Low T-cell responses to CD3 plus CD28 monoclonal antibodies are predictive of development of AIDS

OBJECTIVE: Decreased T-cell reactivity in vitro is strongly associated with progression to AIDS and low CD4+ T-cell numbers. Low T-cell responses in vitro induced by CD3 monoclonal antibody (mAb) are predictive for progression to AIDS independent of low CD4+ T-cell counts and high HIV-1 RNA levels. We developed a whole-blood lymphocyte culture system in which T cells were stimulated by a combination of CD3 and CD28 mAb. Combined stimulation of CD28, a costimulatory molecule, and CD3 considerably enhances T-cell responses in vitro and reduces variation coefficients, which may increase the prognostic power of T-cell responses. DESIGN: A prospective study of HIV-1-infected homosexual men followed for 35 months. METHODS: The predictive value of low T-cell responses to CD3 plus CD28 mAb relative to low CD4+ T-cell counts, high HIV-1 RNA levels and the presence of syncytium-inducing (SI) HIV-1 variants was evaluated longitudinally in 202 HIV-1-infected homosexual men followed for 35 months. RESULTS: In multivariate analysis, decreased T-cell responses at baseline were predictive of development of AIDS, independent of low CD4+ T-cell numbers and high HIV-1 RNA levels. In a time-dependent model, HIV-1 RNA levels lost their predictive value, whereas low T-cell responses, low CD4+ T-cell numbers and the presence of SI HIV-1 variants independently predicted AIDS. CONCLUSIONS: These data demonstrate that combined use of virological and immunological markers may be useful in monitoring disease progression and response to antiretroviral therapy.     

Seroconversion for human herpesvirus 8 during HIV infection is highly predictive of Kaposi's sarcoma

BACKGROUND: The finding of antibodies against human herpesvirus 8 (HHV-8) is associated with the occurrence of Kaposi's sarcoma in persons infected with HIV. However, the predictive value of HHV-8 antibodies for Kaposi's sarcoma in HIV infection is unknown. METHODS: The Amsterdam Cohort Studies on HIV infection and AIDS started in 1984 for homosexual men and in 1985 for injecting drug users. Serum samples from 1459 homosexual men and 1167 drug users were tested for antibodies to recombinant HHV-8 lytic-phase capsid (ORF65) antigen and latent-phase nuclear (ORF73) antigen. Individuals were retrospectively identified as HHV-8-positive or HHV-8-negative at enrolment or HHV-8 seroconverter during the study. Kaposi's sarcoma-free survival time was compared between HIV-infected men who were positive for HHV-8 at enrolment and those who later seroconverted for HHV-8. Hazard ratios were estimated for Kaposi's sarcoma, lymphoma, and opportunistic infection according to the HHV-8 serostatus. RESULTS: The incidence of HHV-8 seroconversion among drugs users was 0.7 per 100 person-years based on 31 seroconversions, whereas an incidence of 3.6 was found among homosexual men based on 215 seroconversions. The hazard ratio for Kaposi's sarcoma was 3.15 (95% CI: 1.89-5.25) in HIV-infected individuals if HHV-8 antibodies were present either at enrolment or at HIV seroconversion. In HIV-infected persons who later seroconverted to HHV-8, Kaposi's sarcoma developed more rapidly: hazard ratio of 5.04 (95% CI: 2.94-8.64), an additional risk of 1.60 (95% CI: 1.01-2.53; P = 0.04). Time-dependent adjustment for CD4+ cell count and HIV RNA had no impact on the additional risk, although the CD4+ cell count was an independent risk factor for Kaposi's sarcoma. HHV-8 infection did not increase the risk of AIDS-related lymphoma or opportunistic infections. CONCLUSIONS: The incidence of HHV-8 infection is higher in homosexual men than in drug users. The presence of HHV-8 antibodies in HIV-infected persons increases the risk of Kaposi's sarcoma. Among HIV-infected persons, those who subsequently seroconvert for HHV-8 are at highest risk. These results strongly confirm the causal role of HHV-8 in Kaposi's sarcoma and emphasize the clinical relevance of HHV-8 seroconversion before and after the HIV infection.     

