HIV-1 Subtype C Vpr Amino Acid Residue 45Y and Specific Conserved Fragments Are Associated with Neurocognitive Impairment and Markers of Viral Load.

There is increasing evidence that HIV-1 viral protein R (Vpr) plays an important role in the pathogenesis of cognitive impairment. We investigated the relationship between HIV-1 subtype C Vpr sequence variation and HIV-associated neurocognitive impairment as measured by global deficit score (GDS) in treatment-naive individuals. We used different bioinformatic tools and statistical models to correlate vpr variation and cognitive function. We identified a tyrosine at position 45 (45Y) as a signature for neurocognitive impairment and histidine (45H) as a signature in the non-impaired individuals. The presence of signature 45Y was associated by 3.66 times higher GDS, 525 times higher plasma viral load, 15.84 times higher proviral load, and 60% lower absolute CD4-T cell count compared with those without the signature. Additionally, we identified four conserved Vpr fragment sequences, PEDQGPQREPYNEWTLE (5-21), LGQYIY (42-47), TYGDTW (49-54), and PEDQGPQREPYNEW (5-18), that were associated with higher plasma viral load and proviral load. The implication of these findings is that variation of Vpr leads to neurocognitive impairment in HIV infection and worsens the progression of disease in general by promoting the production of provirus, promoting HIV replication and depletion of CD4+ T cells in the periphery.

HIV-1 subtype C Tat exon-1 amino acid residue 24K is a signature for neurocognitive impairment.

Variation and differential selection pressures on Tat genes have been shown to alter the biological function of the protein, resulting in pathological consequences in a number of organs including the brain. We evaluated the impact of genetic variation and selection pressure on 147 HIV-1 subtype C Tat exon 1 sequences from monocyte-depleted peripheral lymphocytes on clinical diagnosis of neurocognitive impairment. Genetic analyses identified two signature amino acid residues, lysine at codon 24 (24K) with a frequency of 43.4% and arginine at codon 29 (29R) with a frequency of 34.0% in individuals with HIV-associated neurocognitive impairment. The analyses also revealed two signature residues, asparagine, 24 N (31.9%), and histidine, 29H (21.3%), in individuals without neurocognitive impairment. Both codons, 24 and 29, were associated with high entropy but only codon 29 was under positive selection. The presence of signature K24 increased by 2.08 times the risk of neurocognitive impairment, 3.15 times higher proviral load, and 69% lower absolute CD4 T-cell count compared to those without the signature. The results support a linkage between HIV-1 C Tat N24K polymorphism, proviral load, immunosuppression, and neurocognitive impairment. The signature may induce more neurotoxic effects, which contributes to establishment and severity of HIV-associated neurocognitive impairment.

Prevalence and patterns of HIV drug resistance in patients with suspected virological failure in North-Western Tanzania.

BACKGROUND: More than 15 million people in sub-Saharan Africa receive ART. Treatment failure is common, but the role of HIV drug resistance in treatment failure is largely unknown because drug resistance testing is not routinely done. This study determined the prevalence and patterns of HIV drug resistance in patients with suspected virological failure. MATERIALS AND METHODS: A single high viral load of >1000 viral RNA copies/mL of plasma at any point during ART was considered as suspected virological failure. HIV-1 RNA was extracted from plasma samples of these patients using the QIAamp Viral RNA kit. The protease and part of the RT regions of the HIV pol gene were characterized. RESULTS: Viral load was determined in 317 patients; 64 (20.2%) had suspected virological failure. We successfully genotyped 56 samples; 48 (85.7%) had at least one major resistance-associated mutation (RAM). Common mutations in RT were M184V (75%), T215Y (41.1%), K103N (39.3%), M41L (32.1%), D67DN (30.3%), G190A (28.6%) and A98G (26.8%). No RAMs were detected in ART regimens based on a ritonavir-boosted PI. CONCLUSIONS: The Tanzanian national guidelines define 'virological failure' as two consecutive viral load measurement results, at 3 month intervals, above the WHO threshold (1000 copies/mL). Here, we show that a single viral load above the WHO threshold is associated with high rates of RAMs. This suggests that a single high viral load measurement could be used to predict virological failure and avoid delays in switching patients from first-line to higher genetic barrier second-line regimens.

