Biomedical subjects

W A O'Brien

Publications and source records attributed to W A O'Brien.

At least 19 recordsLinked to original sources

PubMed2001

Randomized trial of the quantitative and functional antibody responses to a 7-valent pneumococcal conjugate vaccine and/or 23-valent polysaccharide vaccine among HIV-infected adults.

In a double-blinded, randomized trial, human immunodeficiency virus (HIV)-infected adults with > or = 200 CD4 cells/microl received placebo (PL), 7-valent conjugate, or 23-valent pneumococcal polysaccharide (PS) vaccine in one of the following two-dose combinations given 8 weeks apart: conjugate-conjugate, conjugate-polysaccharide, placebo-polysaccharide, placebo-placebo. A total of 67 persons completed the study. Neither significant increases in HIV viral load nor severe adverse reactions occurred in any group. After controlling for confounders, when compared with persons receiving placebo-polysaccharide, persons receiving conjugate-conjugate and conjugate-polysaccharide had higher antibody concentrations (serotypes 4, 6B, 9V and serotype 23F, respectively) and opsonophagocytic titers (functional antibody assay, serotypes 9V, 23F and serotypes 4, 6B, 9V, respectively) after the second dose (P<0.05). The second dose with either conjugate or polysaccharide following the first conjugate dose, however, produced no further increase in immune responses.

Adult↗

PubMed2001

Sensitivity of human immunodeficiency virus type 1 to fusion inhibitors targeted to the gp41 first heptad repeat involves distinct regions of gp41 and is consistently modulated by gp120 interactions with the coreceptor.

T-20 is a synthetic peptide that corresponds to 36 amino acids within the C-terminal heptad repeat region (HR2) of human immunodeficiency virus type 1 (HIV-1) gp41. T-20 has been shown to potently inhibit viral replication of HIV-1 both in vitro and in vivo and is currently being evaluated in a Phase III clinical trial. T-649 is an inhibitory peptide that also corresponds to 36 amino acids within HR2. This sequence overlaps the T-20 sequence but is shifted 10 residues toward the N terminus of gp41. Both inhibitors are thought to exert their antiviral activity by interfering with the conformational changes that occur within gp41 to promote membrane fusion following gp120 interactions with CD4 and coreceptor molecules. We have shown previously that coreceptor specificity defined by the V3 loop of gp120 modulates sensitivity to T-20 and that a critical region within the N-terminal heptad repeat (HR1) of gp41 is the major determinant of sensitivity (C. A. Derdeyn et al., J. Virol. 74:8358-8367, 2000). This report shows that (i) regions within gp41 distinct from those associated with T-20 sensitivity govern the baseline sensitivity to T-649 and (ii) T-649 sensitivity of chimeric viruses that contain sequences derived from CXCR4- and CCR5-specific envelopes is also modulated by coreceptor specificity. Moreover, the pattern of sensitivity of CCR5-specific chimeras with only minor differences in their V3 loop was consistent for both inhibitors, suggesting that the individual affinity for coreceptor may influence accessibility of these inhibitors to their target sequence. Finally, an analysis of the sensitivity of 55 primary, inhibitor-naive HIV-1 isolates found that higher concentrations of T-20 (P < 0.001) and T-649 (P = 0.016) were required to inhibit CCR5-specific viruses compared to viruses that utilize CXCR4. The results presented here implicate gp120-coreceptor interactions in driving the complex conformational changes that occur in gp41 to promote fusion and entry and suggest that sensitivity to different HR1-directed fusion inhibitors is governed by distinct regions of gp41 but is consistently modulated by coreceptor specificity.

Amino Acid Sequence↗

PubMed2000

Resistance to apoptosis in HIV-infected CD4+ T lymphocytes is mediated by macrophages: role for Nef and immune activation in viral persistence.

