptomatic HIV-positive individuals.

OBJECTIVE: To evaluate the prognostic value of an elevated CD8 lymphocyte count in the early stages of HIV infection. DESIGN: A prospective study ongoing since January 1986. METHODS: One hundred and fifty-two asymptomatic HIV-positive individuals with a CD4 lymphocyte count > 400 x 10(6)/l at enrollment were included. Disease progression was defined as a CD4 count < 200 x 10(6)/l. RESULTS: During the follow-up period, CD4 count decreased in 33 individuals; CD8 count increased to > 1500 x 10(6)/l in 38 individuals and doubled in 35. The risk of a decreasing CD4 count was estimated to be 1.7-fold higher, although not significantly so, after the elevation of the CD8 count to > 1500 x 10(6)/l than before or in the absence of such an increase. However, this predictive value disappeared when five baseline parameters found to predict the outcome (neopterin, beta 2-microglobulin, p24 antigen, anti-p18 antibody and immunoglobulin A) were adjusted. CONCLUSION: Elevated CD8 count appears to be a weak marker for disease progression.     

Serum soluble CD8 molecule is a marker of CD8 T-cell activation in HIV-1 disease

To characterize CD8 T-cell activation during HIV-1 infection we measured serum soluble CD8 (sCD8) levels longitudinally in seroconverters and in individuals with established HIV infection who were in different stages of illness. CD8 T-cell activation occurs very early in HIV infection. Serum sCD8 levels were elevated in 91.5% of the first seropositive samples in seroconverters. Furthermore, CD8 T-cell activation persists throughout HIV infection. sCD8 predicted the occurrence of AIDS in HIV-seropositive individuals and so the addition of serum sCD8 levels to CD4 T-cell measurements increased the power in predicting the onset of AIDS. The serum level of sCD8 was particularly relevant to the prediction of subsequent CD4 T-cell fall relatively early in infection, for example, in the 3 years after seroconversion. However, later in HIV infection, for example within 2 years prior to development of AIDS, sCD8 levels were less predictive. sCD8 correlated with levels of beta 2-microglobulin and neopterin, which reflect activation of cell types other than CD8. Thus, serum sCD8 level can be a useful marker of specific CD8 T-cell activation, and is an independent predictor of prognosis in HIV infection.     

HIV-2-induced immunosuppression among asymptomatic West African prostitutes: evidence that HIV-2 is pathogenic, but less so than HIV-1.

Two hundred and forty-one prostitutes working in The Gambia were tested for retroviral infections and their immune system evaluated. Sixty-three were seropositive for HIV-2 only, five for HIV-1 only and six for both HIV-1 and HIV-2 (26.1, 2.1 and 2.5%, respectively). When compared to seronegative individuals, the 63 women infected with HIV-2 clearly had an abnormal immune system, with significantly lower CD4+ and higher CD8+ lymphocyte counts and percentages, lower CD4+:CD8+ ratios, lower CD25+ (activated) lymphocyte counts, and lower lymphocyte proliferation responses after stimulation with phytohaemagglutinin, purified protein derivative (PPD), Candida or pokeweed mitogen, and higher levels of neopterin and beta 2-microglobulin. However, when the HIV-2-seropositive prostitutes were compared with the five women infected with HIV-1, the former were less abnormal, with significantly higher CD4+ percentages and CD4+:CD8+ ratios and lower CD8+ percentages and counts. Immunological anomalies were seen in five women known to have been infected with HIV-2 for less than 17 months. Coinfection with HTLV-1 resulted in more severe immunological alterations than infection with HIV-2 alone.     

Differences in laboratory values in HIV infection by sex, race, and risk group.

