Showing papers on "Viremia published in 2010"
TL;DR: Treatment of chronically infected chimpanzees with a locked nucleic acid (LNA)–modified oligonucleotide (SPC3649) complementary to miR-122 leads to long-lasting suppression of HCV viremia, with no evidence of viral resistance or side effects in the treated animals.
Abstract: The liver-expressed microRNA-122 (miR-122) is essential for hepatitis C virus (HCV) RNA accumulation in cultured liver cells, but its potential as a target for antiviral intervention has not been assessed. We found that treatment of chronically infected chimpanzees with a locked nucleic acid (LNA)-modified oligonucleotide (SPC3649) complementary to miR-122 leads to long-lasting suppression of HCV viremia, with no evidence of viral resistance or side effects in the treated animals. Furthermore, transcriptome and histological analyses of liver biopsies demonstrated derepression of target mRNAs with miR-122 seed sites, down-regulation of interferon-regulated genes, and improvement of HCV-induced liver pathology. The prolonged virological response to SPC3649 treatment without HCV rebound holds promise of a new antiviral therapy with a high barrier to resistance.
1,708 citations
TL;DR: A new adult wild-type mouse model of chikungunya virus arthritis is described, which recapitulates the self-limiting arthritis, tenosynovitis, and myositis seen in humans and provides insights into pathogenesis and a simple and convenient system to test potential new interventions.
Abstract: Chikungunya virus is a mosquito-borne arthrogenic alphavirus that has recently reemerged to produce the largest epidemic ever documented for this virus. Here we describe a new adult wild-type mouse model of chikungunya virus arthritis, which recapitulates the self-limiting arthritis, tenosynovitis, and myositis seen in humans. Rheumatic disease was associated with a prolific infiltrate of monocytes, macrophages, and NK cells and the production of monocyte chemoattractant protein 1 (MCP-1), tumor necrosis factor alpha (TNF-α), and gamma interferon (IFN-γ). Infection with a virus isolate from the recent Reunion Island epidemic induced significantly more mononuclear infiltrates, proinflammatory mediators, and foot swelling than did an Asian isolate from the 1960s. Primary mouse macrophages were shown to be productively infected with chikungunya virus; however, the depletion of macrophages ameliorated rheumatic disease and prolonged the viremia. Only 1 μg of an unadjuvanted, inactivated, whole-virus vaccine derived from the Asian isolate completely protected against viremia and arthritis induced by the Reunion Island isolate, illustrating that protection is not strain specific and that low levels of immunity are sufficient to mediate protection. IFN-α treatment was able to prevent arthritis only if given before infection, suggesting that IFN-α is not a viable therapy. Prior infection with Ross River virus, a related arthrogenic alphavirus, and anti-Ross River virus antibodies protected mice against chikungunya virus disease, suggesting that individuals previously exposed to Ross River virus should be protected from chikungunya virus disease. This new mouse model of chikungunya virus disease thus provides insights into pathogenesis and a simple and convenient system to test potential new interventions.
376 citations
TL;DR: HCV reinfection is associated with a reduction in the magnitude and duration of viremia, broadened cellular immune responses, and generation of cross-reactive humoral responses that are consistent with development of adaptive immunity that is not sterilizing but protects against chronic disease.
324 citations
University of Alabama at Birmingham1, Los Alamos National Laboratory2, University of Massachusetts Amherst3, Santa Fe Institute4, University of North Carolina at Chapel Hill5, Duke University6, Aaron Diamond AIDS Research Center7, Rockefeller University8, Science Applications International Corporation9
TL;DR: Higher multiplicity of HIV-1 infection in MSM compared with HSX is consistent with the demonstrably higher epidemiological risk of virus acquisition in MSM and could indicate a greater challenge for HIV- 1 vaccines than previously recognized.
Abstract: Elucidating virus-host interactions responsible for HIV-1 transmission is important for advancing HIV-1 prevention strategies. To this end, single genome amplification (SGA) and sequencing of HIV-1 within the context of a model of random virus evolution has made possible for the first time an unambiguous identification of transmitted/founder viruses and a precise estimation of their numbers. Here, we applied this approach to HIV-1 env analyses in a cohort of acutely infected men who have sex with men (MSM) and found that a high proportion (10 of 28; 36%) had been productively infected by more than one virus. In subjects with multivariant transmission, the minimum number of transmitted viruses ranged from 2 to 10 with viral recombination leading to rapid and extensive genetic shuffling among virus lineages. A combined analysis of these results, together with recently published findings based on identical SGA methods in largely heterosexual (HSX) cohorts, revealed a significantly higher frequency of multivariant transmission in MSM than in HSX [19 of 50 subjects (38%) versus 34 of 175 subjects (19%); Fisher’s exact p=0.008]. To further evaluate the SGA strategy for identifying transmitted/founder viruses, we analyzed 239 overlapping 59 and 39 half genome or env-only sequences from plasma viral RNA (vRNA) and blood mononuclear cell DNA in an MSM subject who had a particularly well-documented virus exposure history 3–6 days before symptom onset and 14–17 days before peak plasma viremia (47,600,000 vRNA molecules/ml). All 239 sequences coalesced to a single transmitted/founder virus genome in a time frame consistent with the clinical history, and a molecular clone of this genome encoded replication competent virus in accord with model predictions. Higher multiplicity of HIV-1 infection in MSM compared with HSX is consistent with the demonstrably higher epidemiological risk of virus acquisition in MSM and could indicate a greater challenge for HIV-1 vaccines than previously recognized.