Apoptosis or programmed cell death may play a critical role in AIDS pathogenesis through depletion of both CD4(+) and CD8(+) T lymphocytes. Using a reporter virus, a recombinant HIV infectious clone expressing the green fluorescent protein (GFP), apoptosis was measured in productively infected CD4(+) T lymphocytes, in the presence and absence of autologous macrophages. The presence of macrophages in the culture increased the frequency of nonapoptotic GFP-positive productively infected CD4(+) T lymphocytes. The appearance of nonapoptotic productively infected CD4(+) T lymphocytes in the culture required intercellular contacts between macrophages and PBLs and the expression of the HIV Nef protein. The presence of macrophages did not reduce apoptosis when CD4(+) T lymphocytes were infected with a GFP-tagged virus deleted for the nef gene. TNF-alpha (TNF) expressed on the surface of macrophages prevented apoptosis in nef-expressing, productively infected CD4(+) T lymphocytes. Similarly, following TNF stimulation, apoptosis was diminished in Jurkat T cells transfected with a nef-expressing plasmid. TNF stimulation of nef-expressing Jurkat T cells resulted in NF-kappaB hyperactivation, which has been shown to deliver anti-apoptotic signals. Our results indicate that intercellular contacts with macrophages increase the rate of productively infected nonapoptotic CD4(+) T lymphocytes. The survival of productively infected CD4(+) T lymphocytes requires Nef expression as well as activation by TNF expressed on the surface of macrophages and might participate in the formation and maintenance of viral reservoirs in HIV-infected persons.

Animals↗

PubMed2000

Comparison of immunologic restoration and virologic response in plasma, tonsillar tissue, and cerebrospinal fluid in HIV-1-infected patients treated with double versus triple antiretroviral therapy in very early stages: The Spanish EARTH-2 Study. Early Anti-Retroviral Therapy Study.

The objective of antiretroviral therapy is to obtain an almost complete and durable suppression of viral replication in all compartments to facilitate recovery of the immune system. We assessed the virologic effect in plasma, tonsillar tissue, and cerebrospinal fluid (CSF) in 94 HIV-1-infected patients with CD4 counts >500 x 106 cells per liter and viral load >5000 copies/ml randomly assigned to triple antiretroviral therapy (two nucleoside reverse transcriptase inhibitors (NRTIs) plus one protease inhibitor) versus double therapy (two NRTIs). We also analyzed the immunologic recovery in this cohort of patients. Lymphoid tissue and cerebrospinal fluid viral load, development of genotypic resistance, proliferative responses to HIV-1 specific antigens, and other immunophenotypic markers were analyzed. The proportion of patients who achieved a decrease in HIV RNA levels to <200 copies/ml was significantly greater in the triple therapy group than in the two drug groups (p =.0002 for each pair-wise difference). At week 52, tonsillar tissue HIV RNA from 5 patients treated with triple therapy was lower than the limit of detection, whereas the mean +/- standard error in patients with double therapy (n = 5) was 5.03 +/- 0.34 copies/mg/tissue. In all 10 patients, CSF viral load (VL) was <20 HIV-1 RNA copies/ml at week 52. CSF cell counts and protein levels tended to decrease after 52 weeks of antiretroviral therapy. After 1 year of therapy, 13 of 21 patients (62%) in the double-therapy groups (zidovudine plus lamivudine [n = 9] and stavudine plus lamivudine [n = 12]) had evidence of M184V mutation. None of the 10 samples of patients receiving triple therapy could be amplified because of low HIV RNA levels. The mean increase in CD4 cells at week 52 was greater in the stavudine and lamivudine and indinavir group than in the double-treatment arms (186 versus 67 and 102, respectively; p =.03). In patients treated with triple therapy, the increase in naive T cells (CD4 and CD8) was greater than in patients treated with double therapy. Markers of activation decreased further in patients treated with the regimen that included protease inhibitors. Proliferative responses to HIV-1 p24 antigen were never recovered after double or triple therapy. Our study suggests that even in very early stages of HIV-1 disease only therapy with two NRTIs and one protease inhibitor reduces plasma, lymphoid tissue, and CSF VL to undetectable levels. HIV-1-related immune system abnormalities improved but were still defective after 1 year of antiretroviral therapy.