Preinvasive cervical lesions and high prevalence of human papilloma virus among pregnant women in Cameroon.

INTRODUCTION: With the exception of breast cancer, gynecologic neoplasms constitute the most common cancers that complicate pregnancy. Pregnancy therefore presents a window of opportunity for all pregnant women who do not take part in routine free cervical cancer screening program to undergo a free voluntary cytological test and human papillomavirus (HPV) DNA testing. This study aimed to determine prevalent HPV genotypes among pregnant women using exfoliated cells from cervical swabs and determine risk factors responsible for the upsurge of cervical precancerous lesions. METHODS: In a cross-sectional study conducted from October 2017 to March 2018, a total of 482 pregnant women were enrolled. Cervical swabs and samples for cytology were collected from each enrolled participant during their routine prenatal consultation. The Papanicolaou's (Pap) staining technique was performed and all cervical swab samples were amplified through conventional PCR. HPV genotypes were identified using the Roche Linear Array Genotyping Assay. SAS 9.2 software (SAS Institute Inc., USA) was used for statistical analysis and p values >0.05 were considered significant. RESULTS: Among the 482 participants, 354 (73.4%) had normal cytology and 128 (26.6%) had abnormal cytology. HPV DNA was identified in 62/464 (13.4%). The most prominent HPV types identified were HPV 16 (24%), HPV 18 (36.4%), HPV 45 (28%), HPV 53 (18.9%) and HPV 67 (24.3%). Early intercourse, number of sexual partners and age at first pregnancy were some of the risk factors that influenced the etiology of preinvasive cervical lesion. CONCLUSIONS: Prevalent HPV types identified in our study were HPV 16, 18, 45, 53 and 67. Organizing effective screening programs in prenatal care facilities is crucial in order to detect prevalent HR-HPV types and precursors for cervical lesions. The addition of HPV vaccination in the national immunization program with focus on the different epidemiological HPV genotypes circulating in the country is warranted.

Interaction analysis of statistically enriched mutations identified in Cameroon recombinant subtype CRF02_AG that can influence the development of Dolutegravir drug resistance mutations.

BACKGROUND: The Integrase (IN) strand transfer inhibitor (INSTI), Dolutegravir (DTG), has been given the green light to form part of first-line combination antiretroviral therapy (cART) by the World Health Organization (WHO). DTG containing regimens have shown a high genetic barrier against HIV-1 isolates carrying specific resistance mutations when compared with other class of regimens. METHODS: We evaluated the HIV-1 CRF02_AG IN gene sequences from Cameroon for the presence of resistance-associated mutations (RAMs) against INSTIs and naturally occurring polymorphisms (NOPs), using study sequences (n = 20) and (n = 287) sequences data derived from HIV Los Alamos National Laboratory database. The possible impact of NOPs on protein structure caused by HIV-1 CRF02_AG variations was addressed within the context of a 3D model of the HIV-1 IN complex and interaction analysis was performed using PyMol to validate DTG binding to the Wild type and seven mutant structures. RESULTS: We observed 12.8% (37/287) sequences to contain RAMs, with only 1.0% (3/287) of the sequences having major INSTI RAMs: T66A, Q148H, R263K and N155H. Of these,11.8% (34/287) of the sequences contained five different IN accessory mutations; namely Q95K, T97A, G149A, E157Q and D232N. NOPs occurred at a frequency of 66% on the central core domain (CCD) position, 44% on the C-terminal domain (CTD) position and 35% of the N-terminal domain (NTD) position. The interaction analysis revealed that DTG bound to DNA, 2MG ions and DDE motif residues for T66A, T97A, Q148H, N155H and R263K comparable to the WT structure. Except for accessory mutant structure E157Q, only one MG contact was made with DTG, while DTG had no MG ion contacts and no DDE motif residue contacts for structure D232N. CONCLUSIONS: Our analysis indicated that all RAM's that resulted in a change in the number of interactions with encompassing residues does not affect DTG binding, while accessory mutations E157Q and D232N could affect DTG binding leading to possible DTG resistance. However, further experimental validation is required to validate the in silico findings of our study.

