HLA phenotype is a factor in determining rate of disease progression and outcome in HIV-1-infected individuals.

HLA allele frequencies were examined for possible association(s) with the rate of disease progression and with the disease outcome (AIDS diagnosis) in a population of HIV-1-infected individuals. Certain alleles were associated with the relative rate of CD4+ T-cell decline. Association of particular alleles with several disease outcomes associated with infection was also observed. It is important to keep these two aspects (disease progression, AIDS diagnosis) separate when studying HLA in the HIV-1-infected population. Alleles that may play a role in the rate of virus speed by effecting the immune response may be different from those found to be associated with a particular disease. We feel that the only truly informative data, in this regard, can be generated from a relative precise determination of the time of infection (to study disease progression) and adequate numbers of individuals with specific diseases to study specific disease association. If such data can be generated we will have a much better understanding of the pathogenetic process(es) of HIV-1 infection.     

HIV-1 biological phenotype in long-term infected individuals evaluated with an MT-2 cocultivation assay.

OBJECTIVE: We have previously demonstrated that detection of syncytium-inducing (SI) HIV-1 in asymptomatic seropositive individuals is associated with rapid progression to AIDS. In the present study, we sought to develop and evaluate an HIV-1 phenotyping assay for the screening of large numbers of individuals. METHODS: Efficiency of HIV-1 isolation from patient peripheral blood mononuclear cells (PBMC) was studied with donor PBMC or seven different CD4+ T-cell lines as target cells. The biological phenotype of sequential isolates from 20 long-term asymptomatic HIV-1-seropositive individuals was determined by two different assays. RESULTS: Non-SI isolates, efficiently recovered by cocultivation with donor PBMC, were never isolated with T-cell lines as target cells. Direct cocultivation with MT-2 cells, but not with six other CD4+ T-cells, resulted in the efficient recovery of SI isolates. HIV-1 MT-2 tropism and SI capacity were shown to be coupled properties at the clonal level. SI isolates emerged in 10 out of 20 longitudinally-studied individuals. In these long-term infected individuals, appearance of SI isolates was associated with progression to AIDS. CONCLUSIONS: Direct cocultivation of patient PBMC with the MT-2 cell line is a sensitive, specific and convenient method to detect SI isolates. The availability of an assay suitable for the screening of large groups allows further study of the value of HIV-1 biological phenotyping as a prognostic marker.     

In-vitro resistance to zidovudine and alpha-interferon in HIV-1 isolates from patients: correlations with treatment duration and response.

OBJECTIVE: To measure in-vitro antiviral drug susceptibilities of human immunodeficiency virus type 1 (HIV-1) isolates recovered from patients treated with alpha-interferon or zidovudine and patients not treated with these drugs and to examine the relation of these susceptibility measurements to duration of therapy, disease stage, and response to alpha-interferon therapy. DESIGN: Cross-sectional study. SETTING: Outpatient HIV clinic. PATIENTS: Twenty-six ambulatory HIV-1-infected patients: Fifteen of these patients were receiving alpha-interferon therapy, and 11 had never received such therapy. Nine patients were participating in a clinical trial of combination therapy with zidovudine and alpha-interferon. MEASUREMENTS: The 50% inhibitory concentration (IC50) of zidovudine and alpha-interferon was determined for HIV-1 isolates recovered from each patient. Plasma concentrations of HIV-1 p24 antigen in the nine patients in the clinical trial were measured monthly after alpha-interferon was added to zidovudine monotherapy. RESULTS: Zidovudine IC50 (range, 0.01 to 4.87 microM) increased steadily with duration of zidovudine therapy (r = 0.57, P = 0.003). In contrast, alpha-interferon IC50 (range, 0.8 to 415 units/mL) was not related to duration of alpha-interferon treatment; in fact, high IC50s were found in isolates from patients who had never received exogenous alpha-interferon therapy. Resistance to alpha-interferon was greater in isolates from the 15 patients with the acquired immunodeficiency syndrome (AIDS) (median, 104 units/mL) than in those from the 10 patients without AIDS (median, 50 units/mL). Interferson activity was detected in plasma samples from 23 of 24 patients and was also at higher levels in patients with AIDS than in HIV-infected patients without AIDS. Reductions in plasma concentrations of HIV-1 p24 antigen in nine patients after beginning alpha-interferon therapy were greater in those with more susceptible isolates (r = -0.72, P = 0.03). CONCLUSIONS: Interferon resistance, possibly due to endogenous interferon, is not related to duration of interferon therapy but may limit the effectiveness of interferon therapy. Determinations of interferon susceptibility may identify patients most likely to benefit from this agent.     