323 citations
TL;DR: In a double-blind trial, Rajesh Gandhi and colleagues detect no significant reduction in viral load after people with low-level HIV viremia added an integrase inhibitor to their treatment regimen.
Abstract: Background: Most HIV-1-infected patients on effective antiretroviral therapy (ART) with plasma HIV-1 RNA levels below the detection limits of commercial assays have residual viremia measurable by more sensitive methods. We assessed whether adding raltegravir lowered the level of residual viremia in such patients. Methods and Findings: Patients receiving ART who had plasma HIV-1 RNA levels below 50 copies/mL but detectable viremia by single copy assay (SCA) were randomized to add either raltegravir or placebo to their ART regimen for 12 weeks; patients then crossed-over to the other therapy for an additional 12 weeks while continuing pre-study ART. The primary endpoint was the plasma HIV-1 RNA by SCA averaged between weeks 10 and 12 (10/12) compared between treatment groups. Fifty-three patients were enrolled. The median screening HIV-1 RNA was 1.7 copies/mL. The HIV-1 RNA level at weeks 10/12 did not differ significantly between the raltegravir-intensified (n=25) and the placebo (n=24) groups (median 1.2 versus 1.7 copies/mL, p=0.55, Wilcoxon rank sum test), nor did the change in HIV-1 RNA level from baseline to week 10/12 (median 20.2 and 20.1 copies/mL, p=0.71, Wilcoxon rank sum test). There was also no significant change in HIV-1 RNA level from weeks 10/12 to weeks 22/24 after patients crossed-over. There was a greater CD4 cell count increase from baseline to week 12 in the raltegravir-intensified group compared with the placebo group (+42versus 244cells/mm 3 ,p=0.082, Wilcoxon rank sum test), which reversed after the cross-over. This CD4 cell count change was not associated with an effect of raltegravir intensification on markers of CD4 or CD8 cell activation in blood. Conclusion: In this randomized, double-blind cross-over study, 12 weeks of raltegravir intensification did not demonstrably reduce low-level plasma viremia in patients on currently recommended ART. This finding suggests that residual viremia does not arise from ongoing cycles of HIV-1 replication and infection of new cells. New therapeutic strategies to eliminate reservoirs that produce residual viremia will be required to eradicate HIV-1 infection. Trial Registration: ClinicalTrials.gov NCT00515827 Please see later in the article for the Editors’ Summary.
291 citations
TL;DR: It is demonstrated for the first time that CHIKV Ags could be detected in vivo in the monocytes of acutely infected patients, and monocytes could be infected and virus growth could be sustained, and a better understanding on the basic mechanisms of infection and early antiviral immune responses is provided.
Abstract: Chikungunya virus (CHIKV) is an alphavirus that causes chronic and incapacitating arthralgia in humans. To date, interactions between the immune system and the different stages of the virus life cycle remain poorly defined. We demonstrated for the first time that CHIKV Ags could be detected in vivo in the monocytes of acutely infected patients. Using in vitro experimental systems, whole blood and purified monocytes, we confirmed that monocytes could be infected and virus growth could be sustained. CHIKV interactions with monocytes, and with other blood leukocytes, induced a robust and rapid innate immune response with the production of specific chemokines and cytokines. In particular, high levels of IFN-alpha were produced rapidly after CHIKV incubation with monocytes. The identification of monocytes during the early phase of CHIKV infection in vivo is significant as infected monocyte/macrophage cells have been detected in the synovial tissues of chronically CHIKV-infected patients, and these cells may behave as the vehicles for virus dissemination. This may explain the persistence of joint symptoms despite the short duration of viremia. Our results provide a better understanding on the basic mechanisms of infection and early antiviral immune responses and will help in the development of future effective control strategies.
249 citations
TL;DR: The data suggest that a significant reduction in the size of viral reservoirs may be achievable in selected individuals who initiate standard ART early in infection, given re-emergence of plasma viremia in an individual with an extraordinarily low viral burden.