Radiographic analysis of the orientation of the distal articular surface of the first metatarsal in the horizontal plane

BACKGROUND: Kaposi's sarcoma (KS) associated with human immunodeficiency virus type 1 (HIV-1) is the most common malignancy in patients with AIDS. It has been most commonly reported in white homosexual men, though a few cases have been reported in blacks. METHODS: We conducted a retrospective analysis of all HIV-1 seropositive patients with biopsy-proven KS seen at Howard University Hospital between February 1985 and June 1995. RESULTS: Of the 73 patients identified, 66 (90%), 4 were white, 2 were Hispanic, and 1 was of unidentified race. The median age was 32 years. Forty-eight (66%) were homosexual or bisexual men, and 10 (14%) were homosexual or bisexual with a history of intravenous drug use (IDU). A history of IDU or blood transfusion was the only risk factor in 7 (9%) and 2 (3%), respectively. The other 6 (8)% were heterosexual. The median survival was 2.2 years. A CD4 count <200 and the presence of an opportunistic infection were associated with shortened survival. CONCLUSIONS: The predominant risk factor for HIV-1-associated KS was homosexual or bisexual activity. Only a few women with KS were identified, and they also reported sexual transmission from male bisexuals and/or drug users. Poor survival was associated with CD4 <200, stage III and IV KS at presentation, and opportunistic infections.     

Presence of the variant mannose-binding lectin alleles associated with slower progression to AIDS. Amsterdam Cohort Study

OBJECTIVE: To examine the association between mannose-binding lectin (MBL) polymorphism and progression to AIDS and death in HIV-1 infection. DESIGN AND METHODS: In 131 HIV-1-infected homosexual seroconverters, survival analyses were performed to determine both the association between MBL genotype and time from HIV-1 seroconversion to AIDS and death, and time from AIDS to death. RESULTS: Of the 131 seroconverters, of whom 61 developed AIDS, 76 were typed as homozygous wild-type and 55 as carriers of variant alleles (52 heterozygous and three homozygous variant alleles). A Survival analyses suggested that HIV-1-infected men with the variant alleles progressed somewhat slower to AIDS [relative hazard (RH), 0.62; 95% confidence interval (CI), 0.36-1.10] and death (RH, 0.73; 95% CI, 0.42-1.25). Interestingly, CD4+ T-cell count determined at the moment of AIDS was found to be significantly lower among persons with the mutation (97 x 10(6)/l versus 204 x 10(6)/l; P=0.03). Furthermore, when AIDS-free times before the diagnosis of an opportunistic infection were compared with those preceding a diagnosis of Kaposi's sarcoma, Kaposi's sarcoma diagnosis was more postponed than that of an opportunistic infection (RH, 0.21; 95% CI, 0.05-0.95; versus RH, 0.67; 95% CI, 0.35-1.27). CONCLUSION: Indications for a weak pre-AIDS protective effect of variant MBL alleles were demonstrated.     

Serum levels of human immunodeficiency virus type 1 (HIV-1) RNA after seroconversion: a predictor of long-term mortality in HIV infection

A cohort of 79 homosexual men with documented dates of human immunodeficiency virus type 1 (HIV-1) seroconversion and baseline CD4 cell counts of > or = 500/microL were followed for up to 11.5 years. HIV-1 RNA was measured from stored sera obtained a median of 7 months after the estimated seroconversion date. AIDS progression and mortality among the men were studied, stratified by median baseline levels of HIV-1 RNA. AIDS progression rates at 11.5 years were 69% and 34%, respectively, among those with higher versus lower than median baseline virus loads (> or = 3040 copies/mL; P = .002), and mortality rates were 61% and 27%, respectively (P = .003). Survival curves continued to diverge throughout the 11.5 years, suggesting that the future clinical course of HIV-1 infection may already be determined at the earliest phases of disease. Initiation of definitive treatment very early in HIV-1 infection may be essential.     