Similar rate of disease progression among individuals infected with HIV-1 genetic subtypes A-D.

OBJECTIVE: HIV-1 is characterized by a high degree of genetic variation and can be divided into at least 10 distinct genetic subtypes. The purpose of this study was to investigate whether the rate of disease progression shows subtype-specific differences. DESIGN: The investigation was divided into two parts; one study in which 49 ethnic Africans were compared with 49 ethnic Swedes irrespective of the subtype of the infecting virus, and a second study in which 126 individuals infected with different genetic subtypes (28 with subtype A, 59 with subtype B, 21 with subtype C and 18 with subtype D) were compared. METHODS: CD4 cell counts, the rate of CD4 cell decline, plasma HIV-1 RNA levels, clinical status and antiviral treatment were prospectively and retrospectively recorded. The HIV-1 subtype had previously been determined by direct sequencing of the V3 domain of the env gene. RESULTS: There were no significant differences in the rate of CD4 cell decline or clinical disease progression between Africans and Swedes over an observation period of 2 years. Similarly, there were no differences in the rate of CD4 cell decline, clinical progression or plasma HIV-1 RNA levels between individuals infected with subtypes A, B, C or D over a mean observation period of 44 months. CONCLUSION: Neither the genetic subtype of the virus nor the ethnicity of the host appear to be major determinants of disease progression.     

Development and progression of atherosclerotic disease in relation to insulin resistance and hyperinsulinemia.

It is unclear whether the role of insulin resistance in the development of atherosclerotic cardiovascular disease is similar in populations in which the incidence of atherosclerotic diseases significantly differs from that in Western countries. The aim of this study was to determine the relationship between insulin resistance and the development of cardiovascular disease in the Japanese population. We conducted 75 g-oral glucose tolerance tests (OGTTs) on 1,928 inhabitants of two towns in Hokkaido, Japan. Subjects using antihypertensive agents and known diabetic patients were excluded from the study. Data from the remaining 1,227 subjects (540 males and 687 females; mean age 56.0 +/- 10.8 years) were used for the analysis, and 1,051 subjects were seen in a follow-up care setting for a period of 8 years. The presence of insulin resistance was defined according to the guidelines reported our previous study: insulin levels of 64.0 mU/l or higher 2 h after the 75 g-OGTT. The insulin-resistant (IR) group had several risk factors such as hypertension, diabetes, treated or untreated hypercholesterolemia, hypertriglyceridemia, low high-density-lipoprotein (HDL) cholesterol levels, and obesity. During the follow-up period of 8 years, the incidence of coronary artery disease, which was adjusted for age, body mass index, sex, systolic blood pressure, fasting plasma glucose, total cholesterol, triglyceride, and HDL cholesterol was significantly (3.2 times) higher in the IR group than in the insulin non-resistant group. The results suggested that insulin resistance is an independent risk factor for coronary artery disease in Japanese subjects, as has also been demonstrated in the case of individuals in Europe and USA.     

Biphasic rate of CD4+ cell count decline during progression to AIDS correlates with HIV-1 phenotype.