Adult↗

PubMed2000

Resistance against reverse transcriptase inhibitors.

The response to antiretroviral therapy in human immunodeficiency virus (HIV)-infected patients is limited by the emergence of drug resistance. This resistance is a consequence of the high rate of HIV mutation, the high rate of viral replication (especially when potent multidrug therapies are not used or taken reliably), and the selective effect of these drugs, which favors emergence of mutations that can establish clinical drug resistance. The introduction of highly active antiretroviral therapy (HAART), which typically includes at least 2 nucleoside reverse transcriptase inhibitors (RTIs) and a protease inhibitor or a nonnucleoside RTI, for most treatment-naive patients results in a reduction of viral load below the limit of detection determined by currently available HIV RNA assays. It is this marked reduction that results in durable viral suppression, usually only possible by the simultaneous use of 3 or 4 drugs. The RTI components of HAART are crucial for these benefits of combination therapy. Specific amino acid changes are associated with resistance to several RTIs, but new mutation complexes have been observed that can confer broad cross-resistance within this class. Genotypic and phenotypic resistance assays to measure drug resistance are being developed, but refinements in both methodology and our ability to interpret results of these assays are necessary before they are introduced into widespread clinical use.

Anti-HIV Agents↗

PubMed2000

Sensitivity of human immunodeficiency virus type 1 to the fusion inhibitor T-20 is modulated by coreceptor specificity defined by the V3 loop of gp120.

T-20 is a synthetic peptide that potently inhibits replication of human immunodeficiency virus type 1 by interfering with the transition of the transmembrane protein, gp41, to a fusion active state following interactions of the surface glycoprotein, gp120, with CD4 and coreceptor molecules displayed on the target cell surface. Although T-20 is postulated to interact with an N-terminal heptad repeat within gp41 in a trans-dominant manner, we show here that sensitivity to T-20 is strongly influenced by coreceptor specificity. When 14 T-20-naive primary isolates were analyzed for sensitivity to T-20, the mean 50% inhibitory concentration (IC(50)) for isolates that utilize CCR5 for entry (R5 viruses) was 0.8 log(10) higher than the mean IC(50) for CXCR4 (X4) isolates (P = 0. 0055). Using NL4.3-based envelope chimeras that contain combinations of envelope sequences derived from R5 and X4 viruses, we found that determinants of coreceptor specificity contained within the gp120 V3 loop modulate this sensitivity to T-20. The IC(50) for all chimeric envelope viruses containing R5 V3 sequences was 0.6 to 0.8 log(10) higher than that for viruses containing X4 V3 sequences. In addition, we confirmed that the N-terminal heptad repeat of gp41 determines the baseline sensitivity to T-20 and that the IC(50) for viruses containing GIV at amino acid residues 36 to 38 was 1.0 log(10) lower than the IC(50) for viruses containing a G-to-D substitution. The results of this study show that gp120-coreceptor interactions and the gp41 N-terminal heptad repeat independently contribute to sensitivity to T-20. These results have important implications for the therapeutic uses of T-20 as well as for unraveling the complex mechanisms of virus fusion and entry.

Anti-HIV Agents↗

PubMed2000

Tumor necrosis factor (TNF)-alpha and TNF receptors in viral pathogenesis.

Tumor necrosis factor-alpha (TNF-alpha) and TNF receptors (TNFR) are members of the growing TNF ligand and receptor families that are involved in immune regulation. The present report will focus on the role of the prototypic ligand TNF and its two receptors, TNFR1 and TNFR2, in viral pathogenesis. Although TNF was reported years ago to modulate viral infections, recent findings on the molecular pathways involved in TNFR signaling have allowed a better understanding of the molecular interactions between cellular and viral factors within the infected cell. The interactions of viral proteins with intracellular components downstream of the TNFR have highlighted at the molecular level how viruses can manipulate the cellular machinery to escape the immune response and to favor the spread of the infection. We will review here the role of TNF and TNFR in immune response and the role of TNF and TNFR signaling in viral pathogenesis.