Herpes zoster, immunological deterioration and disease progression in HIV-1 infection

OBJECTIVE: To study the incidence of herpes zoster, the relationship between herpes zoster and immunological markers, and the prognostic value of herpes zoster for progression of HIV disease. DESIGN AND METHODS: A total of 966 homosexual participants in The Amsterdam Cohort Study were studied. Herpes zoster was defined by its characteristic clinical presentation. Incidence was calculated using Poisson regression, cumulative incidence by the Kaplan-Meier product-limit method and the prognostic value was evaluated using Cox proportional hazards model. RESULTS: The incidence of first episodes of herpes zoster was 3.31 per 1000 person-years (PY) in HIV-seronegatives and 51.51 per 1000 PY in HIV-1-seropositive individuals. Recurrences only occurred in HIV-1-positive patients (25.6%). Cumulative incidences of first episodes increased linearly with the duration of follow-up. In HIV-1-seropositives the incidence was 31.2 per 1000 PY at CD4+ cells > or = 500 x 10(6)/l, 47.2 per 1000 PY [relative risk (RR), 1.51; 95% confidence interval (CI), 0.78-2.94] at CD4+ cells 200-499 x 10(6)/l and 97.5 per 1000 PY (RR, 3.13; 95% CI, 1.54-6.32) at CD4+ cells < 200 x 10(6)/l. Besides CD4+ cell counts, CD3 monoclonal antibodies and phytohaemagglutinin-induced T-cell reactivity were independent predictors for herpes zoster. The hazard ratio for AIDS after herpes zoster was 1.6 (95% CI, 1.1-2.4) and for death 1.7 (95% CI, 1.1-2.5), but these were not independent from CD4+ cell counts. CONCLUSION: In HIV-1 infection the incidence of herpes zoster increases with the decrease of CD4+ cell counts and T-cell reactivity, but herpes zoster is not an independent predictor for disease progression.     

The incubation period to AIDS in injecting drug users estimated from prevalent cohort data, accounting for death prior to an AIDS diagnosis

OBJECTIVE: To estimate the incubation-period distribution (time from seroconversion to AIDS) accounting for death before an AIDS diagnosis (DBAD) in a cohort of injecting drug users (IDU) in Amsterdam, The Netherlands and to compare these estimates with those previously obtained from a contemporaneous study of homosexual and bisexual men in Amsterdam carried out using the same facilities. DESIGN: Participants in a cohort study begun in Amsterdam at the end of 1985 have scheduled follow-up visits every 4 months. All participants of Dutch nationality and who had two or more follow-up visits before January 1996 from which CD4 measurements were available were included in this study. Data concerning AIDS diagnosis and death were verified through review of national and municipal registries. METHODS: Because time of seroconversion was unknown for study participants and because IDU are at substantial risk for DBAD, we used a Markov model with CD4-based stages that allows for DBAD. The parameters in this model were estimated using the method of maximum likelihood and confidence intervals were calculated using bootstrap methods. RESULTS: A total of 173 IDU (134 seroprevalent, 39 seroincident) made 1829 visits. Nearly 10% of the visits were non-consecutive. Forty-five IDU developed AIDS and 25 died without an AIDS diagnosis. We estimated that 24% [95% confidence interval (CI), 17-25%] of IDU die before an AIDS diagnosis. As a result, the median time from seroconversion to AIDS (10.5 years; 95% CI, 9.1-10.7 years) is considerably longer than the median time from seroconversion to death (8.3 years; 95% CI, 7.9-8.5 years). Conditional on survival to an AIDS diagnosis, the median time to AIDS is 8.2 years (95% CI, 7.7-8.7 years). The median survival time after a diagnosis of AIDS is estimated to be 1.0 years. CONCLUSION: The high occurrence of DBAD in IDU has a considerable influence on estimates of the incubation-period distribution. Progression from seroconversion to death was faster in the IDU cohort than in a cohort of homosexual men in Amsterdam (median, 8.3 years and 9.6 years, respectively). However, progression to AIDS conditional on survival to an AIDS diagnosis seems to be similar in both the IDU cohort and in the cohort of homosexual men (median, 8.2 years and 8.3 years, respectively).     

