Drug resistance and predicted virologic responses to human immunodeficiency virus type 1 protease inhibitor therapy

The extent to which human immunodeficiency virus (HIV) type 1 drug resistance compromises therapeutic efficacy is intimately tied to drug potency and exposure. Most HIV-1 protease inhibitors maintain in vivo trough levels above their human serum protein binding-corrected IC(95) values for wild-type HIV-1. However, these troughs are well below corrected IC(95) values for protease inhibitor-resistant viruses from patients experiencing virologic failure of indinavir and/or nelfinavir. This suggests that none of the single protease inhibitors would be effective after many cases of protease inhibitor failure. However, saquinavir, amprenavir, and indinavir blood levels are increased substantially when each is coadministered with ritonavir, with 12-h troughs exceeding corrected wild-type IC(95) by 2-, 7-, and 28-79-fold, respectively. These indinavir and amprenavir troughs exceed IC(95) for most protease inhibitor-resistant viruses tested. This suggests that twice-daily indinavir-ritonavir and, to a lesser extent, amprenavir-ritonavir may be effective for many patients with viruses resistant to protease inhibitors.     

Interferon gamma and interleukin 6 modulate the susceptibility of macrophages to human immunodeficiency virus type 1 infection

The effect of interferon gamma (IFN-gamma) and interleukin 6 (IL-6) on infection of macrophages with human immunodeficiency virus type 1 (HIV-1) was investigated. By using a polymerase chain reaction-based viral entry assay and viral infectivity assay, it was demonstrated that IL-6 and IFN-gamma augmented susceptibility of monocyte-derived macrophages (MDMs) to infection with T-cell tropic CXCR4-utilizing (X4) HIV-1 strains. Consistent with this finding, IFN-gamma and IL-6 augmented fusion of MDMs with T-tropic envelope-expressing cells. The enhanced fusion of cytokine-treated MDMs with T-tropic envelopes was inhibited by the CXCR4 ligand, SDF-1, and by T22 peptide. IFN-gamma and IL-6 did not affect expression of surface CXCR4 or SDF-1-induced Ca(++) flux in MDMs. In contrast to the effect of IFN-gamma on the infection of MDMs with X4 strains, IFN-gamma inhibited viral entry and productive infection of MDMs with macrophage-tropic (M-tropic) HIV-1. Consistent with this finding, IFN-gamma induced a decrease in fusion with M-tropic envelopes that correlated with a modest reduction in surface CCR5 and CD4 on MDMs. It was further demonstrated that macrophage inflammatory protein (MIP)-1alpha and MIP-beta secreted by cytokine-treated MDMs augmented their fusion with T-tropic-expressing cells and inhibited their fusion with M-tropic envelope-expressing cells. These data indicate that proinflammatory cytokines, which are produced during opportunistic infections or sexually transmitted diseases, may predispose macrophages to infection with X4 strains that, in turn, could accelerate disease progression.     

Aminooxypentane-RANTES, an inhibitor of R5 human immunodeficiency virus type 1, increases the interferon gamma to interleukin 10 ratio without impairing cellular proliferation.

Studies have demonstrated that the beta-chemokines RANTES, MIP-1alpha, and MIP-1beta suppress human immunodeficiency type 1 (HIV-1) replication in vitro. Infection with HIV-1 requires expression of CD4 antigen and the chemokine receptor CXCR4 (X4) or CCR5 (R5) on the surface of target cells. The engagement of these receptors with the viral surface proteins is essential for the membrane fusion process. This study investigated the anti-HIV-1 activity of a derivative of RANTES, the CCR5 antagonist aminooxypentane (AOP)-RANTES, on R5 HIV-1 isolates in peripheral blood mononuclear cells. In drug exposure experiments, AOP-RANTES efficiently inhibited viral replication of HIV-1 R5 strains, with a viral breakthrough observed after the withdrawal of the compound. The HIV-1-specific proliferative capacity was maintained under all conditions when compared with controls. An increase in IFN-gamma production accompanied by a parallel decrease in the generation of IL-10 was observed following the in vitro exposure of cells to AOP-RANTES in the presence of three of four HIV-1 R5 isolates. These experiments confirmed that the chemokine receptor antagonist AOP-RANTES was effective as an inhibitor of HIV-1 R5 strain infectivity in peripheral blood mononuclear cells. The capacity of this compound to maintain HIV-1-specific proliferative activity with a shift toward a type 1 cytokine profile makes this compound a unique molecule, one adopting an immunological pathway to limit HIV-1 infection.     