OBJECTIVES: To determine differences in CD4+ and CD8+ lymphocyte values, beta 2-microglobulin (beta 2M), and HIV p24 antigenemia by sex and race among HIV-seropositive and HIV-seronegative injecting drug users (IDU), and to compare these values with those in homosexual men of equivalent status. DESIGN: Baseline values from a cohort of 206 HIV-seropositive and 173 HIV-seronegative IDU were compared with values from a cohort of 288 HIV-seropositive homosexual men and 176 HIV-seronegative controls, who were prospectively followed at 6-month intervals, to examine differences in laboratory values in HIV-infected individuals by sex, race, and risk group. METHODS: Among HIV-seropositives, we compared white and black IDU only (n = 167), and white male IDU (n = 38) with white homosexual men (n = 256). Laboratory values from the cohort of homosexual men at 24, 36 and 48 months of follow-up were compared with IDU values. RESULTS: HIV-infected female IDU had significantly higher CD4+ lymphocyte counts (P < 0.03) and percentages of CD4+ lymphocytes (P < 0.004) than male IDU, resulting in higher CD4:CD8 ratios (P < 0.002). White IDU had significantly higher serum beta 2M levels than black IDU (P < 0.02). Black female IDU were much less likely to be HIV p24-antigenemic (1%) than all other groups (P < 0.005). Compared with homosexual men, male IDU had significantly elevated beta 2M levels (0.58 mg/l higher). When controlled for CD4+ lymphocyte values as a surrogate for length of time HIV-infected, beta 2M and HIV p24 antigenemia differences persisted. CONCLUSIONS: These differences should be considered when HIV p24 antigen, CD4+ lymphocyte counts and beta 2M levels are used as surrogate markers in clinical trials and management of HIV disease.     

Serum beta 2-microglobulin level increases in HIV infection: relation to seroconversion, CD4 T-cell fall and prognosis

Beta 2-microglobulin (beta 2-M), a marker that is increased in serum during immune activation, was investigated during the course of HIV infection. beta 2-M rose promptly in the first phase of HIV infection in people who were participating in a longitudinal study where serum samples and lymphocyte subset data were obtained at 6-monthly intervals. A rise in beta 2-M level in the first seropositive sample was seen in 93% of 50 HIV seroconverters, and those with high (or low) levels of beta 2-M at the end of year 1 tend to remain high (or low) in the ensuing years. Eighty-three per cent of seroconverters experienced a fall in CD4 T cells in the first year. The magnitude of the CD4 T-cell decline, however, did not correlate with the rise in beta 2-M in specific individuals in the first year. Nevertheless, 2-3 years after seroconversion, the initially increased beta 2-M levels did correlate inversely with the (reduced) level of CD4 T cells (P less than 0.001). Thus, the pattern of disease reflected by beta 2-M level is established in the first year of infection and persists through the following 2 years. beta 2-M levels were found to correlate with rate of CD4 T-cell fall in individuals with established HIV infection. Three groups of HIV-seropositive people with similar CD4 T-cell numbers at the first measurements (about 600-800 x 10(6)/l) but different rates of CD4 T-cell fall over the following 2 years were evaluated by beta 2-M levels. The group with stable CD4 T-cell numbers showed a significantly lower level of beta 2-M than the groups with moderately or rapidly declining CD4 T-cell numbers. Increases in beta 2-M levels during the 2 years of observation were found in people exhibiting a rapid decline in CD4 T cells (about 200 cells/year). The level of beta 2-M appears to be an indicator of HIV activity and of the rate of CD4 T-cell fall.(ABSTRACT TRUNCATED AT 250 WORDS)     