Pre-AIDS mortality in the Edinburgh City Hospital HIV cohort

In this paper, we look at the incidence and predictive factors of pre-AIDS mortality among HIV-infected individuals, and injecting drug users (IDUs) in particular, and compare IDUs with non-IDUs. 627 patients (73 per cent IDUs) of the Edinburgh City Hospital HIV Cohort were enrolled pre-AIDS and followed up until September 1994. Analyses were performed using cumulative hazard and cumulative incidence estimators for a competing risks model, the Cox proportional hazards model and the non-parametric hazard estimator of Fusaro et al. (1993). The effects of age and CD4 T-lymphocyte cell count, progressively depleted during HIV progression, were investigated. 60 deaths occurred in AIDS-free patients during follow-up; 25 were drug-related deaths in IDUs. Pre-AIDS mortality was higher among IDUs than non-IDUs (p = 0.07). The cumulative incidences of pre-AIDS death after five years from enrollment were 11 per cent in IDUs and 6 per cent in non-IDUs; the cumulative AIDS incidences were, respectively, 19 per cent and 32 per cent. After eight years, cumulative pre-AIDS death incidence was 15 per cent among IDUs; cumulative AIDS incidence among IDUs was 35 per cent. Both groups had similar risks of medically-related (non-AIDS)-MRNA-death. Age and CD4 count were both individually predictive of MRNA death (relative risks (RRs); 2.1 per decade of life, p < 0.01; and 1.9 for each 100 cells per 100 microliters lost, p < 0.0001), although when used together age was less significant (RR 1.6, p = 0.07). Neither was statistically significant for drug-related mortality, although hazard may be lower in older individuals and may increase with falling CD4 count. The drug-related mortality was 1.1 per cent: 2.3 per cent in the first two years after enrollment, and 0.4 per cent thereafter. We conclude that older HIV-infected individuals are at greater risk of medically-related death before AIDS. This risk increases as CD4 count declines. Drug-related hazard may be greater in younger individuals and may increase as CD4 counts fall, but neither effect was formally significant.     

Prevalence and incidence of cytomegalovirus infection in patients infected with HIV-1. SEROCO group

OBJECTIVES: To study prevalence of the cytomegalovirus (CMV) infection as well as incidence of the CMV seroconversions in HIV-infected subjects enrolled in the French multicentric cohort SEROCO. METHOD: Prevalence of CMV infection at inclusion in the cohort was estimated from 1504 HIV-infected subjects. Incidence of the CMV seroconversion was estimated from 184 subjects CMV seronegative at inclusion. Cox model was used to identify independent factors related to CMV seroconversion. RESULTS: CMV prevalence was high (87.2%) mainly in homosexual men. The incidence of the CMV seroconversions was also high (9, 18/100 person-years), particularly in homosexual men, in subjects declaring sexual intercourse with occasional partner, and in those declaring a sexually transmitted disease during the follow-up. CONCLUSION: The risk to develop serious disease related to CMV in subjects with AIDS being particularly high when the CMV primary infection occurs during the course of the HIV infection, the prevention of CMV primary infections is thus a major element in the counselling of HIV-infected subjects.     

Prevalence of obesity in Spain: the SEEDO''97 study. Spanish Collaborative Group for the Study of Obesity

BACKGROUND: Multiple viral subpopulations coexist in an HIV infected patient with dynamics of selection established between them. In order to get insight on the phenotype of these subpoblations, and its relation with disease progression, we have studied the biological variability of HIV-1 in 113 patients. Variability was related with CD4+ T lymphocyte counts, clinical status, way of viral transmission and antiretroviral treatment. PATIENTS AND METHODS: 113 patients (80 adults and 33 children) were studied for HIV-1 isolation in cocultures of infected and non infected lymphocytes. Viral replication was evaluated as rapid (R)/slow (S) or high (H)/low (L). Syncytia formation was estimated in MT2 cell line (SI/NSI). The tropism toward lymphocytes and monocytes (LM) was studied on H9 and U937 cell lines. RESULTS: Up to 86.7% of viral isolates were R, 56.6% were H and 49.6% were SI. These percentages increased with disease progression. Eight viral strains were R/H/NSI cocultivated in MT2 cells and SI in cocultured lymphocytes (NSI/SI), which may be considered as a new phenotype. All the SI isolates and all the R/H (SI and NSI) isolates were LM. Three categories were established: R/H/SI/LM, R/H/NSI/LM and S/L/NSI/NLM. The first two categories corresponded to patients with CD4+ T lymphocytes <200 x 10(6)/I (56%, 50%). The third category corresponded to patients with > 500 x 10(6)/I (53.3%). CONCLUSIONS: Viral replication and SI phenotype, independently, are useful markers for severity of HIV infection. The biological differences among NSI of the 3 viral phenotype categories, including the new subgroup NSI/SI, may indicate the existence of more pathogenic NSI subpopulations.     