DNA Viruses↗

PubMed1999

A randomized study comparing triple versus double antiretroviral therapy or no treatment in HIV-1-infected patients in very early stage disease: the Spanish Earth-1 study.

BACKGROUND: Most current guidelines state that antiretroviral therapy should be considered for HIV-infected patients with plasma HIV RNA > 5000-10000 copies/ml and CD4 cells > 500 x 10(6) cells/l. However, there is increasing concern about whether this is the optimal point to begin treatment or whether it is better to delay the initiation to more advanced stages. OBJECTIVE: To study the immunological and virological benefits of starting antiretroviral therapy at these early stages. METHODS: A total of 161 HIV-infected asymptomatic patients with CD4 cell count > 500 x 10(6) cells/l and viral load > 10000 copies/ml were randomly assigned to one of five treatment groups: no treatment, twice daily zidovudine and thrice daily zalcitabine (ZDV-ddC), twice daily zidovudine and didanosine (ZDV-ddI), twice daily stavudine and didanosine (D4T-ddI), or a twice daily three-drug regimen with stavudine and lamivudine and ritonavir. The endpoints were progression to < 350 x 10(6) cells/l CD4 cells, to < 500 x 10(6) cells/l with either two Centers for Disease Control class B symptoms or an increase of viral load > 0.5 log10 copies/ml above baseline, or to AIDS or death. In various substudies, the lymphoid tissue and cerebrospinal fluid viral load, development of genotypic resistance, proliferative responses to mitogens and cytomegalovirus, and HIV-1 specific antigens and other immunophenotypic markers were also analysed. RESULTS: Progression rates to study endpoints within 1 year were greater in the control group (31%) than in all groups receiving antiretroviral therapy pooled together (5%; estimated hazard ratio 7.41; 95% confidence interval 5.72-74.55; P < 0.001). The peak mean viral load decrease was greater in the three-drug group when compared with any of the three groups with a two-drug regimen (2.32, 1.65, 1.72 and 1.84, respectively; P < or = 0.001). At 1 year, viral load remained below 20 copies/ml in 30 out of 33 patients in the three-drug group (91%) and in only eight out of 94 patients (9%) in two-drug groups (P = 0.001). The peak mean increase in CD4 cells was also greater in the three-drug group than in the double treatment arms (259 versus 85, 144 and 145 x 10(6) cells/l, respectively; P = 0.001). By comparison, 36% of patients in the three-drug group regimen had to change the therapy as a result of adverse events. Substudies were performed in 60 patients recruited at two sites. Tonsillar tissue HIV RNA was measured in seven patients (two in the two-drug groups and five in the three-drug group) in whom plasma HIV RNA was < 20 copies/ml at 1 year. It was 15151 and 133333 copies/mg tissue in the two patients from the two-drug group, < 40 copies/mg tissue in four patients in the three-drug group, and 485 copies/mg in one patient in the three-drug group. At 1 year there was a mean increase of 4.21+/-2.94% in CD8+CD38+ cells in the control group and a decrease of 9.48+/-3.36% in the two-drug groups (P = 0.01), and 19.87+/-3.64 in the three-drug group (P = 0.001 and P = 0.05, for comparisons with control group and two-drug groups, respectively). Although proliferative responses to cytomegalovirus antigens were significantly greater in those receiving antiretroviral therapy, response to HIV-1 p24 antigen was not detected in any patient in either treatment group. CONCLUSIONS: This study supports the recommendation to start antiretroviral therapy with a three-drug combination during very early stages of HIV-1 disease, at least if viral load is above a cut-off point (10000 copies/ml in our study). The risk of progression was sevenfold higher in non-treated patients at 8 months of follow-up. Some immune system parameters improved toward normal values after 1 year of antiretroviral therapy, but the proliferative response of CD4 T lymphocytes against the p24 HIV-1 antigen was not recovered. Therapeutic approaches with more potent, better-tolerated and more convenient regimens will increasingly favour early intervention with antiretroviral t

Adult↗

PubMed1999

Dynamics of viral load rebound and immunological changes after stopping effective antiretroviral therapy.