HIV感染者/AIDS患者外周血CD38 HLA-DR分子在CD4+ CD8+T淋巴细胞上的表达

目的　观察国内艾滋病病毒 (HIV)感染者 /艾滋病 (AIDS)患者外周血CD38、HLA DR分子在CD+4 、CD+8T淋巴细胞上表达的变化 ,并探讨这些变化的临床意义。方法　用流式细胞仪检测 5 1例正常对照、14例HIV感染者和 3 6例AIDS患者的外周血CD+4 、CD+8T淋巴细胞表面的CD38、HLA DR分子的表达 ,用分枝DNA(bDNA)法检测 11例HIV感染者和 18例AIDS患者的血浆病毒载量。结果　CD+4 HLA DR+细胞百分比显示 ,AIDS组显著高于正常组及HIV组 ;CD+8HLA DR+T细胞百分比显示HIV组与AIDS组间无差异 ,而它们均显著高于正常组。CD+8、CD38+细胞百分比则是AIDS组 >HIV组 >正常组 ,CD+8CD38+、CD+8HLA DR+、CD+4 HLA DR+细胞百分比与病毒载量显著正相关。结论　在HIV感染过程中 ,HLA -DR+、CD38+在CD+4 、CD+8T淋巴细胞上的表达均显著增加 ,反映T淋巴细胞异常激活 ;尤其是CD+8CD38+细胞百分比随着疾病进展逐渐升高 ,预示疾病进展程度。在评价HIV感染者和AIDS患者的免疫状况时 ,不仅要考虑免疫细胞数量和功能的变化 ,还应考虑免疫细胞的激活水平     

Immunological changes in primary HIV-1 infection

Homosexual men with symptomatic primary HIV-1 infection displayed a pronounced lymphopaenia with significantly depressed numbers of CD3+, CD4+ and CD8+ cells and B cells during the first week of illness. Subsequently, the CD8+ cell counts rose in parallel with numbers of CD3+ cells, atypical lymphocytes and activated (CD38+ and HLA-Dr+) cells to attain maximal levels about a month following onset of illness. In contrast CD4+ and B cell numbers remained low for an extended period of time. Early signs of a host response included a transient appearance of interferon-alpha in the blood and raised levels of neopterin and beta 2-microglobulin (beta 2-M). Neither CD4+/CD8+ cell ratio nor beta 2-M resumed completely normal values during a follow-up period of 2 years. These findings shed some light on pathogenetic events during early HIV-1 infection and suggest that the infection, following the acute symptomatic stage, usually enters a stage of chronic active rather than latent infection.     

Clinical and laboratory predictors of survival in Gambian patients with symptomatic HIV-1 or HIV-2 infection.

OBJECTIVES: To determine which clinical and immunological features of patients with symptomatic HIV-1 and HIV-2 infection best predict survival in The Gambia. METHODS: All patients presenting to two hospitals in The Gambia between January 1987 and June 1990 with symptoms or signs suggesting chronic HIV infection were tested for HIV-1 and HIV-2 antibodies. Eighteen HIV-1 and 31 HIV-2-infected patients were recruited to the study, investigated intensively on admission and followed up until the end of 1990. Presenting clinical features, such as Karnofsky score, diagnosis of AIDS according to World Health Organization Bangui or Centers for Disease Control criteria and number of associated infections, together with five immunological measurements, as well as type of HIV infection, were related to length of survival using proportional hazard models fitted to Kaplan-Meier plots of survival times. RESULTS: Karnofsky score and diagnosis of AIDS were the best clinical predictors of survival. Type of HIV infection or number of associated infections did not predict outcome. The most powerful laboratory predictors were log(e) serum neopterin level, CD4 cell count and log(e) serum beta 2-microglobulin (beta 2M) level. The estimated median survival times (90% confidence interval) of the HIV-1 and HIV-2-infected were six (4-11) and 13 (9-20) months, respectively. These survival times do not differ significantly. CONCLUSIONS: The Karnofsky score and measurements of serum neopterin or beta 2M, which are easier and cheaper to perform than CD4 counts, may prove to be useful guides to prognosis for HIV infection in Africa.     

Long-term human immunodeficiency virus infection in asymptomatic homosexual and bisexual men with normal CD4+ lymphocyte counts: immunologic and virologic characteristics.

From a prospective cohort study, 24 asymptomatic men were identified who had been antibody positive for human immunodeficiency virus (HIV) for at least 5 years (median = 9.1) with CD4+ lymphocyte counts greater than or equal to 400 cells/mm3. Of these "nonprogressors", 23 (96%) had evidence of HIV infection by either HIV culture or the polymerase chain reaction (PCR) for HIV DNA, although only 1 (4%) had a positive assay for HIV RNA (by PCR) and no one was positive for p24 antigen. Compared with 24 antibody-negative men and 14 men with AIDS, nonprogressors had higher CD8+ counts and lower natural killer cell activity. Nonprogressors had higher beta 2-microglobulin levels than did seronegative controls, suggesting some degree of immune system activation. Compared with men with AIDS, nonprogressors seemed to have a stronger antibody response to six different HIV-related proteins but did not differ significantly in neutralizing antibody or antibody-dependent cellular cytotoxic activity.     