Abstract: Objectives Sustained suppression of plasma viremia in HIV-infected individuals is attainable with antiretroviral therapy (ART); however, eradication of virus that would allow discontinuation of ART has been hampered by the persistence of HIV reservoirs. It is of great interest to identify individuals who had received ART for prolonged periods of time with extremely low or undetectable HIV reservoirs and monitor plasma viremia following discontinuation of therapy. Methods We measured the size of HIV reservoirs in CD4(+) T cells of individuals on long-term ART and monitored plasma viremia following cessation of ART in one individual with an exceptionally low viral burden after a decade of therapy. Results We demonstrated undetectable levels of HIV DNA in the blood of eight of 45 infected individuals on long-term ART. Among those eight individuals, the frequency of cells carrying infectious virus was significantly lower in those who initiated ART during the early versus the chronic phase of infection. One individual with undetectable HIV DNA in both blood and tissue and a profoundly low level of infectious virus experienced plasma viral rebound 50 days following discontinuation of ART. Conclusions Our data suggest that a significant reduction in the size of viral reservoirs may be achievable in selected individuals who initiate standard ART early in infection. However, given re-emergence of plasma viremia in an individual with an extraordinarily low viral burden, therapeutic strategies aimed at specifically targeting these extremely rare HIV-infected cells with novel interventions may be necessary in order to achieve eradication of virus.
236 citations
TL;DR: Investigation of B cells before and after reduction of HIV plasma viremia by antiretroviral therapy provides new insights on B cells in HIV infection and how early initiation of ART may prevent irreversible immune system damage.
235 citations
TL;DR: Intensification of antiretroviral therapy with a potent HIV-1 integrase inhibitor did not decrease persistent viremia in subjects receiving suppressive regimens, indicating that rapidly cycling cells infected with HIV- 1 were not present.
Abstract: Background
Combination antiretroviral therapy suppresses but does not eradicate human immunodeficiency virus type 1 (HIV-1) in infected persons, and low-level viremia can be detected despite years of suppressive antiretroviral therapy. Short (28d) course antiretroviral intensification of standard combination therapy is a useful approach to determine whether complete rounds of HIV-1 replication in rapidly cycling cells contribute to persistent viremia. We investigated whether intensification with the integrase inhibitor raltegravir decreases plasma viremia in patients on suppressive antiretroviral therapy.
209 citations
TL;DR: Minimization of immunosuppression upon detection of BK‐viremia was associated with excellent graft survival at 5‐years, low rejection rates and excellent renal function, and is a safe, short and long‐term strategy that resulted in freedom from clinically evident Bk‐virus nephropathy.
186 citations
TL;DR: Overall, the replicating Ad5hr-HIV/SIV priming/gp140 protein boosting approach elicited strong systemic and mucosal antibodies with multiple functional activities associated with control of both acute and chronic viremia.
Abstract: We have shown that following priming with replicating adenovirus type 5 host range mutant (Ad5hr)-human immunodeficiency virus (HIV)/simian immunodeficiency virus (SIV) recombinants, boosting with gp140 envelope protein enhances acute-phase protection against intravenous simian/human immunodeficiency virus (SHIV)(89.6P) challenge compared to results with priming and no boosting or boosting with an HIV polypeptide representing the CD4 binding site of gp120. We retrospectively analyzed antibodies in sera and rectal secretions from these same macaques, investigating the hypothesis that vaccine-elicited nonneutralizing antibodies contributed to the better protection. Compared to other immunized groups or controls, the gp140-boosted group exhibited significantly greater antibody activities mediating antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cell-mediated viral inhibition (ADCVI) in sera and transcytosis inhibition in rectal secretions. ADCC and ADCVI activities were directly correlated with antibody avidity, suggesting the importance of antibody maturation for functionality. Both ADCVI and percent ADCC killing prechallenge were significantly correlated with reduced acute viremia. The latter, as well as postchallenge ADCVI and ADCC, was also significantly correlated with reduced chronic viremia. We have previously demonstrated induction by the prime/boost regimen of mucosal antibodies that inhibit transcytosis of SIV across an intact epithelial cell layer. Here, antibody in rectal secretions was significantly correlated with transcytosis inhibition. Importantly, the transcytosis specific activity (percent inhibition/total secretory IgA and IgG) was strongly correlated with reduced chronic viremia, suggesting that mucosal antibody may help control cell-to-cell viral spread during the course of infection. Overall, the replicating Ad5hr-HIV/SIV priming/gp140 protein boosting approach elicited strong systemic and mucosal antibodies with multiple functional activities associated with control of both acute and chronic viremia.
TL;DR: It is suggested that PMNs have a biphasic response to WNV infection, serving as a reservoir for replication and dissemination in early infection and later contributing to viral clearance.
