Building the Pharmacophore Model of HIV-1 Integrase Strand Transfer Inhibitors and Studying Their Inhibition Mechanism

The replication of HIV-1 requires the integration of its cyclic DNA into host DNA by HIV-1 integrase （IN）, which includes two important reactions, 3＇-processing and strand transfer, both catalyzed by HIV-1 IN. Disrupting either of the reactions will fulfill the purpose of inhibiting the replication of HIV-1. In this paper, pharmacophore modeling and molecular docking are employed to investigate the inhibition mechanism of the HIV-1 IN strand transfer inhibitors （INSTIs）. Based on the results, we suggest that the inhibition mechanism of INSTIs involves the inhibitor chelating the cofactors Mg2＋ and its forming hydrogen bonds with some crucial residues adjacent to the DDE active center.

Down-regulation of HIV-1 Infection by Inhibition of the MAPK Signaling Pathway

The human immunodeficiency virus type 1 （HIV-1） can interact with and exploit the host cellular machinery to replicate and propagate itself. Numerous studies have shown that the Mitogen-activated protein kinase （MAPK） signal pathway can positively regulate the replication of HIV-1, but exactly how each MAPK pathway affects HIV-1 infection and replication is not understood. In this study, we used the Extracellular signal-regulated kinase （ERK） pathway inhibitor, PD98059, the Jun N-terminal kinase （JNK） pathway inhibitor, SP600125, and the p38 pathway inhibitor, SB203580, to investigate the roles of these pathways in HIV-1 replication. We found that application of PD98059 results in a strong VSV-G pseudotyped HIV-1NL4-3 luciferase reporter virus and HIV-1NL4-3 virus inhibition activity. In addition, SB203580 and SP600125 also elicited marked VSV-G pseudotyped HIV-INL4-3 luciferase reporter virus inhibition activity but no HIV-1NL4-3 virus inhibition activity. We also found that SB203580 and SP600125 can enhance the HIV-1 inhibition activity of PD98059 when cells were treated with all three MAPK pathway inhibitors in combination. Finally, we show that HIV-1 virus inhibition activity of the MAPK pathway inhibitors was the result of the negative regulation of HIV-1 LTR promoter activity.

Synthesis and HIV-1 Integrase Inhibitory Activity of Furanone Derivatives

Twenty novel furanone derivatives, based on the structure of raltegravir which was the first HIV-1 inte- grase（IN） inhibitor approved by the United States Food and Drug Administration（US FDA）, were designed, synthesized and characterized by ^1H NMR, IR and MS. The biological activities of these compounds against HIV-1 IN in vitro were evaluated. The assay results indicate that the replacement of pyrimidinone with furanone decreased the inhibitory activity of the compounds to HIV-1 IN. Compounds 3i, 3j and 3t show moderate inhibitory activity against HIV-1 IN and selectively inhibit the strand transfer reaction.

Investigation of formation of dimeric G-quadruplex of HIV-1 integrase inhibitor by nuclear magnetic resonance

In this research, an unusually dimeric G-quadruplex of d（GGGTGGGTGGGTGGGT） （SI）, the potent nanomolar HIV-1 integrase inhibitor, was detected by nuclear magnetic resonance （NMR）. This result has been confirmed by electrospray ionization mass spectrometry （ESI-MS） and circular dichroism （CD）.

Three-dimensional Quantitative Structure-activity Relationship Models of HIV-1 Integrase Inhibitors of DKAs

As one of the three viral encoded enzymes of HIV-1 infection, HIV-1 integrase has become an attractive drug target for the treatment. Diketoacid compounds （DKAs） are one kind of potent and selective inhibitors of HIV-1 IN. In the present work, two three-dimensional QSAR techniques （CoMFA and CoMSIA） were employed to correlate the molecular structure with the activity of inhibiting the strand transfer for 147 DKAs. The all-oritation search （AOS） and all-placement search （APS） were used to optimize the CoMFA model. The diketo and keto-enol tautomers of DKAs were also used to establish the CoMFA models. The results indicated that the enol was the dominant conformation in the HIV-1 IN and DKAs complexes. It can provide a new method and reference to identify the bioactive conformation of drugs by using QSAR analysis. The best CoMSIA model, with five fields combined, implied that the hydrophobic field is very important as well as the steric and electrostatic fields. All models indicated favorable internal validation. A comparative analysis with the three models demonstrated that the CoMFA model seems to be more predictive. The contour maps could afford steric, electrostatic, hydrophobic and H-bond information about the interaction of ligand-receptor complex visually. The models would give some useful guidelines for designing novel and potent HIV-1 integrase inhibitors.

