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Current HIV research [journal]
- Evaluation of an In-house HIV-1 Drug Resistance genotypic Testing for using Dried Blood Spot Specimens in China. [JOURNAL ARTICLE]
- Curr HIV Res 2014 Dec 10.
Objectives: We evaluated an In-house assay for HIV-1 drug resistance genotyping by using DBS samples in China. Methods: The amplification sensitivity was assessed using 79 DBS specimens with plasma viral load ranging from 1,000 to 6,000 copies/ml. Precision was assessed using 5 DBS specimens with 5 replicates tested in one test run. Reproducibility was evaluated using other 5 DBS specimens with 5 replicates genotyped in 5 test runs. Nucleotide sequence identity and the degree of concordance in detecting drug resistance mutations were assessed within and between test runs. In addition, nucleotide sequence and drug resistance mutations were compared between 64 matched plasma and DBS specimens. Results: The amplification rate of DBS specimens with plasma viral load of 1,000-6,000 copies/ml was 96.2% (76/79). The nucleotide sequence identity was 99.7±0.34% and 99.6±0.25% within and between test runs, respectively. Moreover, there was a near perfect agreement of detecting drug resistance mutations intra- and inter- test runs with kappa value of 0.972 and 0.963, respectively. Between 64 pairs of plasma and DBS specimens, the nucleotide identity was excellent with 99.5±0.34%. As compared to the results of plasma specimens, the sensitivity and specificity for detecting drug resistance mutations in DBS specimens were 99.4 % (95% CI, 97.4-99.8%) and 99.8% (95% CI, 99.7-99.9%), respectively. Totally 15 discordant drug resistance mutations were found. Among them, 53.3 % (8/15) were caused by mixture base. Conclusions: The In-house HIVDR genotyping assay could be used for testing DBS samples with viral load above 1,000copies/ml in China and had a low intra- and inter- assay variability. DBS is an excellent alternative to plasma for HIV-1 drug resistance genotyping at population levels in China.
- Cardiac Morbidity in an HIV-1 Lipodystrophy Patient Cohort Expressing the TNF-α-238 G/A Single Nucleotide Gene Polymorphism. [JOURNAL ARTICLE]
- Curr HIV Res 2014 Dec 2.
In the current study we investigated the prevalence of the TNF-α 238G/A single nucleotide polymorphism (SNP) of the TNF-α gene in the development of lipodystrophy among HIV-1 infected individuals who had been receiving antiretroviral therapy (ART) in the immunodeficiency clinics of the National AIDS Research Institute (NARI) at Pune, India. We assessed the association of this SNP with the development of lipoatrophy/dyslipidemia and insulin resistance in these patients and measured carotid intima thickening which is a surrogate marker for chronic cardiac morbidity. Our results show that the incidence of the TNF-α 238G/A SNP is ~ two fold higher in patients with lipodystrophy as compared to those without lipodystrophy. Patients with lipodystrophy demonstrated a higher likelihood of the development of metabolic syndrome as evident by increased insulin sensitivity and increased percentage (%) β cell function. Further, a significant increase in left carotid intima thickness was observed in patients with lipodystrophy. Our study validates the association of the TNF-α 238G/A SNP allelic variant with the development of HIV- lipodystrophy via the modulation of TNF-α production, which contributes to dyslipidemia, increased lipolysis, increased insulin resistance, altered differentiation of adipocytes and increased carotid intima thickness. The contribution of genetic determinants such as the TNF-α 238G/A SNP to lipodystrophy, may provide insight into the mechanisms that underlie this disease condition and may be useful in the future for personalized therapy. Additionally, these findings will be useful in monitoring chronic cardiac morbidities among HIV infected individuals who express this SNP.
- HIV Extra cellular Tat : Myth or Reality ? [JOURNAL ARTICLE]
- Curr HIV Res 2014 Dec 2.
The human immunodeficiency virus type 1 (HIV) eradication will require elimination of HIV infected cells. No antiretroviral treatments (ART) or vaccine approaches have been able to reduce significantly the level of HIV infected cells in peripheral blood. This inefficacy is generally explained by the presence of a major reservoir of latent HIV infected cells in the central nervous system (CNS) that would be a sanctuary where Cytotoxic T Lymphocytes (CTL) have no access and would refresh peripheral blood with activated HIV infected cells. In this review, the presence of a major reservoir in the CNS appears to be inconsistent with recent clinical studies measuring HIV DNA. The major reservoirs are gut tissue, rectal tissue and the peripheral blood where HIV infected cells survive in an environment containing CTL. Extra cellular Tat might protect HIV infected cells from CTL dues to its capacity to cross CTL membranes and trigger apoptosis. Evidences of Tat secretion from HIV infected cells is shown with the detection of Tat antibodies in different clinical studies. Presence of neutralizing Tat antibodies in cohorts of patients who were exposed to HIV but who are now seronegative is described. The conclusion of this review is that a vaccine eliciting neutralizing antibodies against Tat might reduce significantly the level of HIV infected cells, what ART or other vaccine approaches have been unable to achieve up to now. It could be a first step toward HIV eradication.