Tumor necrosis factor alpha,interleukin 2, and soluble interleukin 2 receptor levels in human immunodeficiency virus type 1-infected individuals receiving intermittent cycles of interleukin 2

HIV-infected individuals with 200-500 CD4(+) T cell/microl were enrolled in a controlled study of three interleukin 2 (IL-2) plus antiretroviral therapy (ART) regimens: (1) continuous intravenous administration of 12 million international units (MIU) of IL-2 followed by subcutaneous high-dose IL-2 (7.5 MIU, twice daily) for 5 days every 8 weeks; (2) high-dose subcutaneous IL-2 for 5 days every 8 weeks; (3) low-dose (3 MIU, twice daily) subcutaneous IL-2 for 5 days every 4 weeks; and (4) ART alone. Serum concentrations of IL-2, soluble IL-2 receptor (sIL-2R), tumor necrosis factor alpha (TNF-alpha), and IL-6 were determined. A progressive decrease over time of the circulating levels of IL-2 was observed in individuals receiving the highest doses of IL-2, but not in those belonging to the low-dose arm. Conversely, increased levels of sIL-2R were observed in all cytokine-treated individuals. The levels of TNF-alpha increased in the high-dose IL-2 regimens, but decreased in individuals receiving low-dose IL-2. IL-2-related toxicity was significantly correlated to the peak IL-2 serum levels, and was substantially lower in those individuals receiving low-dose IL-2. In conclusion, intermittent IL-2 administration causes the elevation of peripheral CD4(+) T cells, but also a profound cytokine response and systemic toxicity. The latter was correlated to the peak serum level of IL-2, but not to those of TNF-alpha and IL-6.     

Secretory leukocyte protease inhibitor in vaginal fluids and perinatal human immunodeficiency virus type 1 transmission

The presence of both viral particles and antiviral mucosal proteins may represent critical determinants of perinatal human immunodeficiency virus type 1 (HIV-1) transmission. In 60 HIV-1-infected women, concentrations of the innate mucosal protein, secretory leukocyte protease inhibitor (SLPI), were lower in vaginal fluid samples from 17 women whose babies became infected than in samples from nontransmitting women (mean+/-SE, 57+/-11 vs. 557+/-177 ng/mL, respectively; P=.01). Rates of transmission among women with higher SLPI concentrations (>100 ng/mL) were lower than those among women with lower concentrations (<100 ng/mL; 8.7% vs. 40.5%, respectively; P=.01). Concentrations of other putative HIV-1-inhibitory innate immune factors were similar in both groups. Concentrations of vaginal HIV-1 tended to be higher in transmitting than in nontransmitting women (407 vs. 174 virions/mL; P=.09). Increased concentrations of selected innate mucosal immune factors, such as SLPI, seem to be associated with reduced rates of perinatal HIV-1 transmission and may contribute to natural antiretroviral defense.     

The effects of protease inhibitor therapy on human immunodeficiency virus type 1 levels in semen (AIDS clinical trials group protocol 850)

Antiretroviral therapy may lead to decreased shedding of human immunodeficiency virus type 1 (HIV-1) in genital secretions. Thirty men, 19 receiving amprenavir and 11 receiving amprenavir, zidovudine, and lamivudine, donated blood and semen while undergoing treatment, to evaluate the effects of these medications on HIV-1 shedding in semen. Before therapy, 4 men had HIV-1 RNA levels in seminal plasma >6.0 log10 (1 million) copies/mL, markedly higher than levels in blood plasma. Most men (77%) had HIV-1 RNA levels in seminal plasma below the limit of quantification during therapy. Amprenavir alone suppressed HIV-1 RNA levels to <400 copies/mL in seminal plasma in the majority of patients, the first direct demonstration of the antiretroviral effects of a protease inhibitor in the male genital tract. However, 8 men (27%) had measurable HIV-1 in seminal plasma at their last study visit, 4 with increasing levels. Persistent replication of HIV in the genital tract may have implications for the selection of resistant virus and sexual transmission of HIV-1.     