Increased acquired protease inhibitor drug resistance mutations in minor HIV-1 quasispecies from infected patients suspected of failing on national second-line therapy in South Africa.

BACKGROUND: HIV-1C has been shown to have a greater risk of virological failure and reduced susceptibility towards boosted protease inhibitors (bPIs), a component of second-line combination antiretroviral therapy (cART) in South Africa. This study entailed an evaluation of HIV-1 drug resistance-associated mutations (RAMs) among minor viral populations through high-throughput sequencing genotypic resistance testing (HTS-GRT) in patients on the South African national second-line cART regimen receiving bPIs. METHODS: During 2017 and 2018, 67 patient samples were sequenced using high-throughput sequencing (HTS), of which 56 samples were included in the final analysis because the patient's treatment regimen was available at the time of sampling. All patients were receiving bPIs as part of their cART. Viral RNA was extracted, and complete pol genes were amplified and sequenced using Illumina HiSeq2500, followed by bioinformatics analysis to quantify the RAMs according to the Stanford HIV Drug Resistance Database. RESULTS: Statistically significantly higher PI RAMs were observed in minor viral quasispecies (25%; 14/56) compared to non-nucleoside reverse transcriptase inhibitors (9%; 5/56; p = 0.042) and integrase inhibitor RAM (4%; 2/56; p = 0.002). The majority of the drug resistance mutations in the minor viral quasispecies were observed in the V82A mutation (n = 13) in protease and K65R (n = 5), K103N (n = 7) and M184V (n = 5) in reverse transcriptase. CONCLUSIONS: HTS-GRT improved the identification of PI and reverse transcriptase inhibitor (RTI) RAMs in second-line cART patients from South Africa compared to the conventional GRT with ≥20% used in Sanger-based sequencing. Several RTI RAMs, such as K65R, M184V or K103N and PI RAM V82A, were identified in < 20% of the population. Deep sequencing could be of greater value in detecting acquired resistance mutations early.

Short Communication: HIV-1 Drug Resistance Mutation Analyses of Cameroon-Derived Integrase Sequences.

HIV-1 integrase (IN) is a primary target for combination antiretroviral therapy. Only a limited number of studies report on the emergence of resistance-associated mutations (RAMs) in Cameroon. We observed that 1.4% of sequence from treatment-naive patients had IN strand transfer inhibitor (INSTI) RAMs. These mutations confer resistance to raltegravir and elvitegravir. We also observed that 10.1% of the sequences have INSTI accessory RAMs. HIV-1 CRF02_AG was the predominant subtype (44.7%) in this study analyses. The occurrence of INSTI RAMs among the sequences at baseline needs to be monitored carefully.

Cytokine profile in the sputum of subjects with post-tuberculosis airflow obstruction and in those with tobacco related chronic obstructive pulmonary disease.