Demonstration of the Th1 to Th2 cytokine shift during the course of HIV-1 infection using cytoplasmic cytokine detection on single cell level by flow cytometry

OBJECTIVE: To characterize changes of Th1/Th2 cytokine production by peripheral blood mononuclear cells (PBMC) that occur during the course of HIV infection by cytoplasmic cytokine staining on single cell level. DESIGN AND METHODS: Mitogen-stimulated PBMC from 16 healthy donors, 18 HIV-1-infected individuals without AIDS and 14 patients with AIDS were stained intracellularly with fluorescein-labelled MAb against interleukin (IL)-2, IL-4, IL-10 and interferon (IFN)-gamma. Additionally, co-staining of CD4+ T-cell, CD8+ T-cell, natural killer (NK) cell, B-cell and monocytic markers was performed. Fluorescence staining was analysed by three-colour flow-cytometry. RESULTS: A reduced percentage of IL-2 and IFN-gamma (Th1 type)-producing cells among CD4+ T cells from HIV-1-infected individuals could be demonstrated. There was a continuous decrease of IFN-gamma-producing CD4+ T cells in the course of HIV infection and a dramatic reduction of IL-2-expressing cells among CD4+ T cells in patients with AIDS. In contrast to Th1 cytokines, the frequency of Th2 cytokine expressing cells among CD4+ T cells increased in HIV-infected individuals. The maximum frequency of IL-4-expressing cells among CD4+ T cells was seen in HIV-infected individuals without AIDS, whereas the rate of IL-10-producing cells was highest in patients with AIDS. In HIV-infected individuals no significant proportion of Th0 cells expressing both Th1 and Th2 cytokines was detectable. In CD8+ T cells the percentage of IL-2 was expressing cells decreased continuously accompanied by a strong increase of the frequency of IFN-gamma-producing cells. CONCLUSION: The decreased percentage of cells expressing IL-2 and IFN-gamma in conjunction with an increased proportion of IL-4- and IL-10-producing cells among the CD4+ T cells in HIV-1-infected individuals demonstrate a Th1 to Th2 cytokine shift in the course of HIV infection on a single cell level. There was no evidence of a Th1 to Th0 cytokine shift. In addition to the loss of CD4+ T cells in HIV infection, the qualitative changes of Th1/Th2 cytokine expression may serve as a marker for progressive failure of cell-mediated immunity.     

Geography of AIDS-associated Kaposi's sarcoma in Europe

BACKGROUND: Classical Kaposi's sarcoma (KS) is about four times more common in southern Europeans than in northern Europeans. OBJECTIVE: To describe the epidemiology of AIDS-associated KS (AIDS-KS) in Europe and to determine whether it occurs with increased frequency in southern Europe. METHODS: Analysis of the 'European non-aggregate AIDS data set', as of September 1995. Countries with a cumulative total of > or = 50 KS cases as the presenting manifestation of AIDS were included. Homosexual men were excluded from south versus non-south comparisons because of possible confounding effects due to their route of HIV transmission. RESULTS: KS was the presenting manifestation of AIDS for 13.3% (16,367 out of 122,679) of men and 2% (491 out of 24,826) of women. In all countries, the risk for KS was higher in individuals who acquired HIV infection via sexual rather than parenteral transmission. Among AIDS patients, there is little difference by sex in the risk of KS in injecting drug users (IDU) or transfusion recipients. The percentage with KS increased with age among homosexual and bisexual men, from 10% in the age group 15-19 years to 23% in the age group 30-39 years. In all countries, the percentage with KS declined over time. The risk of KS was not significantly higher in southern Europe. The percentage with KS in southern Europe was slightly lower than in northern Europe (P > 0.1) in male IDU (1.8% versus 2.1%), and only slightly higher (P > 0.1) in female IDU (1.5% versus 1.1%), in male transfusion recipients (3.5% versus 3.0%), in female transfusion recipients (2.4% versus 2.3%), and in both heterosexual men (7.5% versus 6.2%) and women (2.0% versus 1.6%) excluding those originating from countries where heterosexual HIV transmission is frequent. CONCLUSIONS: The strong geographic predilection described for classical KS in southern Europe was not seen for AIDS-KS. If KS is caused by a viral infection in an immunodeficient host, our findings suggest the geographical variations in classical KS are not due to variation in prevalence of the causative virus but may be due to geographical variations in the prevalence of a form of mild immunodeficiency.     