Abstract: Polymorphonuclear leukocytes (PMNs) are key in innate immunity, but their role in viral pathogenesis is incompletely understood. In infection due to West Nile virus (WNV), we found that expression of 2 PMNattracting chemokines, Cxcl1 and Cxcl2, was rapidly and dramatically elevated in macrophages. PMNs are rapidly recruited to the site of WNV infection in mice and support efficient replication of WNV. Mice depleted of PMNs after WNV inoculation developed higher viremia and experienced earlier death, compared with the control group, which suggest a protective role for PMNs. In contrast, when PMNs were depleted prior to infection with WNV, and in mice deficient in Cxcr2 (a chemokine receptor gene), viremia was reduced and survival was enhanced. Collectively, these data suggest that PMNs have a biphasic response to WNV infection, serving as a reservoir for replication and dissemination in early infection and later contributing to viral clearance.
TL;DR: Rhesus macaques inoculated intravenously with a high dose of d Dengue virus produced dengue hemorrhage, which may provide a unique platform to define the early events in dengingue virus infection and help identify which blood components contribute to the pathogenesis of denge disease.
TL;DR: The prospective addition of Vpa and RAL, VPA and ENF, or ENF failed to progressively reduce the frequency of RCI, or ablate intermittent and low-level viremia.
Abstract: Background
Human immunodeficiency virus (HIV) infection that persists despite antiretroviral therapy (ART) is a daunting problem. Given the limited evidence that resting CD4+ T cell infection (RCI) is affected by the histone deacetylase (HDAC) inhibitor valproic acid (VPA), we measured the stability of RCI and residual viremia in patients who added VPA with or without raltegravir (RAL), or enfuvirtide (ENF) with or without VPA, to standard ART.
Ragon Institute of MGH, MIT and Harvard1, Harvard University2, Howard Hughes Medical Institute3, University of California, Los Angeles4, University of Colorado Denver5, Praxis6, University of New South Wales7, Aaron Diamond AIDS Research Center8, University of California, San Diego9, University of Tokyo10
TL;DR: Examination of viral replication capacities, HLA types, and virus sequences from 18 HIV-1 controllers identified during primary infection indicates that acute/early stage viruses from persons who become controllers have evidence of reduced replication capacity during the initial stages of infection.
Abstract: Human immunodeficiency virus type 1 (HIV-1) controllers maintain viremia at <2,000 RNA copies/ml without antiretroviral therapy. Viruses from controllers with chronic infection were shown to exhibit impaired replication capacities, in part associated with escape mutations from cytotoxic-T-lymphocyte (CTL) responses. In contrast, little is known about viruses during acute/early infection in individuals who subsequently become HIV controllers. Here, we examine the viral replication capacities, HLA types, and virus sequences from 18 HIV-1 controllers identified during primary infection. gag-protease chimeric viruses constructed using the earliest postinfection samples displayed significantly lower replication capacities than isolates from persons who failed to control viremia (P = 0.0003). Protective HLA class I alleles were not enriched in these early HIV controllers, but viral sequencing revealed a significantly higher prevalence of drug resistance mutations associated with impaired viral fitness in controllers than in noncontrollers (6/15 [40.0%] versus 10/80 [12.5%], P = 0.018). Moreover, of two HLA-B57-positive (B57(+)) controllers identified, both harbored, at the earliest time point tested, signature escape mutations within Gag that likewise impair viral replication capacity. Only five controllers did not express "protective" alleles or harbor viruses with drug resistance mutations; intriguingly, two of them displayed typical B57 signature mutations (T242N), suggesting the acquisition of attenuated viruses from B57(+) donors. These data indicate that acute/early stage viruses from persons who become controllers have evidence of reduced replication capacity during the initial stages of infection which is likely associated with transmitted or acquired CTL escape mutations or transmitted drug resistance mutations. These data suggest that viral dynamics during acute infection have a major impact on HIV disease outcome.
TL;DR: In this paper, the authors studied the effect of CD8+ T-cell depletion on the control of pathogenic lentiviral infection through both innate and adaptive mechanisms in rhesus macaques and found that the importance of adaptive cytotoxic effects in clearance of cells productively infected with SIV.
Abstract: The CD8+ T-cell is a key mediator of antiviral immunity, potentially contributing to control of pathogenic lentiviral infection through both innate and adaptive mechanisms We studied viral dynamics during antiretroviral treatment of simian immunodeficiency virus (SIV) infected rhesus macaques following CD8+ T-cell depletion to test the importance of adaptive cytotoxic effects in clearance of cells productively infected with SIV As previously described, plasma viral load (VL) increased following CD8+ T-cell depletion and was proportional to the magnitude of CD8+ T-cell depletion in the GALT, confirming a direct relationship between CD8+ T-cell loss and viral replication Surprisingly, first phase plasma virus decay following administration of antiretroviral drugs was not slower in CD8+ T-cell depleted animals compared with controls indicating that the short lifespan of the average productively infected cell is not a reflection of cytotoxic T-lymphocyte (CTL) killing Our findings support a dominant role for non-cytotoxic effects of CD8+ T-cells on control of pathogenic lentiviral infection and suggest that cytotoxic effects, if present, are limited to early, pre-productive stages of the viral life cycle These observations have important implications for future strategies to augment immune control of HIV
TL;DR: Data indicate that subsequent to aerogenous exposure to FMDV, the temporally defined critical pathogenesis events involve primary replication in epithelial cells of the pharyngeal mucosa-associated lymphoid tissue crypts and subsequent widespread replication in pneumocytes in the lungs, which coincides with the establishment of sustained viremia.