BACKGROUND: Previous studies have shown that tuberculosis (TB) is a risk factor for chronic airflow limitation. Chronic obstructive pulmonary disease (COPD) is recognized as the result of chronic inflammation, usually related to noxious particles. Post-TB airflow obstruction and tobacco-related COPD have the same functional pathway characterized by persistent airflow limitation. We sought to compare the profile of 29 cytokines in the sputum of subjects with post-TB airflow obstruction and those with COPD related to tobacco. RESULTS: The forced expiratory volume in the first second (FEV1) and forced expiratory volume/forced vital capacity (FEV/FVC) ratio were lower in the COPD patients with the history of smoking compared to the post-TB airflow obstruction subgroup. The stages of the disease were more advanced in COPD / tobacco patients. Among the cytokines, IL-1α, IL-1ß, MIP-1ß, sCD40L and VEGF levels were higher in COPD patients, compared to the controls with p values ​​of 0.003, 0.0001, 0.03, 0.0001 and 0.02 respectively. When the two COPD subgroups were compared, IL-1α, IL-6, TNF-α and IL-8 levels were higher in the COPD patients with the history of tobacco compared to the COPD patients with the history of TB with p-values ​​of 0.031, 0.05, 0.021 and 0.016, respectively. CONCLUSION: COPD related to tobacco is more severe than post-TB airflow obstruction. The pathogenesis of post-TB airflow obstruction appears to involve the cytokines IL-1RA, IL-1α, IL-1ß, IL-17, GRO and sCD40L, while COPD related to tobacco involves more cytokines.

Structural Comparison of Diverse HIV-1 Subtypes using Molecular Modelling and Docking Analyses of Integrase Inhibitors.

The process of viral integration into the host genome is an essential step of the HIV-1 life cycle. The viral integrase (IN) enzyme catalyzes integration. IN is an ideal therapeutic enzyme targeted by several drugs; raltegravir (RAL), elvitegravir (EVG), dolutegravir (DTG), and bictegravir (BIC) having been approved by the USA Food and Drug Administration (FDA). Due to high HIV-1 diversity, it is not well understood how specific naturally occurring polymorphisms (NOPs) in IN may affect the structure/function and binding affinity of integrase strand transfer inhibitors (INSTIs). We applied computational methods of molecular modelling and docking to analyze the effect of NOPs on the full-length IN structure and INSTI binding. We identified 13 NOPs within the Cameroonian-derived CRF02_AG IN sequences and further identified 17 NOPs within HIV-1C South African sequences. The NOPs in the IN structures did not show any differences in INSTI binding affinity. However, linear regression analysis revealed a positive correlation between the Ki and EC50 values for DTG and BIC as strong inhibitors of HIV-1 IN subtypes. All INSTIs are clinically effective against diverse HIV-1 strains from INSTI treatment-naïve populations. This study supports the use of second-generation INSTIs such as DTG and BIC as part of first-line combination antiretroviral therapy (cART) regimens, due to a stronger genetic barrier to the emergence of drug resistance.

Peripheral blood lymphocyte proviral DNA predicts neurocognitive impairment in clade C HIV.

It is not known if proviral DNA in the periphery corresponds to cognitive status in clade C as it does in clade B and recombinant forms. A cross-sectional study was conducted on participants investigated for HIV-associated neurocognitive impairment in South Africa. HIV-1 proviral DNA was quantified using a PCR assay targeting a highly conserved HIV-1 LTR-gag region. Fifty-four (36.7%) participants were cognitively impaired and 93 (63.3%) were not impaired. Forty-three (79.6%) of the cognitively impaired participants were female and 11 (20.4%) were male. There was no significant age difference between cognitively impaired and unimpaired participants (p = 0.42). HIV-1 DNA in cognitively impaired PLWH was significantly higher than in cognitively normal individuals (p = .016). Considering impaired participants, lymphocyte HIV-1 DNA was significantly higher in males than females (p = 0.02). There was a modest positive correlation between lymphocyte HIV-1 DNA and global deficit scores (GDS) r = 0.176; p = 0.03). The two measures of viral load, lymphocyte HIV-1 DNA copies/million and plasma RNA copies/ml, were positively correlated (r = 0.39; p < .001). After adjusting for other covariates, age, sex, treatment status, and the interactions between impairment and treatment, the multivariate regression showed association between proviral load and neurocognitive impairment; omega effect size was 0.04, p value = 0.010. The burden of HIV-1 peripheral blood lymphocyte proviral DNA corresponds to neurocognitive impairment among individuals infected with clade C disease. Therefore, therapeutic strategies to reduce the HIV-1 proviral DNA reservoir in lymphocytes may improve neurocognitive outcomes in PLWH.