Chemokine coreceptor usage by diverse primary isolates of human immunodeficiency virus type 1

We tested chemokine receptor subset usage by diverse, well-characterized primary viruses isolated from peripheral blood by monitoring viral replication with CCR1, CCR2b, CCR3, CCR5, and CXCR4 U87MG.CD4 transformed cell lines and STRL33/BONZO/TYMSTR and GPR15/BOB HOS.CD4 transformed cell lines. Primary viruses were isolated from 79 men with confirmed human immunodeficiency virus type 1 (HIV-1) infection from the Chicago component of the Multicenter AIDS Cohort Study at interval time points. Thirty-five additional well-characterized primary viruses representing HIV-1 group M subtypes A, B, C, D, and E and group O and three primary simian immunodeficiency virus (SIV) isolates were also used for these studies. The restricted use of the CCR5 chemokine receptor for viral entry was associated with infection by a virus having a non-syncytium-inducing phenotype and correlated with a reduced rate of disease progression and a prolonged disease-free interval. Conversely, broadening chemokine receptor usage from CCR5 to both CCR5 and CXCR4 was associated with infection by a virus having a syncytium-inducing phenotype and correlated with a faster rate of CD4 T-cell decline and progression of disease. We also observed a greater tendency for infection with a virus having a syncytium-inducing phenotype in men heterozygous for the defective CCR5 Delta32 allele (25%) than in those men homozygous for the wild-type CCR5 allele (6%) (P = 0.03). The propensity for infection with a virus having a syncytium-inducing phenotype provides a partial explanation for the rapid disease progression among some men heterozygous for the defective CCR5 Delta32 allele. Furthermore, we did not identify any primary viruses that used CCR3 as an entry cofactor, despite this CC chemokine receptor being expressed on the cell surface at a level commensurate with or higher than that observed for primary peripheral blood mononuclear cells. Whereas isolates of primary viruses of SIV also used STRL33/BONZO/TYMSTR and GPR15/BOB, no primary isolates of HIV-1 used these particular chemokine receptor-like orphan molecules as entry cofactors, suggesting a limited contribution of these other chemokine receptors to viral evolution. Thus, despite the number of chemokine receptors implicated in viral entry, CCR5 and CXCR4 are likely to be the physiologically relevant chemokine receptors used as entry cofactors in vivo by diverse strains of primary viruses isolated from blood.     

The association between cigarette smoking and selected HIV-related medical conditions