Circulating soluble Fas levels in patients with hepatitis C virus infection and interferon therapy

Background The clinical relevance of the circulating soluble form of the Fas-Receptor (sFas) was investigated in patients with hepatitis C receiving type 1 interferon (IFN) therapy.Methods sFas was quantified by enzyme-linked immunosorbent assay in 66 hepatitis C virus (HCV) carriers and 30 HCV-naive or previously infected controls. The levels were then monitored during enhanced treatment with type 1 IFNs in 15 chronic hepatitis C patients.Results The HCV carriers had high levels of sFas compared with controls (3.8 ± 1.3 vs 2.7 ± 0.8ng/ml; P < 0.001). sFas levels in patients with chronic HCV infection were directly related to serum alanine aminotransferase levels (r = 0.440; P < 0.001) and the histological grade (r = 0.403; P = 0.019). Among necroinflammatory reactions, only piecemeal necrosis showed a correlation with sFas levels (r = 0.556; P = 0.001). Pretreatment sFas levels, however, were not predictive of therapeutic outcomes. A sustained virological response to enhanced IFN therapy showed a relation to only the pretreatment HCV load. Interestingly, circulating sFas was upregulated when IFN- was administered at short intervals (3MU/every 12h). This upregulation was accompanied by parallel aminotransferase elevation, which was observed regardless of a virological response.Conclusions sFas elevation, in parallel with the severity of liver injury, suggests the possible upregulation of hepatic Fas expression and the Fas-mediated pathway in both HCV- and type 1 IFN-induced liver injury. The essential function of sFas to protect hepatocytes against Fas-mediated liver injury was not evident in these clinical settings.     

Activation of beta-chemokines and CCR5 in persons infected with human immunodeficiency virus type 1 and tuberculosis

Tuberculosis (TB) in human immunodeficiency virus type 1 (HIV-1)-infected persons is associated with progression of HIV-1 disease. The expression of macrophage inflammatory protein (MIP)-1alpha and CCR5 was assessed in HIV-1-infected patients with pulmonary TB (HIV-1/PTB) and without PTB (HIV-1/C), PTB patients not infected with HIV-1 (PTB), and control subjects. Mycobacterium tuberculosis (MTB)-induced MIP-1alpha production was lower in peripheral blood mononuclear cells (PBMC) of HIV-1/PTB patients than in those of PTB patients (P< .05) and was lower in PBMC of HIV-1/C patients than in those of control subjects (P< .005). However, MIP-1alpha production was higher in PBMC of HIV/PTB patients than in those of HIV-1/C patients (P< .01). The pattern of MTB-induced RANTES production was similar to that of MIP-1alpha. However, MTB induced greater expression of mRNA for CCR5 in PBMC of HIV-1/PTB patients than in those of HIV-1/C patients (P< .04). Furthermore, the MTB-induced HIV p24 antigen level in PBMC of HIV-1/PTB patients with a CD4 cell count <500 cells/microL was higher (P< .05) than that in HIV-1/C patients. Thus, perturbations in chemokine pathways in HIV-1/PTB patients may accelerate HIV-1 disease.     

The danish protease inhibitor study: a randomized study comparing the virological efficacy of 3 protease inhibitor-containing regimens for the treatment of human immunodeficiency virus type 1 infection

The Danish Protease Inhibitor (PI) Study has enrolled 318 human immunodeficiency virus (HIV)-infected, PI-naive patients for the purpose of comparing 3 PI-containing regimens for the treatment of HIV infection. The regimens include 2 nucleoside analogues in combination with indinavir (Idr), ritonavir (Rtv), or Rtv and saquinavir (Rtv/Sqv). Similar percentages of patients in the 3 study arms achieved reduced levels (相似文献   

Mycobacterium gordonae: a possible opportunistic respiratory tract pathogen in patients with advanced human immunodeficiency virus, type 1 infection

STUDY OBJECTIVE: To determine if Mycobacterium gordonae is an opportunistic respiratory tract pathogen in patients infected with human immunodeficiency virus, type 1 (HIV-1). DESIGN: Retrospective review of medical records of all patients with positive cultures for M gordonae from 1987 to 1989. PATIENTS: Fifteen patients had positive sputum cultures for M gordonae: five patients had AIDS or had HIV-1 infections with less than or equal to 180 CD4 cells/cu mm, and ten patients had no clinical evidence of HIV-1 infection. RESULTS: Three of the five HIV-1 infected patients had clinical, roentgenographic, and microbiologic evidence of pulmonary infection due to M gordonae that responded to antimycobacterial therapy. One of the two remaining HIV-1 infected patients had disseminated M tuberculosis and possible coinfection with M gordonae, and the other was lost to follow-up. None of the ten patients without evidence of HIV-1 infection was considered to have M gordonae respiratory tract infection. CONCLUSIONS: Sputum isolates of M gordonae should be considered potential opportunistic respiratory tract pathogens in patients with advanced HIV-1 infection and with otherwise unexplained pulmonary infection.     

Trans-dominant inhibitory human immunodeficiency virus type 1 protease monomers prevent protease activation and virion maturation.