NKT cells in HIV-1 infection

Natural killer T （NKT） cells are a unique T cell population that have important immunoregulatory functions and have been shown to be involved in host immunity against a range of microorganisms. It also emerges that they might play a role in HIV-1 infection, and therefore be selectively depleted during the early stages of infection. Recent studies are reviewed regarding the dynamics of NKT depletion during HIV-1 infection and their recovery under highly active antiretroviral treatment （HAART）. Possible mechanisms for these changes are proposed based on the recent developments in HIV pathogenesis. Further discussions are focused on HIV＇s disruption of NKT activation by downregulating CDld expression on antigen presentation cells （APC）. HIV-1 protein Nefis found to play the major role by interrupting the intracellular trafficking of nascent and recycling CDld molecules.

Two Retroviruses Packaged in One Cell Line can Combined Inhibit the Replication of HIV-1 in TZM-bl Cells

The cellular protein tetherin tethers the HIV-1 viral particles on the cellular membrane to inhibit the replication of HIV-1. However, the HIV-1 accessory protein Vpu counteracts the antiviral function of tetherin. In this study, two retroviral vector plasmids were constructed. One inhibited the vpu gene expression; the other one over-expressed the tetherin. Both retroviral vector plasmids could be packaged in the packaging cell line PT67 to obtain the corresponding retroviruses. The retroviral vector plasmids＇ functions of tetherin over-expression or vpu-RNAi were detected at the cell level. Retroviral vector plasmids were transfected to PT67 cells at different ratios from 0T3V to 3TOV, and then mixed retroviruses were harvested. The antiviral functions of mixed retroviruses were detected in HIV-1 infected TZM-bi cells. The results showed that packaged mixed retroviruses could repress the replication of HIV-1 in TZM-bl cells.

Graves’ Disease as a Late Manifestation of Immune Reconstitution Syndrome after Highly Active Antiretroviral Therapy in an HIV-1 Infected Patient

Context: Highly active antiretroviral therapy (HAART) inhibits the HIV replication and consequently increases CD4 levels and decreases viral load. This immune system improvement can trigger various immunological phenomena, entity called Immune Reconstitution Syndrome (IRS). Graves’ disease is a late Immune Reconstitution consequence. Patient: We report the case of a 48 years old man with HIV infection who developed Graves’ disease three years after he was on effective HAART because of the Immune Reconstitution Syndrome. At presentation he had a very low CD4 T-cell count (17 cells/μL). When he started HAART he presented a lipodystrophy syndrome. HAART was changed because of the persistent low CD4-T cells count (less than 100 cell/μL). Afterwards serum lipid levels began to decrease and that was the first manifestation of Graves’ disease, which was diagnosed when CD4 T-cells increased up to 343 cell/μL. Our patient developed Graves’ disease 36 months after initiating effective HAART with protease inhibitors which was coincident with viral suppression and a rise of CD4 T cells. Conclusion: The most immunosuppressed patients with a CD4 T cell count less than 100 cells/μL are at greatest risk for the development of Immune Reconstitution Syndrome after HAART initiation. We conclude that clinicians will have to consider the importance of the early diagnosis of thyroid disease to bring an adequate treatment.

