HIV-1 Drug Resistance Profiles for the HIV Protease and Reverse Transcriptase Gene in Patients Receiving Combination Therapy in Tehran, Iran.

BACKGROUND: Determination of the drug-resistant mutations has a crucial role in the management of HIV-1 infected patients. OBJECTIVE: The aim of the current study was to evaluate drug resistance profile of Reverse transcriptase and Proteasegenes, and to find the correlation between drug resistance mutations and ART regimen to intensifyphysicians'options for the most effective therapy which could also influence the establishment of health-related policies at the national level in Iran. METHOD: HIV-1 RNA of 34 samples was extracted from plasma and RT Nested- PCR was performed and the final products were sequenced. Stanford HIV drug resistance sequence database was used for interpretation of the data. RESULTS: In 14 patients out of 15, the following mutations were observed; Nucleoside RT Inhibitor (NRTI)-Resistance Mutations with the prevalence of 11 patients having this mutation at codon 184 (73%) and Non-Nucleoside RT Inhibitor (NNRTI)-Resistance Mutations with the prevalence of 8 patients having NNRTI mutations at codon 103(53%).In 17 patients, major Protease Inhibitor (PI) Resistance Mutations were found out in 2 (12%) of them while the minor PI was found in7 (41%) patients. CONCLUSION: An antiretroviral treatment consisting of nucleoside reverse transcriptase inhibitor, non-nucleoside reverse transcriptase inhibitor and protease inhibitor, impairs the emergence of a resistant strain and descends its prevalence among the community. Having a high rate mutation in participants of this study raises concerns about treatment failure in HIV infected people in Iran. Observing high mutations rates in participants of this study raises concerns about treatment failure in HIV infected people in Iran.

Different Degrees of Immune Recovery Using Antiretroviral Regimens with Vonavir or Zidovudine/Lamivudine/Efavirenz in HIVPositive Patients Receiving First Line Treatment in Iran.

BACKGROUND: The initial antiretroviral therapy (ART) regimens recommended by most national treatment guidelines in resource-limited settings consist of two Nucleoside Reverse-Transcriptase Inhibitors (NRTIs) and one Non-Nucleoside Reverse- Transcriptase Inhibitor (NNRTI). The NRTIs are Zidovudine (AZT) or Stavudine (d4T) with Lamivudine (3TC); the NNRTI components are either Nevirapine (NVP) or Efavirenz (EFV). Existing data regarding the effectiveness of Vonavir compared to other first-line ART regimens in increasing CD4+ T cell counts are unsatisfactory. METHODS: Immunological outcomes of 134 individuals who were on initial stage of antiretroviral therapy with Vonavir or a combination of Zidovudine/Lamivudine and Efavirenz were analyzed. The immunological response was then assessed during 28 weeks. RESULTS: Both groups demonstrated a significant increase in their CD4+ T cell count which was greater in Zidovudine/Lamivudine and Efavirenz treated group. We observed a noticeable increase in CD4+ T cells rates in the first three months of therapy; however, our results indicated a greater increase of cell counts in individuals with baseline CD4 lower than 100 cells/mm3 treated with Vonavir in first 12 weeks of treatment compared to those with higher baseline CD4. CONCLUSION: A rapid CD4+ Tcell increase occurred shortly after beginning ART consisting either Vonavir or combination of Zidovudine, Lamivudine and Efavirenz. Late increases in CD4+ T cell counts were more pronounced in therapy using Zidovudine/ Lamivudine and Efavirenz.

Evaluation of Acquired HIV Drug Resistance among People Living with HIV Who Have Taken Antiretroviral Therapy for 9-15 Months in 14 Triangular Clinics in Iran, 2015-2016.