Abstract: To characterize the early events of foot-and-mouth disease virus (FMDV) infection in cattle subsequent to simulated natural exposure, 16 steers were aerosol inoculated with FMDV and euthanized at various times. Samples were collected from each steer antemortem (serum, nasal swabs, and oral swabs) and postmortem (up to 40 tissues per animal) and screened for FMDV by virus isolation and for FMDV RNA by real-time reverse transcription polymerase chain reaction. Tissues that tested positive for FMDV or viral RNA were examined by immunohistochemistry and multichannel immunofluorescence microscopy. In previremic steers, FMDV was most consistently localized to nasopharyngeal tissues, thereby indicating this region as the most important site of primary viral replication. The earliest site of microscopic localization of FMDV antigens was the lymphoid follicle-associated epithelium of the pharyngeal mucosa-associated lymphoid tissue of the nasopharynx at 6 hours postaerosolization. At early time points after aerosol inoculation, viral antigens colocalized with cytokeratin-positive pharyngeal epithelial cells; intraepithelial FMDV-negative, MHCII/CD11c-double-positive dendritic cells were present in close proximity to FMDV-positive cells. Onset of viremia coincided with marked increase of viral loads in pulmonary tissues and with substantial decrease of viral detection in nasopharyngeal tissues. These data indicate that subsequent to aerogenous exposure to FMDV, the temporally defined critical pathogenesis events involve (1) primary replication in epithelial cells of the pharyngeal mucosa-associated lymphoid tissue crypts and (2) subsequent widespread replication in pneumocytes in the lungs, which coincides with (3) the establishment of sustained viremia.
TL;DR: Six newborn macaques rapidly developed neutralizing antibodies and had significantly reduced plasma viremia for six months, supporting the use ofneutralizing antibodies in enhancing B cell responses and viral control in perinatal settings.
Abstract: Maternal HIV-1-specific antibodies are efficiently transferred to newborns, but their role in disease control is unknown. We administered neutralizing IgG, including the human neutralizing monoclonal IgG1b12, at levels insufficient to block infection, to six newborn macaques before oral challenge with simian-HIV strain SF162P3 (SHIV(SF162P3)). All of the macaques rapidly developed neutralizing antibodies and had significantly reduced plasma viremia for six months. These studies support the use of neutralizing antibodies in enhancing B cell responses and viral control in perinatal settings.
TL;DR: Analysis of hepatitis C virus pathogenesis during the course of infection in tupaias over a 3-year period suggests that the tupaia is a practical animal model for experimental studies of HCV infection.
Abstract: The lack of a small-animal model has hampered the analysis of hepatitis C virus (HCV) pathogenesis. The tupaia (Tupaia belangeri), a tree shrew, has shown susceptibility to HCV infection and has been considered a possible candidate for a small experimental model of HCV infection. However, a longitudinal analysis of HCV-infected tupaias has yet to be described. Here, we provide an analysis of HCV pathogenesis during the course of infection in tupaias over a 3-year period. The animals were inoculated with hepatitis C patient serum HCR6 or viral particles reconstituted from full-length cDNA. In either case, inoculation caused mild hepatitis and intermittent viremia during the acute phase of infection. Histological analysis of infected livers revealed that HCV caused chronic hepatitis that worsened in a time-dependent manner. Liver steatosis, cirrhotic nodules, and accompanying tumorigenesis were also detected. To examine whether infectious virus particles were produced in tupaia livers, naive animals were inoculated with sera from HCV-infected tupaias, which had been confirmed positive for HCV RNA. As a result, the recipient animals also displayed mild hepatitis and intermittent viremia. Quasispecies were also observed in the NS5A region, signaling phylogenic lineage from the original inoculating sequence. Taken together, these data suggest that the tupaia is a practical animal model for experimental studies of HCV infection.
TL;DR: A non-mouse-adapted DEN2 virus strain (D2Y98P) that is highly infectious in AG129 mice (lacking interferon-α/β and -γ receptors) upon intraperitoneal administration is described, suggesting intact vascular integrity, a cardinal feature in DEN shock syndrome.