Impaired <i>in Vitro</i>Macrophage Function in HIV-1 Infected Remunerated Blood Donors with History of Oral Iron Intake

Both HIV-1 infection and iron overload are independently associated with infection by Mycobacterium tuberculosis due to impaired macrophage function. A prospective study of in vitro assessment of macrophage function was undertaken in a group of asymptomatic HIV-1 infected remunerated (professional) blood donors with (n = 54) or without (n = 54) prevalent practice of oral iron intake (subgroups I and II respectively). The assessment was carried out at enrolment as well as at the point of development of AIDS related illness (ARI). The subgroup I showed higher levels of pro-inflammatory cytokines viz. IL-1β, IL-6 and IL-8, but lowered levels of IL-12p70 in serum as well as in supernatant of monocyte derived macrophage (MDM) cultures both at enrolment and at the point of development of ARI in the subset of cases that developed pulmonary tuberculosis (PT) on follow up compared to the subset that developed categories of ARI other than pulmonary tuberculosis (non-PT) on follow up. The subgroup II of HIV-1 positive donors did not show any such alterations at enrolment or at the point of development of PT or non-PT categories of ARI on follow up. There was significant depression of nitrite level in serum as well as that produced by MDM culture at enrolment in subgroup I regardless of category of ARI developed on follow up while in subgroup II there was significant elevation in these levels at enrolment, more among cases developing PT than those developing non-PT category of ARI. The subgroup I demonstrated increased production of superoxide at enrolment. The present study suggested that depressed production of nitrite and IL-12p70 by macrophages induced by iron overload may be responsible for greater susceptibility of HIV-1 positive donors to M. tuberculosis while superoxide may be a less powerful anti-mycobacterial tool.

Binding of HIV-1 virions to α_4β_7 expressing cells and impact of antagonizing α_4β_7 on HIV-1 infection of primary CD4^+ T cells

HIV-1 envelope glycoprotein is reported to interact with α4β7, an integrin mediating the homing of lymphocytes to gut-associated lymphoid tissue, but the significance of α4β7 in HIV-1 infection remains controversial. Here, using HIV-1 strain Ba L, the gp120 of which was previously shown to be capable of interacting with α4β7, we demonstrated that α4β7 can mediate the binding of whole HIV-1 virions to α4β7-expressing transfectants. We further constructed a cell line stably expressing α4β7 and confirmed the α4β7-mediated HIV-1 binding. In primary lymphocytes with activated α4β7 expression, we also observed significant virus binding which can be inhibited by an anti-α4β7 antibody. Moreover, we investigated the impact of antagonizing α4β7 on HIV-1 infection of primary CD4+ T cells. In α4β7-activated CD4+ T cells, both anti-α4β7 antibodies and introduction of shorthairpin RNAs specifically targeting α4β7 resulted in a decreased HIV-1 infection. Our findings indicate that α4β7 may serve as an attachment factor at least for some HIV-1 strains. The established approach provides a promising means for the investigation of other viral strains to understand the potential roles of α4β7 in HIV-1 infection.

HIV-Specific IL-2^+ and/or IFN-γ^+ CD8^+ T Cell Reponses during Chronic HIV-1 Infection in Former Blood Donors

Objective Conflicting data have been generated from previous studies to determine which kind of relationship exists between HIV-1 specific CD8 Tcell responses and HIV-1 viral load or CD4 count over the course of infection.In this study,153 HIV-1 infected LTNPs were enrolled to investigate the role of HIV-1 specific CD8 T-cell responses in chronic HIV-1 infection among HIV-1 infected former blood donors.Methods The patients were stratified into three groups according to CD4 count：CD4≥500 cells/μL;350 cells/μL≤CD4〈500 cells/μL;CD4〈350 cells/μL.PBMCs were isolated from the patients＇ anticoagulated blood samples.IL-2 and IFN-γ secretions of CD 8 T cells against 17 HIV-1 consensus B full peptide pools were analyzed by using ICS assay.Results An overall inverse correlation were observed between CD4 count and plasma viral load.Although no significant difference was observed during the comparisons of frequency/breadth of HIV-1 specific CD8 T cell responses,CD4 count stratification analysis showed that different correlation pattern existed in three strata：as for patients whose CD4 counts were less than 350 cells/μL,no significant correlations were identified between frequency/breadth of HIV-1 specific CD8 T cell responses and CD4 count/viral load;as for patients whose CD4 counts ranged from 350 cells /μL to 500 cells/μL,significant correlation was only observed between the response breadth of IL-2＋IFN-γ＋ CD8 T cells and CD4 count;however,as for patients whose CD4 counts were more than 500 cells/μL,direct correlations were identified between IL-2＋IFN-γ＋/IL-2＋/IFN-γ＋ CD8 T cells and viral load or CD4 count.Conclusions Universal consistent inverse correlation was only indentified between CD4 count and viral load.The relationship between HIV-1 specific CD8 T cell responses and CD4 count/viral load varied in different CD4 strata,which showed that better preserved CD4 T cells were correlated with better CD8 T cell functions.

