Accumulation of HIV-1 drug resistance in patients on a standard thymidine analogue-based first line antiretroviral therapy after virological failure: implications for the activity of next-line regimens from a longitudinal study in Mozambique

Luca, Andrea De; Sidumo, Zita; Zanelli, Giacomo; Magid, Noorjehan Abdul; Luhanga, Richard; Brambilla, Davide; Liotta, Giuseppe; Marazzi, Maria Cristina; Palombi, Leonardo; Ceffa, Susanna

doi:10.1186/s12879-017-2709-x

Cited by 16 publications

(14 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…This could be because of possible cross resistance mutations in this subgroup of patients as suggested previously [25, 26]. In Mozambique it was shown that resistance mutations were a common cause of virological failure on first line ARTs, the prevalence of which kept on increasing with time on ART [27]. This suggests that in settings like ours where switching to second line ART is not routinely guided by resistance testing, a possible selection and accumulation of drug resistant strains could possibly lead into early failure of second line ART regimen [26, 28], though the time on second line ART was not statistically different in our study between those failing virologicaly and their successful counter parts (6 months vs. 9 months, p = 0.065).…”

Section: Discussionmentioning

confidence: 78%

Magnitude and correlates of virological failure among adult HIV patients receiving PI based second line ART regimens in north western Tanzania; a case control study

et al. 2019

View full text Add to dashboard Cite

Background With a growing access to free ART, switching of ART to second line regimen has also become common following failure of first line ART regimens. Patients failing on first line ART regimens have been shown to stand a high risk of failing on subsequent second line ART regimens. The magnitude of those who are failing virologicaly on second line ART is not documented in our setting. This study was designed to assess the magnitude and correlates of second line ART treatment failure. Methods A retrospective analysis of patients on second line ART for at least 1 year was done at Bugando care and treatment center. Information on demographic, clinical and laboratory data were collected and analyzed using STATA 11. The proportion of patients with Virological failure was calculated and potential correlates of virological failure were determined by logistic regression model. Results In total 197 patients on second line ART were included in this study and 24 (12.18%) of them met criteria for virological failure. The odds of having virological failure on second line ART were independently associated with age of less than 30 years (AOR = 12.5, p = 0.001), being on first line for less than 3 years (AOR = 6.1, p = 0.002) and CD4 at switch to second line ART of less than 200cells/μl (AOR = 16.3, p < 0.001). Conclusion Virological failure among patients on second line ART is common. Predictors of virological failure in this study could assist in planning for strategies to improve the outcome of this subgroup of patients including close clinical follow up of patients at risk, a continued adherence intensification and a targeted resistance testing before switching to second line ART.

show abstract

Section: Discussionmentioning

confidence: 78%

Magnitude and correlates of virological failure among adult HIV patients receiving PI based second line ART regimens in north western Tanzania; a case control study

et al. 2019

View full text Add to dashboard Cite

show abstract

“…Detection of this mutation could be associated with acquisition with already HIV drug resistant strains from infected individuals on either AZT or D4T treatment [31, 32]. Nevertheless, K103 N, V108I, V179E, and Y181C, NNRTI mutations that confer resistance to Efavirenz (EFV) and Nevirapine (NVP) were also detected [28, 33]. Based on the ART drug combinations, these mutations could similarly be associated with the transmission of resistant viral strains from already known populations on treatment.…”

Section: Discussionmentioning

confidence: 99%

Human immunodeficiency virus type 1 ((HIV-1) subtypes in the northwest region, Cameroon