BACKGROUND: This study addresses the dynamic of viral load rebound and immune system changes in a cohort of eight consecutive HIV-1-infected patients in very early stages [all the patients were taking highly active antiretroviral therapy (HAART} and were recruited in the coordinating center from a larger study] who decided to discontinue HAART after 1 year of treatment and effective virologic response. The safety of this procedure and the outcome with reintroduction of the same treatment was also investigated. METHODS: Plasma, cerebrospinal fluid (CSF), and lymphatic tissue viral loads were measured at baseline; lymphocyte immunophenotyping and CD4 lymphocyte proliferative responses to mitogens and specific antigens were assessed. The same antiretroviral therapy was reintroduced as soon as plasma viral load became detectable (above 200 copies/ml). RESULTS: At day 0, plasma viral load was below 20 copies/ml in all eight patients (and below 5 copies/ml in five of eight patients). A rebound in plasma viral load was detected in all patients from day 3 to day 31 with a mean doubling time of 2.01 (SE 0.29) days. Three out of eight patients achieved a peak plasma viral load at least 0.5 log10 above baseline, pretreatment values. Mutations associated with resistance to reverse transcriptase or protease inhibitors were not detected. After 31 days off therapy, CD4 lymphocytes decreased [mean 45% (SE 4) to 37% (SE 3); P = 0.04], CD8+CD28+ lymphocytes decreased [mean 59% (SE 5) to 43% (SE 4); P = 0.03], and CD8+CD38+ lymphocytes increased [mean 55% (SE 3) to 66% (SE 4); P = 0.009]. Mean stimulation indices of lymphocytes treated with phytohemagglutinin (PHA) and CD3 decreased from day 0 to day 31 from 34% (SE 8) to 17% (SE 9) (P = 0.06) and from 24% (SE 8) to 5% (SE 2) (P = 0.02), respectively. These changes were mainly contributed by the group of five patients with plasma viral load below 5 copies/ml at day 0. Viral load dropped below 20 copies/ml in all patients after 1 month of restarting the same antiretroviral regimen. CONCLUSIONS: Discontinuation of HAART after 1 year of successful treatment is followed by a rapid rebound of viral load; this rapidly returns to undetectable levels following reintroduction of the same treatment. In patients with more effective control of virus replication (viremia below 5 copise/ml), discontinuation of treatment was associated with more severe impairment of immunologic parameters.

Adult↗

PubMed1999

Determinant in human immunodeficiency virus type 1 for efficient replication under cytokine-induced CD4(+) T-helper 1 (Th1)- and Th2-type conditions.

Cytokines are potent stimuli for CD4(+)-T-cell differentiation. Among them, interleukin-12 (IL-12) and IL-4 induce naive CD4(+) T cells to become T-helper 1 (Th1) or Th2 cells, respectively. In this study we found that macrophage-tropic human immunodeficiency virus type 1 (HIV-1) strains replicated more efficiently in IL-12-induced Th1-type cultures derived from normal CD4(+) T cells than did T-cell-line-tropic (T-tropic) strains. In contrast, T-tropic strains preferentially infected IL-4-induced Th2-type cultures derived from the same donor CD4(+) T cells. Additional studies using chimeric viruses demonstrated that the V3 region of HIV-1 gp120 was the principal determinant for efficiency of replication. Cell fusion analysis showed that cells expressing envelope protein from a T-tropic strain effectively fused with IL-4-induced Th2-type culture cells. Flow cytometric analysis showed that the level of CCR5 expression was higher on IL-12-induced Th1-type culture cells, whereas CXCR4 was highly expressed on IL-4-induced Th2-type culture cells, although a low level of CXCR4 expression was observed on IL-12-induced Th1-type culture cells. These results indicate that HIV-1 isolates exhibit differences in the ability to infect CD4(+)-T-cell subsets such as Th1 or Th2 cells and that this difference may partly correlate with the expression of particular chemokine receptors on these cells. The findings suggest that immunological conditions are one of the factors responsible for inducing selection of HIV-1 strains.