Similar Neutralizing Activity in the HIV-1 Infected Long Term Non-progressors(LTNPs) and Typical Progressors(TPs)

Neutralizing antibodies are considered to be an important protective parameter used in HIV-1 vaccine evaluation. However, the exact role that neutralizing antibodies plays in controlling the disease progression of HIV-1 infected peoples is still undetermined. In this paper, we compared the protective function of the neutralizing antibody response in the plasma from LTNP and TP against clade B and clade C pseudoviruses. No difference in the neutralizing activities between the plasma from LTNP and TP was found, which was consistent with the most recent reports. In addition, no correlations between the titer or breadth and CD4+ or viral load in HIV-1 infected individuals were found. The protective roles played by neutralizing antibodies in controlling disease progression of HIV-1 infected people need to be considered in a new viewpoint.

Effect of ABCB1 3435C>T transporter gene polymorphism on plasma efavirenz concentration in HIV-1 infected Thai adults

Objective:To investigate the influence of ABCB1 polymorphisms on the plasma level of efavirenz in Thai adult cases infected with HIV-1.Methods:A single nucleotide polymorphism of ABCB13435 C>T(rs1045642)in the gene encoding ABCB1 was genotyped using real-time PCR-based alleles in 149 HIV-infected Thai adults receiving efavirenz treatment.Plasma concentrations of efavirenz were measured by high-performance liquid chromatography 12 hr after administration.The relationship between plasma efavirenz concentrations and ABCB13435 C>T polymorphisms was analyzed.Results:Logistic regression analysis showed no significant predictors of high plasma efavirenz concentration in relation to age,gender,body weight,CD4 count and plasma HIV-1 RNA,blood biochemical parameters,antiretroviral duration or ABCB13435 C>T polymorphisms,except for height(OR=0.902,95%CI:0.835-0.973)(P<0.05).The minor allele frequency of ABCB13435 C>T was0.446.The frequency of the heterozygous mutant ABCB13435 C/T was 53.02%(n=79),ABCB13435 T/T homozygous mutant was 18.12%(n=21)and the wild type ABCB13435 C/C genotype was 28.86%(n=43).The overall median plasma concentration of efavirenz in 149 HIV-infected Thai cases was 2.41 mg/L[IQR:(1.46-4.12)mg/L].The plasma concentration of efavirenz was higher in cases with ABCB13435 T/T homozygous mutant[2.73 mg/L,IQR:(2.02-4.19)mg/L]and ABCB13435 C/T heterozygous mutant[2.29 mg/L,IQR:(1.41-4.28)mg/L]genotypes compared to the wild type ABCB13435 C/C homozygous[2.1 mg/L,IQR:(1.37-3.53)mg/L].However,there was no statistically significant difference in the efavirenz concentration between the different genotypes(P>0.05).Objective:To investigate the influence of ABCB1 polymorphisms on the plasma level of efavirenz in Thai adult cases infected with HIV-1.Methods:A single nucleotide polymorphism of ABCB13435 C>T(rs1045642)in the gene encoding ABCB1 was genotyped using real-time PCR-based alleles in 149 HIV-infected Thai adults receiving efavirenz treatment.Plasma concentrations of efavirenz were measured by high-performance liquid chromatography 12 hr after administration.The relationship between plasma efavirenz concentrations and ABCB13435 C>T polymorphisms was analyzed.Results:Logistic regression analysis showed no significant predictors of high plasma efavirenz concentration in relation to age,gender,body weight,CD4 count and plasma HIV-1 RNA,blood biochemical parameters,antiretroviral duration or ABCB13435 C>T polymorphisms,except for height(OR=0.902,95%CI:0.835-0.973)(P<0.05).The minor allele frequency of ABCB13435 C>T was 0.446.The frequency of the heterozygous mutant ABCB13435 C/T was 53.02%(n=79),ABCB13435 T/T homozygous mutant was 18.12%(n=27)and the wild type ABCB13435 C/C genotype was 28.86%(n=43).The overall median plasma concentration of efavirenz in 149 HIV-infected Thai cases was 2.41 mg/L[IQR:(1.46-4.12)mg/L].The plasma concentration of efavirenz was higher in cases with ABCB13435 T/T homozygous mutant[2.73 mg/L,IQR:(2.02-4.19)mg/L]and ABCB13435 C/T heterozygous mutant[2.29 mg/L,IQR:(1.41-4.28)mg/L]genotypes compared to the wild type ABCB13435 C/C homozygous[2.1 mg/L,IQR:(1.37-3.53)mg/L].However,there was no statistically significant difference in the efavirenz concentration between the different genotypes(P>0.05).Conclusions:There is no statistical significance for a tendency toward higher plasma efavirenz concentration in the ABCB13435 T/T and ABCB13435 C/T genotypes.No parameters of physiological characteristics in this study except for height were found to be predictors of high plasma efavirenz concentration in Thai HIV-1 infected cases.

