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Treatment-associated polymorphisms in protease are significantly associated with higher viral load and lower CD4 count in newly diagnosed drug-naive HIV-1 infected patients.

ABSTRACT: BACKGROUND:The effect of drug resistance transmission on disease progression in the newly infected patient is not well understood. Major drug resistance mutations severely impair viral fitness in a drug free environment, and therefore are expected to revert quickly. Compensatory mutations, often already polymorphic in wild-type viruses, do not tend to revert after transmission. While compensatory mutations increase fitness during treatment, their presence may also modulate viral fitness and virulence in absence of therapy and major resistance mutations. We previously designed a modeling technique that quantifies genotypic footprints of in vivo treatment selective pressure, including both drug resistance mutations and polymorphic compensatory mutations, through the quantitative description of a fitness landscape from virus genetic sequences. RESULTS:Genotypic correlates of viral load and CD4 cell count were evaluated in subtype B sequences from recently diagnosed treatment-naive patients enrolled in the SPREAD programme. The association of surveillance drug resistance mutations, reported compensatory mutations and fitness estimated from drug selective pressure fitness landscapes with baseline viral load and CD4 cell count was evaluated using regression techniques. Protease genotypic variability estimated to increase fitness during treatment was associated with higher viral load and lower CD4 cell counts also in treatment-naive patients, which could primarily be attributed to well-known compensatory mutations at highly polymorphic positions. By contrast, treatment-related mutations in reverse transcriptase could not explain viral load or CD4 cell count variability. CONCLUSIONS:These results suggest that polymorphic compensatory mutations in protease, reported to be selected during treatment, may improve the replicative capacity of HIV-1 even in absence of drug selective pressure or major resistance mutations. The presence of this polymorphic variation may either reflect a history of drug selective pressure, i.e. transmission from a treated patient, or merely be a result of diversity in wild-type virus. Our findings suggest that transmitted drug resistance has the potential to contribute to faster disease progression in the newly infected host and to shape the HIV-1 epidemic at a population level.

SUBMITTER: Theys K

PROVIDER: S-EPMC3487874 | biostudies-other | 2012 Oct

REPOSITORIES: biostudies-other

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Treatment-associated polymorphisms in protease are significantly associated with higher viral load and lower CD4 count in newly diagnosed drug-naive HIV-1 infected patients.

Theys Kristof K Deforche Koen K Vercauteren Jurgen J Libin Pieter P van de Vijver David Amc DA Albert Jan J Asjö Birgitta B Balotta Claudia C Bruckova Marie M Camacho Ricardo J RJ Clotet Bonaventura B Coughlan Suzie S Grossman Zehava Z Hamouda Osamah O Horban Andrzei A Korn Klaus K Kostrikis Leondios G LG Kücherer Claudia C Nielsen Claus C Paraskevis Dimitrios D Poljak Mario M Puchhammer-Stockl Elisabeth E Riva Chiara C Ruiz Lidia L Liitsola Kirsi K Schmit Jean-Claude JC Schuurman Rob R Sönnerborg Anders A Stanekova Danica D Stanojevic Maja M Struck Daniel D Van Laethem Kristel K Wensing Annemarie Mj AM Boucher Charles Ab CA Vandamme Anne-Mieke AM

Retrovirology 20121003

<h4>Background</h4>The effect of drug resistance transmission on disease progression in the newly infected patient is not well understood. Major drug resistance mutations severely impair viral fitness in a drug free environment, and therefore are expected to revert quickly. Compensatory mutations, often already polymorphic in wild-type viruses, do not tend to revert after transmission. While compensatory mutations increase fitness during treatment, their presence may also modulate viral fitness ...[more]