- Reviving an Old HIV-1 Gene: the HIV-1 Antisense Protein. [JOURNAL ARTICLE]
- Curr HIV Res 2014 Dec 2.
The existence of an HIV-1 protein translated from an antisense transcript was suggested over 25 years ago. However, this Antisense Protein (ASP) gene has still not been completely accepted by the HIV-1 research community. The aim of this review is to discuss recent findings, which suggest that ASP needs to be considered as a viral gene, playing an important role in HIV-1 replication and persistence. In past years, several studies have highlighted the existence of HIV-1 antisense transcripts. More recently, we and others have convincingly demonstrated that this transcript produces a protein with a unique distribution and a rapid turnover, when expressed in mammalian cells. Furthermore, a role in autophagy and HIV-1 replication has been associated with this protein. In light of these recent reports, we believe that ASP needs to be added to the schematic representation of the HIV-1 proviral DNA and requires further investigation, as it could represent a new potential target for anti-retroviral therapies and vaccine strategies.
- The Combination of Pill Count and Self-Reported Adherence is a Strong Predictor of First-Line ART Failure for Adults in South Africa. [Journal Article]
- Curr HIV Res 2014; 12(5):366-75.
Suboptimal adherence to antiretroviral therapy (ART) is a strong predictor of virologic failure (VF) among people with HIV. Various methods such as patient self-report, pill counts and pharmacy refills have been utilized to monitor adherence. However, there are limited data on the accuracy of combining methods to better predict VF in routine clinical settings. We examined various methods to assess adherence including pill count, medication possession ratio (MPR), and self-reported adherence in order to determine which was most highly associated with VF after > 6 months on ART.We conducted a secondary analysis of data from a case-control study. At enrollment, pharmacy refill data were collected retrospectively from the medical chart, pill counts were completed to derive a pill count adherence ratio (PCAR) and a self-report questionnaire was administered to all participants. Parametric smooth splines and receiver operator characteristic (ROC) analyses were carried out to assess the accuracy of the adherence methods.458 patients were enrolled from October 2010 to June 2012. Of these, 158 (34.50%) experienced VF (cases) and 300 (65.50%) were controls. The median (IQR) PCAR was 1.10 (0.99-1.14) for cases and 1.13 (1.08-1.18) for controls (p<0.0001). The median MPR was 1.00 (0.97-1.07) for cases and 1.03 (0.96-1.07) for controls (p=0.83). Combination of PCAR and self-reported questions was highly associated with VF.In this setting, a combination of pill count adherence and self-report adherence questions had the highest diagnostic accuracy for VF. Further validation of this simple, low-cost combination is warranted in large prospective studies.
- Improved Survival with Co-Trimoxazole Prophylaxis among People Living with HIV/AIDS Who Initiated Antiretroviral Treatment in Henan Province, China. [Journal Article]
- Curr HIV Res 2014; 12(5):359-65.
This study aims to evaluate the effect of co-trimoxazole (CTX) prophylaxis on mortality reduction among HIV-infected patients receiving antiretroviral therapy (ART) in Henan Province, China.We conducted a retrospective study.All individuals aged 15 years and older who initiated ART between 2008 and 2010 in Henan Province with completed CTX prophylaxis treatment information were included. The effect of CTX prophylaxis was estimated using Kaplan-Meier survival analysis and multivariate Cox proportional hazard modeling for mortality at 3-months and 12- months after ART initiation.Overall mortality among patients receiving both ART and CTX was nearly double at 3-months after ART initiation compared with that at 12-months (12.4 per 100 PY vs 6.3 per 100 PY, p<0.01). After adjusting for gender, age, TB history, year of ART initiation and CD4 count at ART initiation, CTX was associated with a significant reduction in 12-month mortality (adjusted hazard ratio (AHR) = 0.65, 95% confidence interval (CI): 0.44 - 0.95; p = 0.027) compared with persons not receiving CTX. The protective effect was more pronounced in the first 3 months after ART initiation (AHR = 0.53, 95% CI: 0.32 - 0.89; p = 0.017).CTX prophylaxis together with ART reduced mortality of adult HIV patients during the first 12 months of ART in Henan Province, China. The effect was highest in the first 3 months of ART. CTX should be prescribed to all HIV-infected adults who initiate ART.