Estimated Binding Energies of Drug-Like and Nondrug-Like Molecules in the Active Site of HIV-1 Integrase, 1BIS.pdb, and Two Mutant Models: Y143R and N155H

Lipinski’s “Rule of Five” was introduced for predicting oral bioavailability to describe drug-like molecules. For the purpose of this research the rules were used to separate potential inhibitors of HIV-1 integrase (1BIS.pdb) into two groups: drug-like and nondrug-like. If one of Lipinski’s “Rule of Five” was not followed the potential inhibitor was classified as nondrug-like. Thirty molecules were identified from the literature, twenty-four drug-like and six nondrug-like, that were docked into the active site of 1BIS.pdb (considered the non-mutated protein) and two mutant models, Y143R and N155H. These are two of the mutations that have led to increased resistance to HIV-1 integrase drugs such as raltegravir and elvitegravir. The computational software, ICM-Pro (Molsoft L.L.C.), was used to determine the estimated binding energy (EBE) of the drug/protein complex. It was found that the nondrug-like molecules generally had a more negative EBE, that is, tighter binding with 1BIS. pdb, though there were several exceptions in the drug-like group. With the protein mutant model Y143R, the majority of drug-like (58%) and nondrug-like molecules (67%) had tighter binding. However, for the mutant model N155H, there was the same percent (46%) of drug-like molecules with tighter binding with the mutant model as with 1BIS.pdb. The drug-like molecules were used when there was a ≥1 kcal/mole difference between 1BIS.pdb and either of the two mutant models to suggest a pharmacophore with structural characteristics for an HIV-1 integrase inhibitor.

Risk Factors Associated with Mother-to-Child Transmission of HIV-1, Spontaneous Abortion and Infant Mortality in HIV-1 Infected Women in Burkina Faso: A Prospective Study

Background: Despite efforts to fight, HIV/AIDS mother-to-child transmission of HIV-1 (MTCT), as well as abortion and infant mortality, remains a problem in sub-Saharan Africa. Indeed, a low level of CD4 and a high viral load can be associated with these situations. The aim of this study was to determine the risk factors associated with the occurrence of MTCT, spontaneous abortion and infant mortality in HIV-1 infected women in Ouagadougou, Burkina Faso. This was a prospective study conducted from May 2014 to September 2017 and involved 423 HIV-1 infected women followed at Saint Camille Hospital in Ouagadougou, Burkina Faso. Sociodemographic data were collected through a questionnaire. The CD4 count and HIV-1 viral load were determined using respectively BD FACSCount and Abbott m2000rt instruments. Bivariate analysis and multinomial logistic regression were performed for associations with a significance threshold for p Results: The average age of women was 38.75 ± 7.98 years. Rates of MTCT, abortion and infant mortality were 16.31%, 30.49% and 34.75%, respectively. The number of pregnancies was associated with the number of infant deaths (p = 0.002). A correlation between the number of pregnancies and infant mortality was observed (p = 0.002) with a relatively high rate (28.6%) among women who had three pregnancies. In addition, marital status was associated with HIV-1 infection in infants (p = 0.042) and spontaneous abortion (p = 0.033). HIV-1 infected women with low CD4 counts (less than 350 cells/μL) and those with viral load more than 1000 copies/mL were about twice as likely to have an spontaneous abortion [OR (IC 95%): 2.50 (1.085 - 5.760);p = 0.03] and [OR (95% CI): 2.16 (1.043 - 4.505);p = 0.04]. Conclusions: The results of this study show the need to improve the treatment of HIV-1 infected women in order to restore CD4 levels and make viral load of HIV-1 undetectable.