Correction: Molecular dynamic simulations to investigate the structural impact of known drug resistance mutations on HIV-1C Integrase-Dolutegravir binding.

[This corrects the article DOI: 10.1371/journal.pone.0223464.].

Molecular dynamic simulations to investigate the structural impact of known drug resistance mutations on HIV-1C Integrase-Dolutegravir binding.

Resistance associated mutations (RAMs) threaten the long-term success of combination antiretroviral therapy (cART) outcomes for HIV-1 treatment. HIV-1 Integrase (IN) strand transfer inhibitors (INSTIs) have proven to be a viable option for highly specific HIV-1 therapy. The INSTI, Dolutegravir is recommended by the World Health Organization for use as first-line cART. This study aims to understand how RAMs affect the stability of IN, as well as the binding of the drug Dolutegravir to the catalytic pocket of the protein. A homology model of HIV-1 subtype C IN was successfully constructed and validated. The site directed mutator webserver was used to predict destabilizing and/or stabilizing effects of known RAMs while FoldX confirmed any changes in protein energy upon introduction of mutation. Also, interaction analysis was performed between neighbouring residues. Three mutations known to be associated with Raltegravir, Elvitegravir and Dolutegravir resistance were selected; E92Q, G140S and Y143R, for molecular dynamics simulations. The structural quality assessment indicated high reliability of the HIV-1C IN tetrameric structure, with more than 90% confidence in modelled regions. Change in free energy for the three mutants indicated different effects, while simulation analysis showed G140S to have the largest affect on protein stability and flexibility. This was further supported by weaker non-bonded pairwise interaction energy and binding free energy values between the drug DTG and E92Q, Y143R and G140S mutants suggesting reduced binding affinity, as indicated by interaction analysis in comparison to the WT. Our findings suggest the G140S mutant has the strongest effect on the HIV-1C IN protein structure and Dolutegravir binding. To the best of our knowledge, this is the first study that uses the consensus wild type HIV-1C IN sequence to build an accurate 3D model to understand the effect of three known mutations on DTG drug binding in a South Africa context.

Drug Resistance Mutations Against Protease, Reverse Transcriptase and Integrase Inhibitors in People Living With HIV-1 Receiving Boosted Protease Inhibitors in South Africa.

The South African national combination antiretroviral therapy (cART) roll-out program started in 2006, with over 4.4 million people accessing treatment since it was first introduced. HIV-1 drug resistance can hamper the success of cART. This study determined the patterns of HIV-1 drug-resistance associated mutations (RAMs) in People Living with HIV-1 (PLHIV-1). Receiving first (for children below 3 years of age) and second-line (for adults) cART regimens in South Africa. During 2017 and 2018, 110 patients plasma samples were selected, 96 samples including those of 17 children and infants were successfully analyzed. All patients were receiving a boosted protease inhibitor (bPI) as part of their cART regimen. The viral sequences were analyzed for RAMs through genotypic resistance testing. We performed genotypic resistance testing (GRT) for Protease inhibitors (PIs), Reverse transcriptase inhibitors (RTIs) and Integrase strand transfer inhibitors (InSTIs). Viral sequences were subtyped using REGAv3 and COMET. Based on the PR/RT sequences, HIV-1 subtypes were classified as 95 (99%) HIV-1 subtype C (HIV-1C) while one sample as 02_AG. Integrase sequencing was successful for 89 sequences, and all the sequences were classified as HIV-1C (99%, 88/89) except one sequence classified CRF02_AG, as observed in PR/RT. Of the 96 PR/RT sequences analyzed, M184V/I (52/96; 54%) had the most frequent RAM nucleoside reverse transcriptase inhibitor (NRTI). The most frequent non-nucleoside reverse transcriptase inhibitor (NNRTI) RAM was K103N/S (40/96, 42%). Protease inhibitor (PI) RAMs M46I and V82A were present in 12 (13%) of the sequences analyzed. Among the InSTI major RAM two (2.2%) sequences have Y143R and T97A mutations while one sample had T66I. The accessory RAM E157Q was identified in two (2.2%). The data indicates that the majority of the patients failed on bPIs didn't have any mutation; therefore adherence could be major issue in these groups of individuals. We propose continued viral load monitoring for better management of infected PLHIV.