PMID: 23031662

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Project description:Males are more susceptible than females to infections due to the differences in endocrine-immune interactions. Furthermore, it is reported that lowering cell cholesterol impairs viral replication and infection in vitro. However, the production of oxysterols in vivo by oxidation of cholesterol may result in inhibition of HIV replication. Therefore, this study was designed to determine the associations of gender and serum total cholesterol with CD4+ T cell counts and/or WHO clinical stages, and HIV ribonucleic acid (RNA) load in antiretroviral therapy (ART) naive study population with known sero-positive time of stay in Addis Ababa. METHODS: A cross-sectional study was conducted from February to August 2013 on 594 HIV-1 infected ART-naïve adult study participants in four hospitals Addis Ababa. CD4+ T-cell count, HIV RNA load, hemoglobin and fasting serum total cholesterol were determined. Socio-demographic characteristics, WHO clinical stages, and height and weight were collected from patients' chart and triangulated by structured questionnaire. Pearson chi-square test, Spearman rank correlation and univariate and multivariate linear/logistic regression analyses were carried out to determine associations.Mean HIV RNA load was found to be lower in women than in men (p?<?0.05). CD4+ T cell count and serum total cholesterol were found to be significantly correlated with HIV RNA load (p?<?0.01). Women were at lower risk of having higher HIV RNA load in comparison to men. In addition, having lower concentrations of serum total cholesterol was found to be independent predictor of higher HIV RNA load in comparison to those with higher concentrations of cholesterol in serum (p?<?0.05). The multivariate binomial logistic regression also showed that the immune status was better in women than men, and in the presence of higher serum total cholesterol (p?<?0.05).Gender and serum total cholesterol were found to be associated and independent predictors of HIV RNA load, and CD4+ cell count and/or WHO clinical stages. There is a significant lower HIV RNA load and better CD4+ T cell count in women and those study participants with higher serum total cholesterol.

Project description:Recently, dolutegravir (DTG)-based combined therapy, a more effective and safer first-line antiretroviral therapy (ART), has been recommended by the World Health Organization for the treatment of Human Immunodeficiency Virus (HIV) since July 2018. However, its effectiveness in CD4+ T-cells count recovery and viral load suppression has not been studied yet in Ethiopia, where HIV is endemic. Therefore, we aimed to conduct a pilot assessment on the effect of DTG-based therapy on CD4+ T-cell count and viral load count among people living with HIV (PLWH) in Ethiopia. A longitudinal prospective cohort study was conducted from July 2020 to February 2021. 109 PLWH who are ART naive but plan to initiate DTG-based therapy were recruited. HIV viral ribonucleic acid (RNA) copies were determined using polymerase chain reaction. To compute the difference in viral load and CD4+ T-cell counts between the baseline, 3rd, and 6th months, a Friedman test was used. The study included 109 PLWH who had never received antiretroviral medication. Participants taking DTG-based treatment showed significantly decreasing median (IQR) values of viral load count (copies/mL) from 446,812 (237649.5-732994.5) at baseline to 34 (23.5-46) at 3 months and 0.0 (0-19) at 6 months of treatment follow-up. Although the treatment increases the proportion of participants with HIV-1 RNA 50 copies/mL from 0 (0% at baseline) to 87 (79.8%) and 100 (91.7%) at the 3rd and 6th months of treatment, respectively, On the other hand, the CD4+ T-cell count increased significantly during treatment: median (IQR): 209 (81.5-417.5) versus 291 (132-522) versus 378 (181-632.5) cells/L at baseline, the 3rd and 6th months of the treatment follow-up period, respectively. We found dolutegravir-based therapy was a promising option with high virological suppression rates and CD4+ T-cell count recovery, demonstrating a restoration of cellular immunity. Moreover, Viral load suppression rates were high after the initiation of the treatment. We recommend further research should be conducted with a larger number of participants to acquire greater awareness of the treatment outcomes.

Dataset Information

Treatment-associated polymorphisms in protease are significantly associated with higher viral load and lower CD4 count in newly diagnosed drug-naive HIV-1 infected patients.

Publications

Treatment-associated polymorphisms in protease are significantly associated with higher viral load and lower CD4 count in newly diagnosed drug-naive HIV-1 infected patients.

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