OBJECTIVE: To clarify the effect of cigarette smoking on the development of conditions associated with HIV infection. DESIGN: Prospective and retrospective cohort study, with interview and examination twice a year since 1988. METHODS: Data on 516 HIV-infected men from cohorts of homosexual and bisexual men in San Francisco, Denver and Chicago, who were repeatedly interviewed and examined between 1988 and 1992, were analysed. After excluding men who did not have well-defined dates of seroconversion and those who were classified as ex- or intermittent smokers, 232 men remained for analysis: 106 were smokers and 126 were non-smokers. Univariate and Kaplan-Meier survival analyses were performed to assess the relationship between cigarette smoking and loss of CD4+ T-lymphocytes, diagnosis of any AIDS-defining illness, and specific diagnosis of Kaposi's sarcoma, Pneumocystis carinii pneumonia (PCP), oral candidiasis, hairy leukoplakia, and community-acquired pneumonia. RESULTS: By univariate analyses, cigarette smoking was not associated with clinical AIDS, loss of CD4+ cells, Kaposi's sarcoma or PCP, but was significantly associated with oral candidiasis [relative risk (RR), 1.32; 95% confidence interval (CI), 1.02-1.70], hairy leukoplakia (RR, 1.51; 95% CI, 1.15-1.99), and community-acquired pneumonia (RR, 2.62; 95% CI, 1.30-5.27). Dose-response effect was also evident for these three conditions (all P < 0.01). Kaplan-Meier survival analysis indicated no association between cigarette smoking and time of progression to clinical AIDS, Kaposi's sarcoma (KS), or PCP (P = 0.62, 0.54 and 0.11, respectively) but showed that cigarette smokers developed oral candidiasis, hairy leukoplakia, and pneumonia more quickly than non-smokers (P = 0.031, 0.006 and 0.009, respectively). CONCLUSIONS: Cigarette smoking was not associated with an increased likelihood or rate of developing KS, PCP or AIDS, but was associated with developing community-acquired pneumonia, oral candidiasis, and hairy leukoplakia in these HIV-infected men.     

Low T cell reactivity to combined CD3 plus CD28 stimulation is predictive for progression to AIDS: correlation with decreased CD28 expression

In 219 HIV-1-infected men of the Amsterdam cohort we measured CD4+ T cell numbers and in vitro T cell responses to CD3 MoAbs with or without CD28 costimulation and phytohaemagglutinin (PHA). The value of these markers was estimated for disease progression within 4 years. CD28 expression on T cells has been related to T cell responses. CD28 costimulation considerably enhanced T cell reactivity (approximately 8-10-fold) with lower coefficients of variation compared with reactivity to CD3 MoAb alone (median 5 versus 20). T cell reactivity to CD3 plus CD28 MoAb was decreased during HIV-1 infection and was besides CD4+ T cell numbers the only independent predictor for progression to AIDS. Compared with the group with high CD4+ T cell numbers the relative risk (RR) for the group with intermediate levels was 2.28, with low levels 5.20. In the groups with intermediate and low CD3 plus CD28 responses the RR was 2.04 and 4.16, respectively. The combined RR for both was 4.65 and 21.63. The independence of this marker was confirmed when the group with low CD4+ T cell numbers was subdivided into groups with high, intermediate and low T cell responses. The expansion of CD8+CD28- T cells was already apparent in HIV- homosexual men, but CD8+CD28+ T cells specifically decreased in patients with AIDS. CD28 expression on T cells correlated moderately with T cell responses to CD3 plus CD28 MoAb. T cell reactivity to CD3 MoAb in the presence of CD28 MoAb is a stronger prognostic marker than T cell reactivity to CD3 MoAb alone.     

Macrophages and CD4+ T lymphocytes from two multiply exposed, uninfected individuals resist infection with primary non-syncytium-inducing isolates of human immunodeficiency virus type 1

Despite multiple, high-risk sexual exposures, some individuals remain uninfected with human immunodeficiency virus type 1 (HIV-1). CD4+ lymphocytes from these individuals are less susceptible to infection in vitro with some strains of HIV-1, suggesting that the phenotype of the virus may influence its ability to interact with certain CD4+ cells. In the present study, we examined the susceptibility of CD4+ T lymphocytes and macrophages from two exposed uninfected individuals (EU2 and EU3) to infection with a panel of biologically cloned isolates of HIV-1 having either a non-syncytium-inducing (NSI) or a syncytium-inducing (SI) phenotype. Our results indicate that CD4+ T lymphocytes from EU2 and EU3 are resistant to infection with NSI isolates of HIV-1 but are susceptible to infection with primary SI isolates. In addition, we found that macrophages from EU2 and EU3 are resistant to infection with both NSI and SI isolates. The latter finding was confirmed by using several uncloned NSI and SI isolates obtained from patients during acute HIV-1 infection. In further experiments, env clones encoding glycoproteins characteristic of NSI or SI viruses were used in single-cycle infectivity assays to evaluate infection of CD4+ lymphocytes and macrophages from EU2 and EU3. Consistent with our previous results, we found that macrophages from these individuals are resistant to infection with NSI and SI env-pseudotyped viruses, while CD4+ T lymphocytes are resistant to NSI, but not SI, pseudotyped viruses. Overall, our results demonstrate that CD4+ cells from two exposed uninfected individuals resist infection in vitro with primary, macrophage-tropic, NSI isolates of HIV-1, which is the predominant viral phenotype found following HIV-1 transmission. Furthermore, infection with NSI isolates was blocked in both CD4+ T lymphocytes and macrophages from these individuals, suggesting that there may be a common mechanism for resistance in both cell types.     

