河北省治疗前人群HIV-1耐药毒株分子传播网络研究

目的 了解河北省抗病毒治疗前人群HIV-1耐药毒株流行与分子传播网络情况。方法 用in-house的方法扩增HIV-1 pol区基因序列,并利用TN93模型计算pol序列基因距离,构建HIV-1分子网络图。结果 研究发现17名HIV-1感染者出现耐药突变,耐药突变率为6.16%(17/276),其中,NNRTI类耐药率为4.35%(12/276),PI类耐药率为1.09%(3/276), NRTI类耐药率为0.36%(1/276),NNRTI类和PI类双重耐药率为0.36%(1/276);多因素Logistic回归分析显示年龄和亚型是HIV-1产生耐药的影响因素,虽然HIV-1耐药突变在CRF07_BC(2.44%)亚型中的分布明显低于CRF01_AE(8.03%)和B(3.70%)亚型,然而CRF07_BC序列构建的分子传播网络最多,传播速度最快。结论 河北省治疗前HIV-1耐药突变处于较高水平, 应制定措施实时监测未治疗人群中HIV-1耐药毒株流行情况。     

Viral load and burden modification following early antiretroviral therapy of primary HIV-1 infection.

OBJECTIVE: The aim of this study was to monitor the effect on viral DNA and RNA of early treatment with highly aggressive antiretroviral therapy (HAART), in comparison with zidovudine (ZDV) monotherapy or no treatment in subjects with primary HIV-1 infection (PHI). DESIGN AND METHODS: Of the 28 patients selected, four were untreated, four received ZDV alone, 10 received a triple combination (ZDV, lamivudine (3TC) and saquinavir (SQV)) and 10 received a quadruple combination (ZDV, 3TC, SQV and ritonavir (RTV)). Seroconversion was monitored by means of Western blot profile analysis. A quantitative polymerase chain reaction (PCR) assay in the HIV gag region was used to monitor viral DNA and the nucleic acid sequence based amplification (NASBA) system for viraemia (HIV-RNA). RESULTS: There was a certain level of heterogeneity in the baseline values of HIV-DNA and RNA. Early HAART led to a rapid recovery in the number of CD4 cells and the CD4/CD8 cell ratio and a reduction in HIV-RNA to undetectable levels, which was significantly greater than in the untreated patients or those treated with ZDV. Although a reduction in DNA levels was also observed in the HAART-treated subjects, this variation was not significant. CONCLUSIONS: The parameters of viral replication and CD4 cell recovery were only slightly better in the patients receiving ZDV monotherapy than in the untreated patients, thus confirming that the course of the infection is hardly affected by the monotherapy. The early introduction of HAART greatly reduces plasma viraemia and restores the number of CD4 cells for up to 1 year. HIV-DNA remains detectable, although at low levels, thus confirming that the early established reservoir of infected cells is little affected. Longer periods of observation and the introduction of complementary approaches, such as immunomodulatory therapies, will provide further information concerning the possibility of radically interfering with the natural evolution of the disease.     

Correlates of HIV-1 shedding in cervicovaginal secretions and effects of antiretroviral therapies

OBJECTIVES: To evaluate the determinants of HIV-1 RNA shedding in cervicovaginal secretions and the effects of antiretroviral therapy in a group of infected women. METHODS: A total of 122 women from whom paired peripheral blood and cervicovaginal lavage samples were available were enrolled in the study. HIV-1 RNA was quantified in the plasma and cell-free fraction of cervicovaginal lavages by the nucleic acid sequence-based amplification assay (lower limit of detection 80 copies/ml). RESULTS: Seventy-one per cent of the women had detectable viral load in the cervicovaginal lavage and this appeared to be correlated to plasma viral load and to the degree of immunodeficiency as expressed by the absolute number of CD4 cells. Antiretroviral-treated patients had a lower risk of shedding the virus in the genital tract, but this association was limited to patients treated with highly active antiretroviral therapy (HAART). However, in 25% of women with undetectable plasma viral load, a genital shedding of the virus was demonstrated. CONCLUSION: Plasma viral load may fail as a marker of infectivity of genital secretions. HAART treatment seems to be more efficacious in suppressing viral shedding at the genital level. The female genital tract represents a distinct compartment for HIV-1 replication/evolution.     

The effect of atorvastatin treatment on HIV-1-infected patients interrupting antiretroviral therapy

We conducted a pilot study to assess the effect of atorvastatin on HIV replication. Patients with stable HAART-controlled infection interrupted therapy and were randomly assigned to a control group or to start atorvastatin 40 or 80 mg/day. Statin groups showed lower serum cholesterol but similar viral loads and CD4 T-cell counts to the control group at weeks 4 and 12. Paradoxically, baseline serum cholesterol, but not atorvastatin, influenced viral rebound at week 4.     