OBJECTIVE: To determine the kinetics of decline of CD4+ lymphocytes in HIV-1-infected asymptomatic homosexual men. METHODS: CD4+ lymphocytes were enumerated in a cohort of 187 HIV-1-infected initially asymptomatic homosexual men seen at 3-month intervals over 5 years. During follow-up, 45 men progressed to AIDS (excluding cases presenting with Kaposi's sarcoma). Correlation between rate of CD4+ cell decline and presence of a particular HIV-1 biological phenotype was analysed in 43 participants. RESULTS: CD4+ cell counts declined slowly and continuously in HIV-1-seropositive men who remained asymptomatic during follow-up. A biphasic CD4+ cell count decline was observed in the group who developed AIDS: the decline was slow and steady (5.6 x 10(6)/l per month, similar to that observed in the asymptomatic group) until 18 months before AIDS diagnosis, but became three to five times faster thereafter. Rapid CD4+ cell decline was significantly related to syncytium-inducing, fast-replicating HIV-1 isolates; during the period of slow and steady CD4+ cell count decline, non-syncytium-inducing isolates were predominant. CONCLUSIONS: At an average of 18 months preceding AIDS diagnosis, a three to fivefold increase in the rate of loss of CD4+ lymphocytes occurs, and may be related to the appearance of a more virulent HIV-1 phenotype.     

Relationship between drug resistance and HIV-1 disease progression or death in patients undergoing resistance testing

OBJECTIVE: To evaluate factors associated with drug resistance detected by genotypic antiretroviral resistance testing (GART), and to determine the association between the level of resistance and subsequent human immunodeficiency type 1 (HIV-1) disease progression or death. DESIGN: Observational cohort study. METHODS: We identified highly active antiretroviral therapy (HAART)-treated patients who had GART as part of clinical management. Factors associated with greater numbers of resistance mutations were assessed by ordinal logistic regression. Survival analysis was used to assess time to a new opportunistic condition or death following GART. RESULTS: A total of 572 patients were identified who had GART: of these, 50% had 0-2 resistance mutations, 33% had 3-6 mutations, and 17% had >/= 7 mutations. In multivariate analysis, prolonged use of HAART in the setting of incomplete viral suppression was significantly associated with more drug resistance. Patients with fewer resistance mutations were significantly more likely to achieve viral suppression after GART than patients with more mutations. Compared to patients with two or less resistance mutations, those with three to six mutations, or seven or more mutations were not at higher risk of HIV-1 disease progression or death over a median follow-up of 15 months. In contrast, continued HAART use following GART was strongly associated with slower disease progression, particularly at lower CD4 cell counts. CONCLUSION: These results support the hypothesis the drug-resistant HIV-1 may be less pathogenic than wild-type virus, and that continued use of HAART might provide clinical benefit, despite persistent viremia and HIV-1 drug resistance.     

虚拟表型方法在HIV-1耐药检测中的应用

艾滋病病毒Ⅰ型(HIV-1)耐药性检测,已成为抗病毒治疗中进行合理用药的重要依据。基因型和表型耐药检测是最常用的HIV耐药检测方法,这两种方法的局限性在于:基因型方法不能直接提供药物耐受信息,表型方法比较耗时。根据上述两种方法之间的良好相关性提出的虚拟表型耐药检测方法,尽管也存在不足,但是提供了另外一种方便的得到耐药信息的方法,从而更好地指导抗病毒治疗。     

Kinetics of HIV-1 in cerebrospinal fluid and serum after zidovudine treatment

Two patients with HIV-1 infection associated with neurological complications were repeatedly followed with cerebrospinal fluid (CSF) and serum analyses before, and 1 to 2.5 years after single zidovudine treatment. Retrospectively, HIV-RNA levels were analyzed with quantitative PCR assay. The number of HIV-RNA copies in CSF was decreased already 1 week after initiation of zidovudine, and continued to decrease during 5 months of follow up, while the serum levels increased during the same period. The difference between HIV levels in CSF and serum compartments following zidovudine treatment indicates that the CSF viral load does not merely reflect blood levels. Single zidovudine treatment did not reduce the viral load in CSF to non-detectable levels but had a better and more long-lasting anti-HIV effect in CSF than in peripheral blood.     