Cell Fusion↗

PubMed1998

Natural killer cells from HIV-1+ patients produce C-C chemokines and inhibit HIV-1 infection.

Human NK cells have been shown to produce cytokines (e.g., IFN-gamma and TNF-alpha) and the chemokine macrophage inflammatory protein (MIP)-1alpha following stimulation with the combination of two monokines, IL-15 plus IL-12. The C-C chemokines MIP-1alpha, MIP-1beta, and RANTES have been identified as the major soluble macrophage-tropic HIV-1-suppressive factors produced by CD8+ T cells, which exert their action at the level of viral entry. Here, we demonstrate that monokine-activated NK cells, isolated from both normal and HIV-1+ donors, produce similar amounts of MIP-1alpha, MIP-1beta, and RANTES protein, in vitro. Further, supernatants of monokine-activated NK cells obtained from both normal donors and AIDS patients showed potent (routinely > or = 90%) suppressive activity against HIV-1 replication in vitro, compared with unstimulated control supernatants. NK cell supernatants inhibited both macrophage-tropic HIV-1(NFN-SX) and T cell-tropic HIV-1(NL4-3) replication in vitro, but not dual-tropic HIV-1(89.6). Importantly, the C-C chemokines MIP-1alpha, MIP-1beta, and RANTES were responsible only for a fraction of the HIV-1-suppressive activity exhibited by NK cell supernatants against macrophage-tropic HIV-1. Collectively these data indicate that NK cells from normal and HIV-1+ donors produce C-C chemokines and other unidentified factors that can inhibit both macrophage- and T cell-tropic HIV-1 replication in vitro. Since NK cells can be expanded in patients with HIV-1, AIDS, and AIDS malignancy in vivo, this cell type may have an important role in the in vivo regulation of HIV-1 infection.

Acquired Immunodeficiency Syndrome↗

PubMed1998

Apoptosis of CD8+ T cells is mediated by macrophages through interaction of HIV gp120 with chemokine receptor CXCR4.

CD8-positive T cells are thought to play an important role in the control of infection by human immunodeficiency virus (HIV) as a result of their cytotoxic activity and by releasing soluble factors. In AIDS patients, the absolute number of CD8+ T lymphocytes is decreased in peripheral blood and their turnover rate is increased, suggesting that there is more cell renewal and cell death occurring. Anti-retroviral therapy raises CD8+ T-cell counts in HIV-infected patients. Here we report that the death rate of CD8+ T cells by apoptosis increased markedly during HIV infection of peripheral blood mononuclear cells in vitro. Apoptosis is induced in a dose-dependent manner by recombinant envelope glycoprotein gp120 from HIV strain X4, or by stromal-derived factor-1 (SDF-1), the physiological ligand of the chemokine receptor CXCR4. Apoptosis is mediated by the interaction between tumour-necrosis factor-alpha bound to the membrane of macrophages (mbTNF) and a receptor on CD8+ T cells (TNF-receptor II, or TNFRII). The expression of both of these cell-surface proteins is upregulated by HIV infection or by treatment with recombinant gp120 or SDF-1. Apoptosis of CD8+ T cells isolated from HIV-infected patients is also mediated by macrophages through the interaction between mbTNF and TNFRII. These results indicate that the increased turnover of CD8+ T cells in HIV-infected subjects is mediated by the HIV envelope protein through the CXCR4 chemokine receptor.

Antigens, Surface↗

PubMed1998

Impact on the immune system of undetectable plasma HIV-1 RNA for more than 2 years.