A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. AIDS Clinical Trials Group 320 Study Team

BACKGROUND: The efficacy and safety of adding a protease inhibitor to two nucleoside analogues to treat human immunodeficiency virus type 1 (HIV-1) infection are not clear. We compared treatment with the protease inhibitor indinavir in addition to zidovudine and lamivudine with treatment with the two nucleosides alone in HIV-infected adults previously treated with zidovudine. METHODS: A total of 1156 patients not previously treated with lamivudine or protease inhibitors were stratified according to CD4 cell count (50 or fewer vs. 51 to 200 cells per cubic millimeter) and randomly assigned to one of two daily regimens: 600 mg of zidovudine (or stavudine) and 300 mg of lamivudine, or that regimen with 2400 mg of indinavir. The primary end point was the time to the development of the acquired immunodeficiency syndrome (AIDS) or death. RESULTS: The proportion of patients whose disease progressed to AIDS or death was lower with indinavir, zidovudine, and lamivudine (6 percent) than with zidovudine and lamivudine alone (11 percent; estimated hazard ratio, 0.50; 95 percent confidence interval, 0.33 to 0.76; P=0.001). Mortality in the two groups was 1.4 percent and 3.1 percent, respectively (estimated hazard ratio, 0.43; 95 percent confidence interval, 0.19 to 0.99; P=0.04). The effects of treatment were similar in both CD4 cell strata. The responses of CD4 cells and plasma HIV-1 RNA paralleled the clinical results. CONCLUSIONS: Treatment with indinavir, zidovudine, and lamivudine as compared with zidovudine and lamivudine alone significantly slows the progression of HIV-1 disease in patients with 200 CD4 cells or fewer per cubic millimeter and prior exposure to zidovudine.     

HIV-1 disease progression and AIDS-defining disorders in rural Uganda

BACKGROUND: The majority of people infected with HIV-1 live in Africa, yet little is known about the natural history of the disease in that continent. We studied survival times, disease progression, and AIDS-defining disorders, according to the proposed WHO staging system, in a population-based, rural cohort in Uganda. METHODS: In 1990 we recruited a random sample of people already infected with HIV-1 (as prevalent cases) detected during the initial survey round of a general-population study to form a natural-history cohort. Individuals from the general-population cohort who seroconverted between 1990 and 1995 (incident cases) were also invited to enroll. Participants were seen routinely every 3 months and when they were III. FINDINGS: By the end of 1995, 93 prevalent cases and 86 incident cases had been enrolled. Four patients in the prevalent group were in stage 4 (AIDS) at the initial visit. During the next 5 years, 37 prevalent cases progressed to AIDS. Seven incident cases progressed to AIDS and the cumulative progression to AIDS at 1, 3, and 5 years after seroconversion was 2%, 6%, and 22%, respectively. The cumulative probability of AIDS at 4 years from entering stages 1, 2, and 3 was 11%, 33%, and 58%, respectively. There were 47 deaths among prevalent cases and seven among incident cases during follow-up. The cumulative mortality 4 years after patients entered stages 1, 2, 3, and 4 was 9%, 33%, 56%, and 86%, respectively. The median survival after the onset of AIDS was 9.3 months. INTERPRETATION: Our results are important for the setting of priorities and rationalisation of treatment availability in countries with poor resources. We found that progression rates to AIDS are similar to those in developed countries for homosexual cohorts and greater than for cohorts infected by other modes of transmission. However, we have found that the rates of all-cause mortality are much higher and the progression times to death are shorter than in developed countries.