Prospective evaluation of the effects of antiretroviral therapy on body composition in HIV-1-infected men starting therapy

OBJECTIVE: Little prospective data are published on the natural history of HIV-associated lipodystrophy (HIVLD) in individuals beginning their first antiretroviral regimen. To investigate this a study was designed to explore changes in body composition occurring with antiretroviral therapy. STUDY DESIGN: A non-randomized, prospective, exploratory study of 40, HIV-infected men, naive to treatment, beginning antiretroviral therapy. Regular assessments of body composition, and metabolic and immunological parameters were performed. RESULTS: Mean follow-up was 96 (SD 45) weeks of therapy. There were increases in limb fat, central abdominal fat and lean mass over the initial 24 weeks of therapy followed by a selective, progressive loss of limb fat from week 24. There was a median 13.6% [interquartile range (IQR), 0.9-26.3] loss of limb fat per year from week 24 onwards. Treatment with stavudine, higher baseline HIV RNA, higher baseline 'T' score and lower week 24 lean mass were associated with higher rate of limb fat loss from week 24. In multivariate analysis, treatment with stavudine was the strongest independent factor associated with rate of limb fat loss (P = 0.05). Hypercholesterolaemia developed early in treatment, whereas hypertriglyceridaemia, hyperinsulinaemia and decreased bone mineral density developed later. The largest changes in CD4 cell counts and HIV viral load, seen early into treatment, were associated with gain rather than loss of fat. CONCLUSIONS: This is the first prospective study demonstrating that treatment with antiretrovirals results in progressive, selective loss of limb fat. Loss of limb fat occurred after the period of most intense immune restoration, making an immune aetiology unlikely.     

The effects of HIV-1 infection on endocrine organs

Early in the HIV epidemic, multiple endocrine and metabolic abnormalities were observed in HIV-infected patients. These abnormalities were either related glandular infection or infiltration with opportunistic diseases or the effects of systemic inflammation and severe illness on hormonal function and metabolic homeostasis. This review describes the epidemiology and pathogenesis of dyslipidemia, disorders of bone homeostasis, and dysfunction of the adrenal, gonadal, and thyroid axes in the untreated HIV-infected patient. While this review is most applicable to the HIV epidemic in the developing world where effective antiretroviral therapy is not available, understanding the effect of systemic inflammation on endocrine and metabolic function in the untreated HIV-infected person has valuable lessons for the pathogenesis of endocrine disease in HIV-infected patients receiving antiretroviral treatment.     

A conditionally replicating HIV-1 vector interferes with wild-type HIV-1 replication and spread.

Defective-interfering viruses are known to modulate virus pathogenicity. We describe conditionally replicating HIV-1 (crHIV) vectors that interfere with wild-type HIV-1 (wt-HIV) replication and spread. crHIV vectors are defective-interfering HIV genomes that do not encode viral proteins and replicate only in the presence of wt-HIV helper virus. In cells that contain both wt-HIV and crHIV genomes, the latter are shown to have a selective advantage for packaging into progeny virions because they contain ribozymes that cleave wt-HIV RNA but not crHIV RNA. A crHIV vector containing a triple anti-U5 ribozyme significantly interferes with wt-HIV replication and spread. crHIV vectors are also shown to undergo the full viral replicative cycle after complementation with wt-HIV helper-virus. The application of defective interfering crHIV vectors may result in competition with wt-HIVs and decrease pathogenic viral loads in vivo.     

Effect of highly active antiretroviral therapy on cervicovaginal HIV-1 RNA

OBJECTIVES: To determine the frequency of cervicovaginal lavage and plasma HIV-1 RNA levels that are below detectable levels (< 400 copies/ml) among women on highly active antiretroviral therapy (HAART), non-HAART and on no therapy. To compare the effect of initiating HAART on the timing of HIV-1 RNA suppression in the blood plasma and genital tract among antiretroviral-na?ve women. METHODS: Data were obtained from 205 HIV-infected women with paired plasma and cervicovaginal lavage viral load measurements. Seven antiretroviral-na?ve women starting HAART had viral load measurements performed daily for one week, at 2 weeks and at 1 month after initiating therapy. Viral load quantification was carried out by nucleic acid sequence-based amplification assay. The lower limit of detection was 400 copies/ml. RESULTS: Plasma and cervicovaginal HIV-1 RNA was detectable in 71 and 26% of the women, respectively. Among women with plasma viral loads less than 400, 400-9999, and 10,000 copies/ml or over, genital tract HIV-1 RNA was detected in 3, 17 and 48%, respectively (P < 0.001). Fifty-one per cent of the women with CD4 cell counts of less than 200/mm3 had detectable cervicovaginal viral loads compared with 18% among women with CD4 cell counts of 200/mm3 or over (P < 0.001). Cervicovaginal HIV-1 RNA was less than 400 copies/ml in 85% of those on HAART, 69% of those on non-HAART and 69% of those on no therapy (P < 0.045). In seven antiretroviral-na?ve women initiating HAART, cervicovaginal HIV-1 RNA decreased by 0.7-2.1 log10 within 1-14 days of starting therapy. CONCLUSION: The cervicovaginal HIV-1 RNA level was positively correlated with plasma HIV-1 RNA and negatively with the CD4 cell count. The use of HAART was significantly associated with below-detectable levels of HIV-1 RNA in both plasma and the genital tract. HIV-1 RNA suppression in the genital tract may occur rapidly after initiating therapy.     