Gender differences in clinical progression of HIV-1-infected individuals during long-term highly active antiretroviral therapy

OBJECTIVE: To assess gender differences in the long-term clinical, virological and immunological outcomes during highly active antiretroviral therapy (HAART). METHODS: This longitudinal observational multicentre study followed 2460 HIV-infected patients who had begun a protease inhibitor-based regimen for a median period of 43 months. Outcome measures were virological suppression (< 500 copies/ml), confirmed virological rebound after suppression, and death or new AIDS-defining illness (ADI). RESULTS: At baseline, 690 female patients (28.0%) had significantly lower age, higher prevalence of heterosexual contact and lower prevalence of intravenous drug use as risk factors for HIV infection compared with males. Furthermore, females had a lower number of AIDS-defining illnesses, higher CD4 cell counts and lower viral loads.No gender differences were reported in terms of proportion of patients achieving viral suppression or exhibiting rebound after achieving viral suppression. Female patients experienced reduced clinical progression during follow-up compared with males (P = 0.008) by Kaplan-Meier analysis; however this difference was not significant in an adjusted analysis. In a multivariate model, the interaction between gender and risk factor for HIV or viral load showed that female drug users and female patients with a baseline HIV RNA viral load of 10(4)-10(5) copies/ml had a favourable clinical outcome compared with males (P = 0.035 and P = 0.015, respectively). CONCLUSION: No differences were found between genders in terms of virological and immunological outcomes during long-term HAART. Nevertheless, a lower risk of clinical progression was reported among female patients with intermediate baseline viral load than in males.     

Appearance of predictors of disease progression in relation to the development of AIDS

To study the natural history of HIV-1 infection in relation to serological and immunological profiles, 199 asymptomatic HIV-1-antibody (HIV-1-core-antibody)-seropositive and 76 seroconverted homosexual men were followed prospectively for 39 months. AIDS was diagnosed in 38 men. The AIDS attack rate was 20.8% after 39 months. The AIDS attack rate in the HIV-I-core-antibody positives was 12.1, versus 30.1% in the HIV-1-core-antibody negatives (P less than 0.001), and it was 13.3% in the HIV-1-antigen (HIV-1-Ag) negatives versus 53.9% in the HIV-1-Ag positives (P less than 0.001). The AIDS attack rate after 39 months was 10.9% in men with counts greater than or equal to 0.5 x 10(9)/l and 49.9% in those with CD4+ lymphocyte counts less than 0.5 x 10(9)/l. AIDS attack rates after 30 months in the same cohort have been previously reported [1], and were as follows: 6.8% in the core-antibody positives versus 35.7% in the core-antibody negatives. 6.9% in the HIV-1-Ag negatives versus 43.9% in the HIV-1-Ag positives, and 6.1% in those with CD4+ lymphocyte counts greater than or equal to 0.5 versus 51.9% in those with CD4+ lymphocyte counts less than 0.5 x 10(9)/l. The disappearance of core antibody, the appearance of antigen and the occurrence of low CD4+ lymphocyte counts preceded AIDS by a mean (s.d.) of 21.3 (8.9), 17.7 (8.8) and 15.7 (8.9) months, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Broad spectrum of coreceptor usage and rapid disease progression in HIV-1-infected individuals from Central African Republic

To study the progression of HIV-1 infection and coreceptor usages in Central African Republic, clinical data, plasma viral load, and coreceptor usage of sequential HIV-1 isolates were analyzed in a seroincident prospective cohort (PRIMOCA). Twenty-three HIV-1 infected individuals from the Central African Armed Forces were followed from 1995 to 2000. Viruses were isolated from 17 patients at various time points after seroconversion and their coreceptor usage was examined using GHOST cells expressing CD4 and one of the HIV-1 chemokine coreceptors CCR5, CXCR4, BOB/GPR15, and Bonzo/STRL33/CXCR6. Eleven patients died from AIDS. Eight of them died between 2 and 5 years after seroconversion, after a brief symptomatic stage. Patients who rapidly progressed to AIDS and death displayed the highest viral loads after seroconversion. All isolates obtained soon after seroconversion used CCR5, albeit, in some cases, CXCR4, BOB, or Bonzo were also used. Most isolates remained R5 (59 out of 61 isolates), although viruses using CXCR4 appeared in some cases of progression to AIDS. In several cases, a broad tropism was observed during the course of infection, with a frequent usage of BOB and Bonzo in addition to CCR5. Rapid progression to disease and short survival time among Central African HIV-1 patients appear more frequent than those reported in industrialized countries. Viral coreceptor used was mainly CCR5, but, interestingly, a large part of isolates also used BOB and Bonzo. However, there was no strict correlation between the clinical outcome and extended viral tropism.