Markers for disease progression in intravenous drug users infected with HIV-1.

We evaluated the number and percentage of CD4+ T cells, the ratio of CD4+ T cells to CD8+ T cells, the serum levels of beta 2- microglobulin and urinary levels of neopterin for their ability to predict disease progression (defined as clinical AIDS and/or oral candidiasis in combination with a CD4+ T cell count less than 400 x 10(6)/l). Thirty-eight intravenous drug users (IVDU) infected with HIV-1 without HIV-1-related symptoms were followed for a median observation period of 45 months. Cumulative incidence of disease progression was computed by the product-limit approach. The CD4+: CD8+ T-cell ratio (P = 0.001), the number (P = 0.002) and percentage (P = 0.05) of CD4+ T cells, and urinary neopterin (P = 0.007) were significant predictors for disease progression. Serum beta 2-microglobulin, which has been found to be of similar prognostic value as neopterin in homosexual men, did not show predictive power in this study of IVDU. The urinary neopterin concentrations obtained at entry of the study correlated with the values of the CD4+:CD8+ T-cell ratio and number and percentage of CD4+ T cells which were obtained at the end of the follow-up. These findings should help to identify, among HIV-1-infected IVDU, those at high risk of disease progression.     

Soluble CD163 made by monocyte/macrophages is a novel marker of HIV activity in early and chronic infection prior to and after anti-retroviral therapy

CD163, a monocyte- and macrophage-specific scavenger receptor, is shed during activation as soluble CD163 (sCD163). We have previously demonstrated that monocyte expansion from bone marrow with simian immunodeficiency virus (SIV) infection correlated with plasma sCD163, the rate of AIDS progression, and the severity of macrophage-mediated pathogenesis. Here, we examined sCD163 in human immunodeficiency virus (HIV) infection. sCD163 was elevated in the plasma of individuals with chronic HIV infection (>1 year in duration), compared with HIV-seronegative individuals. With effective antiretroviral therapy (ART), sCD163 levels decreased in parallel with HIV RNA levels but did not return to HIV-seronegative levels, suggesting the presence of residual monocyte/macrophage activation even with plasma viral loads below the limit of detection. In individuals with early HIV infection (≤1 year in duration), effective ART resulted in decreased sCD163 levels that were comparable to levels in HIV-seronegative individuals. sCD163 levels in plasma were positively correlated with the percentage of CD14+CD16+ monocytes and activated CD8+HLA-DR+CD38+ T lymphocytes and were inversely correlated with CD163 expression on CD14+CD16+ monocytes. With ART interruption in subjects with early HIV infection, sCD163 and plasma virus levels spiked but rapidly returned to baseline with reinitiation of ART. This study points to the utility of monocyte- and macrophage-derived sCD163 as a marker of HIV activity that links viral replication with monocyte and macrophage activation. These observations underscore the significance of monocyte and macrophage immune responses with HIV pathogenesis.     

Immunological alterations in uncomplicated Plasmodium falciparum malaria. Relationship between parasitaemia and indicators of macrophage activation

Numerical alterations of circulating lymphocytes were investigated in 37 Brazilian patients with uncomplicated Plasmodium falciparum malaria and in a group of 15 healthy controls. The number of CD4+ T helper/inducer cells was significantly lower in patients than controls, whereas absolute numbers of CD8+ suppressor/cytotoxic T cells did not differ between the groups. TNF and neopterin levels were markedly increased in the plasma of patients and remained slightly elevated after chemotherapy with clindamycin. Neopterin, but not TNF levels, were significantly correlated with parasitaemia. TNF was inversely related to monocyte counts. Interferon gamma could not be detected in the plasma of control subjects and was observed in only one patient. We conclude that in uncomplicated falciparum malaria the distribution of phenotypes of circulating lymphocytes are altered slightly and that the high plasma levels of TNF and neopterin indicate excessive release of these molecules by activated macrophages and the activation of cellular immune mechanisms during the infection.     