AIMS: The aim of this study was to evaluate drug resistance patterns among Iranian people living with HIV who have taken antiretroviral therapy for 9-15 months. METHODS: A cross-sectional study was conducted between December 2015 and May 2016. Two hundred fifty-two blood samples were collected from all eligible HIV-infected patients at fourteen healthcare settings, located in major provinces in Iran. The samples were examined for presence of drug resistance strains and viral load level. Moreover, a phylogenetic tree, using neighbor joining, was constructed and HIV subtypes were determined. RESULTS: The most common subtypes were CRF35-AD (47.6%) and A1 (42.8%), followed by 45_CPX (4.8%) and C (4.8%). The resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs), nucleoside reverse transcriptase inhibitors (NRTIs), and protease inhibitors was reported as 19.2, 19.2, and 10.3%, respectively. M184I/V mutation was the most frequent (31.6%) mutation among NRTI-based regimens. Moreover, K103E/N was the most frequent (34.2%) NNRTI mutation. CONCLUSIONS: This is the first study to illuminate the emergence of the CPX genotype among Iranian patients. The drug resistance rate of NNRTIs was similar to that of NRTIs. By assessing drug resistance, it is possible to evaluate the efficacy of treatment and patient adherence to treatment.

Transient Inhibition of FGFR2b-ligands signaling leads to irreversible loss of cellular ß-catenin organization and signaling in AER during mouse limb development.

The vertebrate limbs develop through coordinated series of inductive, growth and patterning events. Fibroblast Growth Factor receptor 2b (FGFR2b) signaling controls the induction of the Apical Ectodermal Ridge (AER) but its putative roles in limb outgrowth and patterning, as well as in AER morphology and cell behavior have remained unclear. We have investigated these roles through graded and reversible expression of soluble dominant-negative FGFR2b molecules at various times during mouse limb development, using a doxycycline/transactivator/tet(O)-responsive system. Transient attenuation (≤ 24 hours) of FGFR2b-ligands signaling at E8.5, prior to limb bud induction, leads mostly to the loss or truncation of proximal skeletal elements with less severe impact on distal elements. Attenuation from E9.5 onwards, however, has an irreversible effect on the stability of the AER, resulting in a progressive loss of distal limb skeletal elements. The primary consequences of FGFR2b-ligands attenuation is a transient loss of cell adhesion and down-regulation of P63, ß1-integrin and E-cadherin, and a permanent loss of cellular ß-catenin organization and WNT signaling within the AER. Combined, these effects lead to the progressive transformation of the AER cells from pluristratified to squamous epithelial-like cells within 24 hours of doxycycline administration. These findings show that FGFR2b-ligands signaling has critical stage-specific roles in maintaining the AER during limb development.

Signaling by FGFR2b controls the regenerative capacity of adult mouse incisors.

Rodent incisors regenerate throughout the lifetime of the animal owing to the presence of epithelial and mesenchymal stem cells in the proximal region of the tooth. Enamel, the hardest component of the tooth, is continuously deposited by stem cell-derived ameloblasts exclusively on the labial, or outer, surface of the tooth. The epithelial stem cells that are the ameloblast progenitors reside in structures called cervical loops at the base of the incisors. Previous studies have suggested that FGF10, acting mainly through fibroblast growth factor receptor 2b (FGFR2b), is crucial for development of the epithelial stem cell population in mouse incisors. To explore the role of FGFR2b signaling during development and adult life, we used an rtTA transactivator/tetracycline promoter approach that allows inducible and reversible attenuation of FGFR2b signaling. Downregulation of FGFR2b signaling during embryonic stages led to abnormal development of the labial cervical loop and of the inner enamel epithelial layer. In addition, postnatal attenuation of signaling resulted in impaired incisor growth, characterized by failure of enamel formation and degradation of the incisors. At a cellular level, these changes were accompanied by decreased proliferation of the transit-amplifying cells that are progenitors of the ameloblasts. Upon release of the signaling blockade, the incisors resumed growth and reformed an enamel layer, demonstrating that survival of the stem cells was not compromised by transient postnatal attenuation of FGFR2b signaling. Taken together, our results demonstrate that FGFR2b signaling regulates both the establishment of the incisor stem cell niches in the embryo and the regenerative capacity of incisors in the adult.