Production of infectious human immunodeficiency virus (HIV) requires proper polyprotein processing by the dimeric viral protease. The trans-dominant inhibitory activity of a defective protease monomer with the active site Asp-25 changed to Asn was measured by transient transfection. A proviral plasmid that included the drug-selectable Escherichia coli gpt gene was used to deliver the wild-type (wt) or mutant proteases to cultured cells. Coexpression of the wt proviral DNA (HIV-gpt) with increasing amounts of the mutant proviral DNA (HIV-gpt D25N) results in a concomitant decrease in proteolytic activity monitored by in vivo viral polyprotein processing. The viral particles resulting from inactivation of the protease were mostly immature, consisting predominantly of unprocessed p55gag and p160gag-pol polyproteins. In the presence of HIV-1 gp160 env, the number of secreted noninfectious particles correlated with the presence of increasing amounts of the defective protease. Greater than 97% reduction in infectivity was observed at a 1:6 ratio of wt to defective protease DNA. This provides an estimate of the level of inhibition required for effectively preventing virion processing. Stable expression of the defective protease in monkey cells reduced the yield of infectious particles from these cells by 90% upon transfection with the wt proviral DNA. These results show that defective subunits of the viral protease exert a trans-dominant inhibitory effect resulting from the formation of catalytically compromised heterodimers in vivo, ultimately yielding noninfectious viral particles.     

The effect of highly active antiretroviral therapy on binding and neutralizing antibody responses to human immunodeficiency virus type 1 infection

The effect on humoral immune responses of highly active antiretroviral therapy (HAART) commenced during primary or chronic human immunodeficiency virus type 1 (HIV-1) infection was investigated. HAART inhibited the development of anti-gp120 antibodies when initiated during primary infection and could sometimes reduce antibody titers in patients treated within 2 years of HIV-1 infection. Conversely, antibody responses in patients infected for several years were less sensitive to HAART. Administering HAART during primary infection usually did not substantially affect the development of weak neutralizing antibody responses against autologous virus. However, 2 patients treated very early after infection did not develop neutralizing responses. In contrast, 3 of 4 patients intermittently adherent to therapy developed autologous neutralizing antibodies of unusually high titer, largely coincident with brief viremic periods. The induction of strong neutralizing antibody responses during primary HIV-1 infection might require the suppression of virus replication by HAART, to allow for the recovery of immune competency, followed by exposure to native envelope glycoproteins.     

Ex vivo and in vitro effect of human immunodeficiency virus protease inhibitors on neutrophil apoptosis

Polymorphonuclear leukocytes (PMNL) from human immunodeficiency virus (HIV)-infected patients exhibit accelerated apoptosis and impaired functional activity. HIV protease inhibitor-based therapy produces improvements in both acquired and innate immune responses. Ex vivo and in vitro effects of HIV protease inhibitors on apoptosis and chemotaxis of PMNL were evaluated. After therapy, there was a rapid and significant decrease of PMNL apoptosis, which correlated with increased chemotactic function. These findings were found both in patients with immunological and virological response and in control subjects who showed an increase in CD4(+) T cell counts but no concomitant decline in HIV load. After in vitro treatment with ritonavir or indinavir, apoptosis of both HIV-infected and -uninfected PMNL markedly decreased and correlated with significant enhancement of chemotaxis. These results suggest that HIV protease inhibitors may improve the PMNL function by reducing the apoptosis rate and that this effect may, at least in part, be independent of their antiviral activity.     

Recent herpes simplex virus type 2 infection and the risk of human immunodeficiency virus type 1 acquisition in India

To estimate the impact of prevalent and incident herpes simplex virus type 2 (HSV-2) infection on the acquisition of human immunodeficiency virus type 1 (HIV-1), stored serum samples from a cohort of 2732 HIV-1-seronegative patients attending 3 sexually transmitted infection clinics and 1 reproductive tract infection clinic in Pune, India, were screened for HSV-2-specific antibodies. Incident HSV-2 infection was defined serologically as "recent" if a negative result of testing for HSV-2 could be documented within the previous 6 months or "remote" if >6 months had elapsed since the last negative test result. The prevalence of HSV-2 at enrollment was 43%. The HSV-2 incidence was 11.4 cases/100 person-years, and the HIV-1 incidence was 5.8 cases/100 person-years. The adjusted hazard ratios of HIV-1 acquisition from exposure to HSV-2 infection were 1.67 for prevalent HSV-2, 1.92 for remote incident HSV-2, and 3.81 for recent incident HSV-2. Recent incident HSV-2 infection was associated with the highest risk of HIV-1 in this study, which suggests that prevention of HSV-2 infection may reduce the risk of HIV-1 acquisition.