Comparison of spinal fluid beta 2-microglobulin levels with CD4+ T cell count, in vitro T helper cell function, and spinal fluid IgG parameters in 163 neurologically normal adults infected with the human immunodeficiency virus type 1.

Beta 2-microglobulin levels were measured in the cerebrospinal fluid (CSF) and serum of 163 human immunodeficiency virus-positive (HIV+) persons with normal neurologic physical examinations. None were on antiretroviral therapy. Only 3% had a positive CSF HIV p24 antigen test. The CSF beta 2-microglobulin levels increased as the CD4+ T cell count decreased. Intrathecal production of beta 2-microglobulin was suggested by finding CSF concentrations greater than serum concentrations in 15% of patients. The CSF beta 2-microglobulin levels rose as in vitro T helper cell function deteriorated, independent of CD4+ T cell count. CSF beta 2-microglobulin levels paralleled CSF IgG, IgG index, and IgG synthesis. Higher CSF beta 2-microglobulin levels were found in persons with positive CSF oligoclonal bands. CSF beta 2-microglobulin concentration may serve as a marker for subclinical neurologic damage due to HIV. If this is established, defining the effect of anti-HIV interventions on CSF beta 2-microglobulin would be warranted.     

Continuing intrathecal immunoactivation despite two years of effective antiretroviral therapy against HIV-1 infection

OBJECTIVE: To study the effect of antiretroviral combination treatment on intrathecal immunoactivation in HIV-1 infection. METHOD: Lumbar punctures were performed at baseline, and after 4 months, 1 and 2 years on 30 neurologically asymptomatic, treatment-naive HIV-1-infected patients started on antiretroviral treatment with three or more drugs. Levels of neopterin, beta2-microglobulin and HIV-1 RNA were measured in cerebrospinal fluid (CSF) and blood. RESULTS: All patients continued the study until the 4-month follow-up, although seven discontinued before the 1-year control, and an additional five discontinued before the control after 2 years. Neopterin, beta2-microglobulin and HIV-1 RNA decreased significantly both in CSF and blood, but although 100% of the patients decreased their CSF concentrations of beta2-microglobulin and HIV-1 RNA to normal levels, only 55% had normal CSF neopterin concentrations after 2 years treatment. CONCLUSIONS: In addition to CSF viral load, antiretroviral combination therapy substantially decreases the intrathecal immunoactivation as reflected by CSF neopterin and beta2-microglobulin in neuroasymptomatic HIV-1-infected patients. However, almost half of the patients still have slightly increased CSF neopterin concentrations after 2 years of effective treatment, which might reflect an ongoing low-grade viral replication in brain tissue.     

Elevated neopterin and beta 2-microglobulin levels in blood and cerebrospinal fluid occur early in HIV-1 infection

Neopterin and beta 2-microglobulin (beta 2-M) concentrations in cerebrospinal fluid (CSF) and blood were measured in 56 individuals in various stages of HIV-1 infection. Elevated levels of neopterin as well as beta 2-M were found in the CSF of three patients with primary HIV-1 infection and also in subjects in the early stages of chronic HIV-1 infection, with the highest levels in HIV-1 isolation-positive people. There was a clear correlation between the concentrations of the two substances and the levels seemed to increase in parallel with progress of infection. A similar pattern was found in blood. Higher concentrations of neopterin and beta 2-M in CSF than in blood were found in patients with advanced dementia in particular. These findings indicate that the cellular immune system in the central nervous system (CNS) may be activated during the early stages of HIV-1 infection without concomitant overt neurological symptoms. The pathological processes in CNS and blood seem to develop in parallel rather than being restricted to one compartment.