Abstract: The spread of dengue (DEN) worldwide combined with an increased severity of the DEN-associated clinical outcomes have made this mosquito-borne virus of great global public health importance. Progress in understanding DEN pathogenesis and in developing effective treatments has been hampered by the lack of a suitable small animal model. Most of the DEN clinical isolates and cell culture-passaged DEN virus strains reported so far require either host adaptation, inoculation with a high dose and/or intravenous administration to elicit a virulent phenotype in mice which results, at best, in a productive infection with no, few, or irrelevant disease manifestations, and with mice dying within few days at the peak of viremia. Here we describe a non-mouse-adapted DEN2 virus strain (D2Y98P) that is highly infectious in AG129 mice (lacking interferon-α/β and -γ receptors) upon intraperitoneal administration. Infection with a high dose of D2Y98P induced cytokine storm, massive organ damage, and severe vascular leakage, leading to haemorrhage and rapid death of the animals at the peak of viremia. In contrast, very interestingly and uniquely, infection with a low dose of D2Y98P led to asymptomatic viral dissemination and replication in relevant organs, followed by non-paralytic death of the animals few days after virus clearance, similar to the disease kinetic in humans. Spleen damage, liver dysfunction and increased vascular permeability, but no haemorrhage, were observed in moribund animals, suggesting intact vascular integrity, a cardinal feature in DEN shock syndrome. Infection with D2Y98P thus offers the opportunity to further decipher some of the aspects of dengue pathogenesis and provides a new platform for drug and vaccine testing.
TL;DR: Lack of CD4 recovery in individuals in whom ART suppresses HIV replication is associated with complex immune alterations, and immune activation, likely driven by altered gut permeability and resulting in augmented Treg activity could play a pivotal role in this process.
Abstract: Background:Persistently reduced CD4+ T-lymphocyte counts in the face of undetectable HIV viremia are seen in a sizable percentage of HIV-infected patients undergoing antiretroviral therapy (ART). We analyzed the immune correlates of this phenomenon.Materials and methods:Sixty-seven HIV-infected pati
TL;DR: Risk factors for viral failure were line regimen dependent and second-line ART recipients had a higher rate of viremia, albeit with infrequent PI drug resistance mutations, compared with long-term recipients of antiretroviral therapy.
Abstract: BACKGROUND We assessed risk factors for viremia and drug resistance among long-term recipients of antiretroviral therapy (ART) in South Africa. METHODS In 2008, we conducted a cross-sectional study among patients receiving ART for 12 months or more. Genotypic resistance testing was performed on individuals with a viral load higher than 400 RNA copies/ml. Multiple logistic regression analysis was used to assess associations. RESULTS Of 998 participants, 75% were women with a median age of 41 years. Most (64%) had been on treatment for more than 3 years. The prevalence of viremia was 14% (n = 139): 12% (102/883) on first-line [i.e. nonnucleoside reverse-transcriptase inhibitor (NNRTI)-based regimen] and 33% (37/115) on second-line (i.e. protease inhibitor (PI)-based regimen) ART. Of viremic patients, 78% had drug resistance mutations. For NRTIs, NNRTIs and PIs, the prevalence of mutations was 64, 81 and 2%, respectively, among first-line failures and 29, 54 and 6%, respectively, among second-line failures. M184V/I, K103N and V106A/M were the most common mutations. Significant risk factors associated with viremia on first-line regimen included concurrent tuberculosis treatment [odds ratio (OR) 6.4, 95% confidence interval (CI) 2.2-18.8, P < 0.01] and a recent history of poor adherence (OR 2.7, 1.3-5.6, P = 0.01). Among second-line failures, attending a public clinic (OR 4.6, 95% CI 1.8-11.3, P < 0.01) and not having a refrigerator at home (OR 6.7, 95% CI 1.2-37.5, P = 0.03) were risk factors for virological failure. CONCLUSION Risk factors for viral failure were line regimen dependent. Second-line ART recipients had a higher rate of viremia, albeit with infrequent PI drug resistance mutations. Measures to maintain effective virologic suppression should include increased adherence counseling, attention to concomitant tuberculosis treatment and heat-stable formulations of second-line ART regimens.
TL;DR: Despite the highly conserved nature of gag, clear evidence of evolution was observed in the plasma virus, largely due to synonymous substitutions, and evolution was rare in proviral clones, suggesting that ongoing replication in ES does not permit the significant reseeding of the latent reservoir.
Abstract: A subset of HIV-1-infected patients known as elite controllers or suppressors (ES) control the virus naturally. We have previously demonstrated sequence discordance between proviral and plasma gag clones in ES, much of which can be attributed to selective pressure from the host (J. R. Bailey, T. M. Williams, R. F. Siliciano, and J. N. Blankson, J. Exp. Med. 203:1357-1369, 2006). However, it is not clear whether ongoing viral replication continues in ES once the control of viremia has been established or whether selective pressure impacts this evolution. The cytotoxic T-lymphocyte (CTL) response in ES often targets Gag and frequently is superior to that of HIV-1 progressors, partially due to the HLA class I alleles B*57/5801 and B*27, which are overrepresented in ES. We therefore examined longitudinal plasma and proviral gag sequences from HLA-B*57/5801 and -B*27 ES. Despite the highly conserved nature of gag, we observed clear evidence of evolution in the plasma virus, largely due to synonymous substitutions. In contrast, evolution was rare in proviral clones, suggesting that ongoing replication in ES does not permit the significant reseeding of the latent reservoir. Interestingly, there was little continual evolution in CTL epitopes, and we detected de novo CTL responses to autologous viral mutants. Thus, some ES control viremia despite ongoing replication and evolution.