HIV-1 Integrase Diversity and Resistance-Associated Mutations and Polymorphisms Among Integrase Strand Transfer Inhibitor-Naive HIV-1 Patients from Cameroon.

The World Health Organization (WHO) has put forth recommendations for the use of integrase (IN) strand transfer inhibitors (INSTIs) to be part of the first-line combination antiretroviral therapy regimen to treat HIV infections. The knowledge of pretreatment drug resistance against INSTIs is still scarce in resource-limited settings (RLS). We characterized the integrase gene to identify resistance-associated mutations (RAMs) in 56 INSTI-naive patient viral sequences from Cameroon. Study analysis used 37 sequences with fragment size ≥500 bp or of good quality .The majority of the sequences were identified as CRF02_AG 54.% (n = 20/37) and 45.9% (n = 17/37), other subtype viral sequences include (A, CRF36_cpx, F,G, and C). A total of 18.9% (n = 7/37) of the sequences had RAMs, with only 5.4% (n = 2/37) having major RAMs (Y143R/C/D/G and P145S), against INSTIs. Accessory RAMs were present in 8.1% (n = 3/37) of the sequences, of which one sequence contained solely E157Q, and another Q95K. One patient sequence had three accessory RAMs (G140E, E157Q, and G163R). We identified major RAMs to INSTIs, which might have a potential clinical impact to dolutegravir rollout in RLS, including Cameroon. This is the first study to describe RAMs among INSTI-naive people living with HIV-1 (PLHIV-1) infected with CRF02_AG and other subtypes in Cameroon.

Near full-length HIV-1 subtype B sequences from the early South African epidemic, detecting a BD unique recombinant form (URF) from a sample in 1985.

HIV-1 subtype C is the most prevalent subtype in South Africa. Although subtype B was previously detected in South Africa, there is limited sequence information available. We characterized near full-length HIV-1 subtype B sequences from samples collected at the start of the South African HIV-1 epidemic, in the 1980s. Five samples were analysed by PCR amplification, Sanger DNA sequencing and phylogenetic analyses. The viral genomes were amplified in two overlapping fragments of 5.5 kb and 3.7 kb. The sequences were subtyped using REGA version 3.0, RIP version 3.0 and jpHMM. Maximum Likelihood phylogenetic trees were inferred with MEGA version 6. Four HIV-1 patient sequences were subtyped as pure HIV-1 subtype B. One sequence was characterized as a novel HIV-1 subtype B and D recombinant. The sequences clustered phylogenetically with other HIV-1 subtype B sequences from South Africa, Europe and the USA. We report the presence of an HIV-1 subtype B and D recombinant strain detected in the beginning of the epidemic. This indicates that viral recombination events were already happening in 1985, but could have been missed as sequence analyses were often limited to small genomic regions of HIV-1.

Rate of viral load change and adherence of HIV adult patients treated with Efavirenz or Nevirapine antiretroviral regimens at 24 and 48 weeks in Yaoundé, Cameroon: a longitudinal cohort study.