Abongwa

Nyamache

Torimiro

et al. 2019

Virol J

View full text Add to dashboard Cite

Background The high genetic diversity of HIV-1 has been shown to influence the global distribution, disease progression, treatment success, and the development of an effective vaccine. Despite the low HIV prevalence in Cameroon, all the major HIV subtypes alongside several circulating recombinant forms (CRFs) and unique recombinant forms (URFs) have been reported in Cameroon. To date, HIV-1 diversity in some parts of Cameroon has been largely studied however, information on circulating HIV-1 subtypes in the Northwest region (NWR) of Cameroon is dearth. Therefore the aim of this study was to determine the current circulating HIV-1 subtypes among adults in the NWR of Cameroon. Methods The genetic analysis of the reverse transcriptase region of the po l gene was performed on 81 samples. The samples were collected from drug naïve patients aged between 18 and 61 years residing within the rural and urban towns in the NWR during the period between February and April 2016. Viral RNA was extracted from plasma, reverse-transcribed, further amplified by nested-PCR before sequencing using an in-house protocol. Generated sequences were then phylogenetically analyzed together with references using MEGA 7. Results Phylogenetic analysis revealed a broad viral diversity including CRF02 _AG (74.1%), F2 (7.4%), D (7.4%), G (3.7%), A1 (1.2%), CRF22_01A1 (2.5%), CRF06_cpx (1.2%), CRF09_cpx (1.2%), CRF11_cpx (1.2%). Three close epidemic clusters were found among F2 (1) and CRF02_AG (2) variants. For the first time we are reporting the CRF22_01A1 subtype in this region. Conclusion Our findings update HIV-1 subtypes information in Cameroon and uphold previous studies that CRF02_AG is the most prevalent subtype. This CRF02_AG subtype may have important public health, research, and clinical consequences.

show abstract

“…However, in the G208R and T210K mutants, the total negative charge at this interface is reduced, resulting in less lattice destabilizing repulsion force. A hyperstable capsid deviating from a fine balance could have deleterious effects for the virus, which may explain why these mutations are rarely seen in patient samples [26].…”

Section: Resultsmentioning

confidence: 99%

MxB restricts HIV-1 by targeting the tri-hexamer interface of the viral capsid

Smaga

Summers

et al. 2018

Preprint

View full text Add to dashboard Cite

Myxovirus resistance protein B (MxB) is an interferon-inducible restriction factor of HIV-1 that blocks nuclear import of the viral genome. Evidence suggests that MxB recognizes higher-order interfaces of the HIV capsid lattice, but the mechanistic details of this interaction are not known. Previous studies have mapped the restriction activity of MxB to its N-terminus encompassing a triple arginine motif 11RRR13. Here we demonstrate a direct and specific interaction between the MxB N-terminus and helical assemblies of HIV-1 capsid protein (CA) using highly purified recombinant proteins. We performed thorough mutagenesis to establish the detailed molecular requirements for the CA interaction with MxB. The results map MxB binding to the interface of three CA hexamers, specifically interactions between positively charged MxB N-terminal residues and negatively charged CA residues. Our crystal structures show that the CA mutations affecting MxB interaction and restriction do not alter the conformation of capsid assembly. In addition, 30 microsecond long all-atom molecular dynamics (MD) simulations of the complex between the MxB N-terminus and the HIV CA tri-hexamer interface show persistent MxB binding and identify a MxB-binding pocket surrounded by three CA hexamers. These results establish the molecular details of the binding of a lattice-sensing host factor onto HIV capsid, and provide insight into how MxB recognizes HIV capsid for the restriction of HIV-1 infection.Author summaryThe human antiviral protein MxB is a restriction factor that fights HIV infection. Previous experiments have demonstrated that MxB targets the HIV capsid, a protein shell that protects the viral genome. To make the conical shaped capsid, HIV CA proteins are organized into a lattice composed of hexamer and pentamer building blocks, providing many interfaces for host proteins to recognize. Through extensive biochemical and biophysical studies and molecular dynamics simulations, we show that MxB is targeting the HIV capsid by recognizing the region created at the intersection of three CA hexamers. We are further able to map this interaction to a few CA residues, located in a negatively-charged well at the interface between the three CA hexamers. This work provides detailed residue-level mapping of the targeted capsid interface and how MxB interacts. This information could inspire the development of capsid-targeting therapies for HIV.

show abstract

Accumulation of HIV-1 drug resistance in patients on a standard thymidine analogue-based first line antiretroviral therapy after virological failure: implications for the activity of next-line regimens from a longitudinal study in Mozambique

Cited by 16 publications

References 17 publications

Magnitude and correlates of virological failure among adult HIV patients receiving PI based second line ART regimens in north western Tanzania; a case control study

Magnitude and correlates of virological failure among adult HIV patients receiving PI based second line ART regimens in north western Tanzania; a case control study

Human immunodeficiency virus type 1 ((HIV-1) subtypes in the northwest region, Cameroon

MxB restricts HIV-1 by targeting the tri-hexamer interface of the viral capsid

Contact Info

Product

Resources

About