Utility of a Relatively Affordable In-House HIV-1 Genotyping Assay for Drug Resistance Testing among Non B HIV-1 Infected Drug Naive Patients in Nigeria

Background: The introduction of antiretroviral (ARV) in resource-limited settings has increased life expectancy among non-B HIV-1 infected individuals. We used a validated In-house genotyping assay to characterize non-B HIV-1 and to determine drug resistance mutations among treatment-naive patients. Methods: Plasma samples from 105 HIV-1 infected drug-naive adult patients attending a tertiary hospital Jos, Nigeria were subjected to HIV-1 RNA extraction, reverse transcription amplification, and population-based sequencing of the partial pol gene on the ABI 3130xl genetic analyzer. Subtyping and phylogenetic analyses were performed by REGA Subtyping Tool v2.0 and MEGA v5.0 respectively. Drug resistance profiles were evaluated according to IAS-USA 2013 drug resistance mutations list. Result: One hundred samples (95.2%) were successfully genotyped. The distribution of the non-B HIV-1 subtypes were;CRF02_AG-48%, G-41.0%, CRF06_cpx-6.0%, and A-5.0%. Ten percent of the isolates had at least one major drug resistance mutation in the pol gene. The drug-class specific resistance prevalences were 6.0% for NRTIs;M41L-1.0%, K65KR-1.0%, M184IM-1.0%, M184V-2.0%, and T215ADNT-1%, 8.0% for NNRTIs;K103N-2%, 1.0% for K101E, E138A, G190A, P225HP, Y181I, Y188L, Y181C including protease inhibitors’ Q58E (1.0%). Conclusion: HIV-1 was heterogeneously distributed;CRF02_AG and G predominate and some known major mutations associated with NRTIs and NNRTIs were determined. The In-house assay is suitable for both characterization of non-B HIV-1 subtypes and detection of drug resistance at a significant lower cost than available commercial genotyping assays. This finding underscores the need to consider use of low-cost In-house genotyping assay as an alternative in resource-limited settings with non-B HIV-1 epidemic.

Synthesis of a New Lopinavir Phosphinic Analog as HIV-1 Inhibitor

HIV/AIDS has been one of the most devastating global diseases. HIV-1 protease proteolytic action is responsible for the manufacture of grown, infectious species, consequently HIV-1 protease has become an attractive goal in the treatment and therapy of HIV. Several HIV-1 protease inhibitors based therapeutic agents are under investigation or currently in the market. Lopinavir (ABT-378) has a great value in this research field. Therefore, different methods have appeared aiming to develop efficient analogs by the utilization of variable techniques, since Lopinavir had showed low bioavailability when being prescribed alone, and various side effects after the combination of Lopinavir with another HIV-1 inhibitors such as Ritonavir, which is available in the markets nowadays under the brand name Kaletra. Replacement of the hydroxyethylene moiety in Lopinavir structure, which is responsible for the monohydroxylated metabolites with the stable to hydrolysis phosphinic group has been considered, since that hydroxyl group in the central core is responsible for the interaction with the carboxylic acid in the catalytic aspartyl residue of HIV-1 by hydrogen bonding and consequently supports the drug affinity to the protease. The small scale processes for the synthetic strategies for the new candidate phosphinic analog of Lopinavir protease inhibitor (PL1) is presented here in along with some preliminary pharmacological data.

polymorphism Analysis of Resistance Genes in Chinese Populations with HIV-1 Infection