OBJECTIVE: To investigate the impact of prolonged HIV suppression on the immune system by analysing the expression of several lymphocyte surface markers in a group of HIV-1-infected patients who maintained undetectable HIV-1 RNA levels for more than 24 months. PATIENTS AND METHODS: The study included a highly selected group of nine HIV-1-infected asymptomatic subjects and seven HIV-1-seronegative controls. The inclusion criteria of HIV-1-infected patients was to have plasma HIV-1 RNA levels below 20 (1.3 log10) copies/ml for at least 24 months while under antiretroviral treatment with nucleoside analogues. The patient population was retrospectively taken from a cohort of 1418 treated subjects. Mean initial absolute CD4+ T-cell count and percentage were 468+/-234 x 10(6)/l (range, 202-935 x 10(6)/l) and 25+/-6% (range, 16-33%), respectively. Plasma HIV-1 RNA quantification was determined using a standard and ultrasensitive reverse transcriptase polymerase chain reaction assay. Median HIV-1 RNA plasma level before antiretroviral treatment was 3.14 log10 copies/ml (range, 1.74-3.73 log10 copies/ml). Two or three-colour immunophenotyping was performed on whole blood and frozen peripheral blood mononuclear cells by flow cytometry. RESULTS: A significant increase was noted in CD4+ lymphocyte counts at the end of the study in HIV-1-positive patients. In addition, the CD4: CD8 ratio rose significantly with respect to baseline, although it remained lower than in the controls. CD45RA+ and CD45RO+ population percentages did not differ between groups. A significant rise in CD45RA+ T cells was observed. Analysis of T-cell activation measuring the expression of human leukocyte antigen-DR and CD25 did not differ between groups. The proportion of CD8+ lymphocytes that were CD28+ was similar in both groups at the end of the follow-up. T-cell receptor Vbeta subfamily analysis showed that an expansion of the T-cell receptor repertoire might occur in these patients. CONCLUSION: Patients who maintain undetectable viral load for prolonged periods of time with antiretroviral therapy may achieve a partial immune restoration of the immune system. Our results suggest that treatment of patients at early stages of HIV infection is warranted.

CD4 Lymphocyte Count↗

PubMed1998

The significance of vitamin A and carotenoid status in persons infected by the human immunodeficiency virus.

Hyporetinemia is associated with increased childhood morbidity and mortality that is reversible with vitamin A supplementation. Although vitamin A deficiency is otherwise rare in developed countries, the prevalence of hyporetinemia in human immunodeficiency virus (HIV)-infected persons is up to 29%. Hyporetinemic HIV-infected patients have a 3.5-5-fold increased risk of death. Furthermore, HIV-infected patients with very low or very high intake of vitamin A and beta-carotene (a vitamin A precursor) have greater rates of disease progression than do patients with intermediate intake. In developing countries up to 60% of HIV-infected pregnant women are hyporetinemic. In such women the relative risk of perinatal HIV transmission may be increased more than fourfold. These data indicate that vitamin A deficiency is common in HIV-infected patients in the developed world and strongly suggest that vitamin A supplementation may be especially useful in adjunctive therapy for HIV-infected pregnant women who reside in the developing world.

Carotenoids↗

PubMed1998

Effect of oral beta-carotene supplementation on plasma human immunodeficiency virus (HIV) RNA levels and CD4+ cell counts in HIV-infected patients.

We conducted a pilot, open-label study to assess the effect of short-term beta-carotene administration (180 mg/d with meals for 4 weeks) on the plasma human immunodeficiency virus (HIV) RNA levels and CD4+ lymphocyte counts in 21 HIV-infected patients. We found that plasma HIV RNA levels and CD4+ lymphocyte counts did not change following this short course of beta-carotene supplementation. Patients with lower serum concentrations of beta-carotene before supplementation were no more likely to have an increase in their CD4+ lymphocyte count or plasma HIV RNA copy number than were those with higher concentrations. No correlation was found between pre- or postsupplementation beta-carotene or vitamin A concentrations and pre- or postsupplementation CD4+ lymphocyte counts or plasma HIV RNA titers. This study provides no support for beta-carotene supplementation for HIV-infected subjects with normal baseline serum levels of beta-carotene and vitamin A.

Administration, Oral↗

PubMed1998

The effect of exercise training on aerobic fitness, immune indices, and quality of life in HIV+ patients.