- Drug resistance mutations from whole blood proviral DNA among patients on antiretroviral drugs in zimbabwe. [Journal Article]
- Curr HIV Res 2014 Nov 21; 12(5):309-16.
There are more than 500 000 HIV-infected people on antiretroviral treatment (ART) in Zimbabwe with very limited laboratory monitoring. To ensure effective treatment and prevent transmission of drug resistance, affordable treatment monitoring is needed to guide individual treatment.125 whole blood samples from patients on first-line ART were investigated for drug resistance mutations using an in-house genotypic testing method. Patients had been on HIV reverse transcriptase inhibitors only, with some having been on both HIV and TB treatment. DNA was extracted from whole blood; amplicons were generated by nested PCR and sequenced. Drug resistance mutations were determined using the Stanford HIV drug resistance database. Exact statistics were used to investigate relationships between drug resistance and predisposing factors.From 125 samples, 108 were successfully analyzed for drug resistance mutations. 11 of the 108 sequences had drug resistance mutations; predominantly M184V and Y181C. For a 100-cell increase in CD4 count, the odds of being resistant were 61% lower than those with the baseline CD4 count (p=0.04, CI: 0.34-0.98). There was no association between concurrent HIV/TB treatment and drug resistance (p=0.41).Although plasma samples are recommended for genotypic testing, the cost of analyzing plasma RNA makes it less feasible in resource limited settings. Lower cost DNA drug resistance testing from whole blood samples was assessed as a treatment-monitoring tool among patients followed by CD4 and clinical monitoring only. The infrequent detection of resistance and higher CD4 is consistent with effective first-line treatment. Further investigation of proviral DNA as a tool to identify drug resistance mutations is warranted.
- Chronic, Highly Productive HIV Infection in Monocytes During Supportive Culture. [Journal Article]
- Curr HIV Res 2014; 12(5):317-24.
Peripheral blood monocytes of HIV-infected individuals carry virus, constituting one potential reservoir. However, most studies of infection in tissue culture find monocytes refractory to HIV replication, suggesting that culture conditions limit the relative susceptibility of this target cell. We employed a tissue culture system optimized for maintenance of human monocytes without differentiation and compared HIV infection efficiency of monocytes and fully differentiated monocyte derived macrophages (MDM). We tested direct virus-cell fusion, expression of cell lineage markers, and productive HIV infection in fresh monocytes, monocytes after varying periods of supportive culture, and fully differentiated MDM comparing cells from individual donors. Fresh, uncultured monocytes allowed modest HIV fusion, however one week culture was sufficient to allow efficient fusion and an increase in expression of CD14, CD16, CD33, and CD105. Compared to freshly isolated monocytes, monocytes infected after a few days in culture produced p24 more quickly, but the peaks of production were similar. Fresh monocytes were highly susceptible to productive HIV infection in supportive culture, roughly equal to MDM from the same donor in expression of extracellular p24 up to five weeks after infection. Taken together our findings indicate that monocytes are biologically capable of supporting chronic, highly productive HIV infection, a capacity that may reflect their status in HIV-infected persons.
- 2´,3´-Dialdehyde of ATP, ADP, and Adenosine Inhibit HIV-1 Reverse Transcriptase and HIV-1 Replication. [Journal Article]
- Curr HIV Res 2014; 12(5):347-58.
The 2´3´-dialdehyde of ATP or oxidized ATP (oATP) is a compound known for specifically making covalent bonds with the nucleotide-binding site of several ATP-binding enzymes and receptors. We investigated the effects of oATP and other oxidized purines on HIV-1 infection and we found that this compound inhibits HIV-1 and SIV infection by blocking early steps of virus replication. oATP, oxidized ADP (oADP), and oxidized Adenosine (oADO) impact the natural activity of endogenous reverse transcriptase enzyme (RT) in cell free virus particles and are able to inhibit viral replication in different cell types when added to the cell cultures either before or after infection. We used UFLC-UV to show that both oADO and oATP can be detected in the cell after being added in the extracellular medium. oATP also suppresses RT activity and replication of the HIV-1 resistant variants M184V and T215Y. We conclude that oATP, oADP and oADO display anti HIV-1 activity that is at in least in part due to inhibitory activity on HIV-1 RT.