TL;DR: A review examines the dynamics of persistent viremia, viral reservoirs, the mechanisms behind viral latency, and methods to purge the viral reservoirs in HIV-1 infection.
TL;DR: It is not the overall magnitude but rather the breadth, magnitude, and functional capacity of CD8 T-cell responses to certain conserved proteins, like Gag, which predict effective antiviral HIV-specific CD8T-cell function.
Abstract: Effective HIV-specific T-cell immunity requires the ability to inhibit virus replication in the infected host, but the functional characteristics of cells able to mediate this effect are not well defined. Since Gag-specific CD8 T cells have repeatedly been associated with lower viremia, we examined the influence of Gag specificity on the ability of unstimulated CD8 T cells from chronically infected persons to inhibit virus replication in autologous CD4 T cells. Persons with broad (≥6; n = 13) or narrow (≤1; n = 13) Gag-specific responses, as assessed by gamma interferon enzyme-linked immunospot assay, were selected from 288 highly active antiretroviral therapy (HAART)-naive HIV-1 clade C-infected South Africans, matching groups for total magnitude of HIV-specific CD8 T-cell responses and CD4 T-cell counts. CD8 T cells from high Gag responders suppressed in vitro replication of a heterologous HIV strain in autologous CD4 cells more potently than did those from low Gag responders (P < 0.003) and were associated with lower viral loads in vivo (P < 0.002). As previously shown in subjects with low viremia, CD8 T cells from high Gag responders exhibited a more polyfunctional cytokine profile and a stronger ability to proliferate in response to HIV stimulation than did low Gag responders, which mainly exhibited monofunctional CD8 T-cell responses. Furthermore, increased polyfunctionality was significantly correlated with greater inhibition of viral replication in vitro. These data indicate that enhanced suppression of HIV replication is associated with broader targeting of Gag. We conclude that it is not the overall magnitude but rather the breadth, magnitude, and functional capacity of CD8 T-cell responses to certain conserved proteins, like Gag, which predict effective antiviral HIV-specific CD8 T-cell function.
TL;DR: HIV-1-specific CD8(+) T cell responses in acute HIV-1 infection appear uniquely able to efficiently suppress viral replication, whereas CD8 (+) T cells responses generated in the chronic phase of infection appear often impaired.
Abstract: Exceedingly high viral loads and rapid loss of CD4(+) T cells in all tissue compartments are a hallmark of acute human immunodeficiency virus type 1 (HIV-1) infection, which is often accompanied by clinical symptoms such as fever, maculopapular rash, and/or lymphadenopathy. The resolution of the clinical symptoms and the subsequent decrease in plasma viremia are associated with the emergence of HIV-1-specific CD4(+) and CD8(+) T cell responses. The remarkable early inhibition of viremia by CD8(+) T cells appears to be precipitated by only a limited number of specific CD8(+) T cell responses, and the plasma viremia is reduced to a "set point" level. Over time, the breadth and magnitude of CD8(+) T cell responses increase, but without a change in the control of viral replication or further reduction in the viral set point. Moreover, the early viral set point, consequent on the first CD8(+) T cell responses, is highly predictive of the later course of disease progression. Thus, HIV-1-specific CD8(+) T cell responses in acute HIV-1 infection appear uniquely able to efficiently suppress viral replication, whereas CD8(+) T cell responses generated in the chronic phase of infection appear often impaired.
TL;DR: Data, generated in a rigorous, high-viral-load SIV-infected macaque model, showed that HAART provided benefits with respect to CNS viral replication and inflammation but that no change in the level of viral DNA and continued CNS inflammation occurred in some macaques.