PURPOSE: Thirty four HIV+ patients participated in a 6-wk aerobic exercise training program to determine whether exercise improved aerobic fitness, immune indices, and quality of life. METHODS: Subjects were assigned to three groups: control (no regular aerobic exercise), moderate exercise, and heavy exercise training. At study entry and exit (in each subject) we evaluated aerobic function with a symptom limited cardiopulmonary exercise test, immune indices with CD4 counts and Candida skin tests, viral replication with plasma HIV RNA measurements, and quality of life with a HIV+ population validated questionnaire. RESULTS: Aerobic fitness increased significantly in both exercise groups relative to the control group; immune indices changed very little among all three groups; however, the Candida skin tests (mm2) increased significantly in the moderate group; viral replication was essentially unchanged in all three groups; quality of life (QOL) markers improved in both exercising groups but not the control group. There were no opportunistic infections during the study. CONCLUSIONS: Exercise training resulted in a substantial improvement in aerobic function while immune indices were essentially unchanged. Quality of life markers improved significantly with exercise. Exercise training is safe and effective in this patient group and should be promoted for HIV+ patients.

Adult↗

PubMed1998

Potential contributions of viral envelope and host genetic factors in a human immunodeficiency virus type 1-infected long-term survivor.

The lack of clinical progression in some individuals despite prolonged human immunodeficiency virus type 1 (HIV-1) infection may result from infection with less-pathogenic viral strains. To address this question, we examined the HIV-1 envelope protein from a donor with a low viral burden, stable CD4(+) T-lymphocyte counts, and little evidence of CD8(+) T-cell expansion, activation, or immune activity. To avoid potential changes in envelope function resulting from selection in vitro, envelope clones were constructed by using viral RNA isolated from uncultured peripheral blood mononuclear cells (PBMC). The data showed that recombinant viruses containing envelope sequences derived from RNA isolated from patient PBMC replicated poorly in primary CD4(+) T cells but demonstrated efficient growth in macrophages. The unusual phenotype of these viruses could not be explained solely by differential utilization of coreceptors since the chimeric viruses, as well as an uncloned isolate obtained from the same visit date, can utilize CCR5. In addition, the donor's own cells appeared resistant to infection with chimeric viruses containing autologous envelope sequences. Genotype analysis revealed that the donor was heterozygous for the previously described 32-bp deletion in CCR5 which may be linked with prolonged survival in HIV-1-infected individuals. These data suggest that the changes in envelope sequences confer properties of viral attenuation, which together with the CCR5 +/Delta32 genotype could account for the long-term survival of this patient.

Amino Acid Sequence↗

PubMed1997

A small-molecule inhibitor directed against the chemokine receptor CXCR4 prevents its use as an HIV-1 coreceptor.

The chemokine receptor CXCR4 is the major coreceptor used for cellular entry by T cell- tropic human immunodeficiency virus (HIV)-1 strains, whereas CCR5 is used by macrophage (M)-tropic strains. Here we show that a small-molecule inhibitor, ALX40-4C, inhibits HIV-1 envelope (Env)-mediated membrane fusion and viral entry directly at the level of coreceptor use. ALX40-4C inhibited HIV-1 use of the coreceptor CXCR4 by T- and dual-tropic HIV-1 strains, whereas use of CCR5 by M- and dual-tropic strains was not inhibited. Dual-tropic viruses capable of using both CXCR4 and CCR5 were inhibited by ALX40-4C only when cells expressed CXCR4 alone. ALX40-4C blocked stromal-derived factor (SDF)-1alpha-mediated activation of CXCR4 and binding of the monoclonal antibody 12G5 to cells expressing CXCR4. Overlap of the ALX40-4C binding site with that of 12G5 and SDF implicates direct blocking of Env interactions, rather than downregulation of receptor, as the mechanism of inhibition. Thus, ALX40-4C represents a small-molecule inhibitor of HIV-1 infection that acts directly against a chemokine receptor at the level of Env-mediated membrane fusion.

Anti-HIV Agents↗