Structured treatment interruptions in antiretroviral management of HIV-1

The consequences of treatment interruptions have been investigated in various patient populations. For patients with controlled viraemia, treatment interruption allowing viral rebound may boost HIV-1-specific immunity. The hypothesis that this will be sufficient to control HIV replication in the absence of treatment has received support in studies of patients initiating treatment during primary infections. In patients with chronic infection, treatment interruption has been shown to boost HIV-1-specific immunity in some cases. In patients with virological failure, despite drug-resistant virus, treatment appears to provide benefit, in that interruption results in a decrease in the CD4 cell count and increases in plasma HIV-1-RNA levels. The removal of drug pressure allows the rapid shift to wild-type virus. Whether this will be of benefit to the patient is not clear. Treatment interruption may help reduce the accumulation of long-term toxicities.     

HIV-1 and bacterial pneumonia in the era of antiretroviral therapy

Community-acquired pneumonia affects approximately 4 million people in the United States, with 40,000 deaths per year. The incidence is increased about 35-fold in HIV-infected individuals, and this rate has decreased since the antiretroviral era has begun. Bacterial pneumonia has decreased from 5 to 20 cases per 100 person-years to less than 1 to 5 cases per 100 person-years in the era of antiretroviral therapy. HIV-1 infection impairs the function of neutrophils in the lung and infects CD4? cells and alveolar macrophages. Opportunistic infections dramatically increase local HIV replication in the lung cells, especially alveolar macrophages and CD4? cells. This enhanced replication increases viral mutations and provides opportunities for viral escape from latent reservoirs. Mortality is increased with more comorbidities in this highly susceptible population. Immunization with vaccines is recommended, especially pneumococcal vaccines, although the vaccine itself may stimulate viral replication. Recent studies show that the lower respiratory tract is a microbial reservoir in HIV-infected individuals rather than being a sterile environment, as originally thought. This may provide new opportunities for preventing opportunistic infections in HIV-infected subjects. Bacterial pneumonia presents an ongoing challenge in these high-risk individuals, particularly in studying the functions of the innate and acquired immune response.     

The immunological effects of concomitant highly active antiretroviral therapy and liposomal anthracycline treatment of HIV-1-associated Kaposi's sarcoma

A combination of highly active antiretroviral therapy (HAART) and liposomal anthracycline chemotherapy is the standard of care for advanced HIV-associated Kaposi's sarcoma, despite concerns that the chemotherapy may adversely affect lymphocyte subsets and HIV viraemia. We showed in 50 patients that liposomal anthracyclines used with HAART did not lead to a significant loss of CD4 or CD8 cells or an increase in HIV-1 viral load during or up to 12 months after chemotherapy.     

The effects of antiretroviral therapy on HIV-1 RNA loads in seminal plasma in HIV-positive patients with and without urethritis.

BACKGROUND: High seminal plasma HIV-1 RNA loads (SVL) have been reported during gonococcal, non-gonococcal and chlamydial urethritis in patients not taking antiretroviral therapy. OBJECTIVE: To examine if urethritis leads to increased SVL in HIV-positive patients taking antiretroviral therapy. METHODS: Men who had been taking therapy for at least 3 months were recruited: 24 had urethitis (PWU) and 16 were without urethritis (controls). At three visits, 1 week apart, blood plasma viral load (BVL) and SVL were assayed by quantitative polymerase chain reaction or the NASBA assay. RESULTS: Most subjects had undetectable SVL (18 PWU, 13 controls). Among those with undetectable BVL prior to first study visit, virus was undetectable in semen in 5/5 episodes of chlamydial urethritis, 6/7 episodes of non-gonococcal urethritis and 4/5 cases of gonococcal urethritis. Two PWU with undetectable BVL just prior to the first study visit had low to moderate SVL, which became undetectable by visit 2 following treatment. Of nine subjects with detectable SVL, eight had detectable BVL (3/3 controls and 5/6 PWU). Of these, 1/3 controls and 4/5 PWU (all with gonococcal urethritis) had poorly controlled BVL just prior to the first study visit. These four PWU had high SVL and one had higher levels in semen than in blood. This patient's SVL was reduced more than 20-fold following treatment for gonococcal urethritis. CONCLUSIONS: Effective antiretroviral therapy appeared to limit the effect of urethritis on SVL. When BVL was poorly controlled by antiretroviral therapy, high SVL occurred during gonococcal urethritis, increasing the potential risk of transmitting both wild type and drug resistant strains of HIV-1.