Abstract: Background During the era of highly active antiretroviral therapy (HAART), the prevalence of HIV-associated central nervous system (CNS) disease has increased despite suppression of plasma viremia. Methods In a simian immunodeficiency virus (SIV) model system in which all animals develop AIDS and 90% develop CNS disease by 3 months after inoculation, pigtailed macaques were treated with a regimen of tenofovir disoproxil fumarate, saquinavir, atazanavir, and an integrase inhibitor starting at 12 days after inoculation and were euthanized at approximately 175 days after inoculation. Results Plasma and cerebrospinal fluid (CSF) viral loads declined rapidly after the initiation of HAART. Brain viral RNA was undetectable at necropsy, but viral DNA levels were not different from those in untreated SIV-infected macaques. CNS inflammation was significantly reduced, with decreased brain expression of major histocompatibility complex class II and glial fibrillary acidic protein and reduced levels of CSF CCL2 and interleukin 6. Brain from treated macaques had significantly lower levels of interferon beta, type 1 interferon-inducible gene myxovirus (influenza) resistance A, and indolamine 2,3-dioxygenase messenger RNA, suggesting that immune hyperactivation was suppressed, and fewer CD4(+) and CD8(+) T cells, suggesting that trafficking of T cells from peripheral blood was reduced. Brain levels of CD68 protein and tumor necrosis factor alpha and interferon gamma RNA were reduced but were not significantly lower, indicating continued CNS inflammation. Conclusions These data, generated in a rigorous, high-viral-load SIV-infected macaque model, showed that HAART provided benefits with respect to CNS viral replication and inflammation but that no change in the level of viral DNA and continued CNS inflammation occurred in some macaques.
TL;DR: Leflunomide, alone or in combination, has potential utility in treatment of complex CMV syndromes and in long-term suppression of viremia and the optimal duration of therapy and the balance of risks and benefits are not yet known.
Abstract: Background. Cytomegalovirus (CMV) viremia that is resistant or refractory to the standard antiviral therapy still constitutes a major threat to high-risk transplant recipients. In addition, multiple CMV recurrences may lead to neutropenia because of repeated courses of therapy with ganciclovir derivatives. Leflunomide, a drug for rheumatoid arthritis, has been reported to have anti-CMV activity. This study reports on its use in 17 transplant recipients with complex CMV syndromes who had failed or were intolerant to other therapies. Methods. Single-center, retrospective study. Clinical data were extracted from the electronic medical record. CMV DNA viral loads were performed by quantitative hybrid capture assay. Results. Leflunomide was initiated after a median of three episodes of CMV viremia, with a mean peak viral load of 245,826 copies/mL. Initial clearance of CMV viremia was observed in 14 of 17 patients (82%), and 9 of 17 (53%) patients achieved a long-term suppression of CMV recurrences. Higher peak viral load and higher viral load at the start of leflunomide therapy were associated with failure to suppress viremia. The duration ofleflunomide therapy ranged from 1 to 24 months (median 3.5 months, interquartile range 2.6-7 months), and the mean time to an undetectable CMV-DNA was 1.9 months. Adverse effects included diarrhea (35%), anemia (18%), and increased liver function tests (12%). Conclusions. Leflunomide, alone or in combination, has potential utility in treatment of complex CMV syndromes and in long-term suppression of viremia. The optimal duration of therapy and the balance of risks and benefits are not yet known.
Albert Einstein College of Medicine1, University of Southern California2, Science Applications International Corporation3, Johns Hopkins University4, University of California, San Francisco5, National Institutes of Health6, Maimonides Medical Center7, Georgetown University Medical Center8, Massachusetts Institute of Technology9
TL;DR: High‐resolution HLA class I and II genotyping of a large multiracial cohort of U.S. women with a high prevalence of HCV and HIV found that HLA genotype influences the host capacity to clear HCV viremia.
TL;DR: A 1-month fluoroquinolone course after transplantation was associated with significantly lower rates of BK viremia at 1 year compared with those with no fluoroquolone.
Abstract: Background and objectives: Nearly 30% of renal transplant recipients develops BK viremia, a prerequisite for BK nephropathy. Case reports have evaluated treatment options for BK virus, but no controlled studies have assessed prophylactic therapies. Fluoroquinolone antibiotics were studied for prevention of BK viremia after renal transplantation.
Design, setting, participants, & measurements: This retrospective analysis evaluated adult renal transplant recipients with at least one BK viral load (blood) between 90 and 400 days after transplantation. Six to 12 months of co-trimoxazole was used for Pneumocystis prophylaxis. In sulfa-allergic/-intolerant patients, 6 to 12 months of atovaquone with 1 month of a fluoroquinolone was used. Fluoroquinolones can inhibit BK DNA topoisomerase. The two groups studied were those that received 30 days of levofloxacin or ciprofloxacin after transplantation and those that did not. The primary endpoint was BK viremia rates at 1 year. Of note, of the 160 patients not receiving fluoroquinolone prophylaxis, 40 received a fluoroquinolone for treatment of a bacterial infection within 3 months after transplantation. Subgroup analysis evaluating these 40 patients against the 120 who had no exposure to fluoroquinolones was completed.
Results: A 1-month fluoroquinolone course after transplantation was associated with significantly lower rates of BK viremia at 1 year compared with those with no fluoroquinolone. In the subgroup analysis, exposure to fluoroquinolone for treatment of bacterial infections within 3 months after transplantation was associated with significantly lower 1-year rates of BK viremia.
Conclusions: This analysis demonstrates that fluoroquinolones are effective at preventing BK viremia after renal transplantation.