BACKGROUND: HIV-load decrease and suppression over time is associated with consistent adherence to antiretroviral therapy (ART). Our study aimed to evaluate the difference in viral load and adherence of patients treated with a combination of either Tenofovir (TDF), Lamivudine (3TC) and Efavirenz (EFV) or TDF / Zidovudine (AZT), 3TC and Nevirapine (NVP) regimens at 24 and 48 weeks. METHODS: A longitudinal study was conducted from May 2016 to June 2017 among 256 HIV infected adult patients who were enrolled at two approved treatment hospitals in Yaoundé, before the start of first-line ART. Whole blood samples were collected using standard operating procedures. HIV-loads were determined by a quantitative RealTime PCR assay. Adherence was evaluated by pharmacy refill data records. Statistical analyses were performed using the PRISM 5.0 software. RESULTS: Off the 256 HIV infected patients enrolled, 180 (70%) patients completed the study and 76 (30%) patients were lost to follow-up. The success rate in achieving viral load < 40 copies/ml was 1.8 times higher with the EFV regimen at 24 weeks and was 1.2 times higher in the NVP regimen at 48 weeks. At 48 weeks the treatment failure rate was 12.0 and 40.0% in patients on EFV and the NVP regimen, respectively. The rate of adherence varied in both ART based regimens with 84.0 to 74.0% for EFV and 65.5 to 62.5% for NVP, at 24 and 48 weeks respectively. CONCLUSION: In our study and setting, the rate of viral load decrease was higher in the NVP based regimen than with the EFV regimen. The adherence rate to ART was higher in the EFV regimen, compared to the NVP regimen. This adds to evidence that the EFV regimen is the preferred ART combination for non-nucleoside reverse transcriptase inhibitors (NNRTIs).

Mutations in Long Terminal Repeats κB Transcription Factor Binding Sites in Plasma Virus Among South African People Living with HIV-1.

HIV-1 subtype C (HIV-1C) is responsible for the majority of infections in sub-Saharan Africa. We selected 63 plasma-derived samples and generated long terminal repeats (LTRs) amplicons from people living with HIV in South Africa to identify transcription factor binding sites. NF-κB plays an important role in regulating the viral gene expression from the viral promoter and controlling viral latency. LTR amplicons were sequenced and phylogenetically analyzed. In our data set, we identified F-κB sites (n = 4; 6%) at position II and (n = 1; 1%) at position I among 63 sequences analyzed. The majority of the sequences identified with H-κB at position II (n = 50; 79%) and position I (n = 55; 87%). Forty-nine (n = 49; 78%) sequences were found to exhibit C-κB site. ZA_LTR052 was identified with a single point mutation. We identified all three NF-κB-binding sites in (n = 44; 70%) the viral promoter-enhancer regions in South African patients.

Author Correction: Analyses of HIV-1 integrase sequences prior to South African national HIV-treatment program and availability of integrase inhibitors in Cape Town, South Africa.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Analyses of HIV-1 integrase sequences prior to South African national HIV-treatment program and available of integrase inhibitors in Cape Town, South Africa.

HIV-Integrase (IN) has proven to be a viable target for highly specific HIV-1 therapy. We aimed to characterize the HIV-1 IN gene in a South African context and identify resistance-associated mutations (RAMs) against available first and second generation Integrase strand-transfer inhibitors (InSTIs). We performed genetic analyses on 91 treatment-naïve HIV-1 infected patients, as well as 314 treatment-naive South African HIV-1 IN-sequences, downloaded from Los Alamos HIV Sequence Database. Genotypic analyses revealed the absence of major RAMs in the cohort collected before the broad availability of combination antiretroviral therapy (cART) and INSTI in South Africa, however, occurred at a rate of 2.85% (9/314) in database derived sequences. RAMs were present at IN-positions 66, 92, 143, 147 and 148, all of which may confer resistance to Raltegravir (RAL) and Elvitegravir (EVG), but are unlikely to affect second-generation Dolutegravir (DTG), except mutations in the Q148 pathway. Furthermore, protein modeling showed, naturally occurring polymorphisms impact the stability of the intasome-complex and therefore may contribute to an overall potency against InSTIs. Our data suggest the prevalence of InSTI RAMs, against InSTIs, is low in South Africa, but natural polymorphisms and subtype-specific differences may influence the effect of individual treatment regimens.