Objective: To analyze the genotypes of CCR5 △ 32,CCR2b-64I and SDF 1-3 A and mutation frequencies of allelicgenes in Chinese populations infected with HIV-1. Methods: Genome DNA from peripheral blood mononuclearcells (PBMCs) of 78 HIV-1 infectors was amplified bypolymerase chain reaction (PCR). CCR5, CCR2b and SDF1gene fragments were obtained from restrictive fragmentlength polymorphism (RFLP) and/or CCR△32, CCR5m303,CCR2b-64I and SDF1-3' A allelic genes' mutationalfrequencies were sequenced directly from PCR products. Results: None of CCR5△32, CCR5m303 gene mutationwere found in 78 subjects with HIV-1 infection. The allelicgene mutation frequencies of CCR2b-64I and SDF1-3'Acorresponding to 14.9-34.0% and 17.6-38.2% of 95% CI, were22.79% and 26.92% respectively. Their colony distributionconformed to the Hardy-Weinberg equilibrium. Conclusion: The HIV-1 infections found at present are allsusceptible population of CCR5△32 and CCR5m303. Thepolymorphism and frequencies of CCR5△32, CCR5m303,CCR2b-64I and SDF1-3'A alleles from Chinese HIV-1infected population were disclosed in this study for the firsttime, which is of significance for studying the geneticresistance to susceptibility to HIV-1 infection as well as AIDSdisease progression.

Optimized Antiretroviral Therapy with Darunavir/Ritonavir, Etravirine and/or Raltegarvir: A Salvage Therapy Option in HIV-1 Infected Patients with Long-Term Therapeutic Failures, about 23 Cases

Objectives: The aims of this study was to analyze the immuno-virologic response after optimised background antiretroviral therapy (OBT) associated to new active antiretroviral treatment (ART) in HIV-1 infected patients with chronic virologic failure. Methods: We conducted a descriptive analysis of the immuno-virologic responses in HIV-1 adult infected patients: 1) harbouring multiple therapeutic failures with ART;2) with no virologic response obtained over 10 years (1997-2008);and 3) treated with OBT combined with new drugs including at least 1 of the 3 active ART among darunavir/ritonavir, etravirine and raltegravir;4) observed between month 0 (M0), before new ART to month 12 (M12) after new ART initialisation. Results: Twenty three patients were included in the study. After OBT, the proportion of patients with undetectable viral load was significantly higher at M6 and M12 than M0 (86% and 73% versus 0%, p = 0.03, respectively). At the same period, the median HIV viral load decreased significantly in 19/23 (83%) patients from 4.3 to 1.69log10 HIV-1 RNA copies/ml (p 3 [0 - 604] to 449/mm3 [130 - 964] between M0 and M12 (p 3 decreased from 57% to 23% (p = 0.02). Tolerability was good and no death was recorded during the 12-month' follow-up. Conclusions: These results show that the combination of OBT with the new ART can offer a salvage therapy in patients presenting a long-term history of virologic failures.

Genetic Diversity and Antiretroviral Drug Resistance among Drug-Naive HIV-1 Infected Pregnant Women Attending Antenatal Clinics in Abidjan, Cote d'Ivoire

To clarify the distribution of HIV-1 subtypes and drug resistance-related mutations, we collected and analysed serum from pregnant women who are ARV drug-naive in Abidjan. The prevalence of HIV-1 subtypes and mutations associated with antiretroviral drug resistance among drug-na?ve HIV-1 infected pregnant women was investigated from plasma of 90 young pregnant primigravida. The HIV-1 pol and env genes were amplified by using primers recognizing conserved viral sequences and sequenced by employing BigDye chemistry. Positions 1 - 99 of the PR and 1 - 350 of the RT genes were analyzed for mutations based on the international AIDS society USA panel. In 39 strains which both genes were sequenced including CFR02_AG 30 (76.9%), subtype A 3 (7.7%), CFR06_cpx 2 (5.1%), CFR09_cpx 1 (2.6%), and discordant sequences suggesting the presence of a few number of recombinant involving CRF02-AG and subtype A 3 (7.7%). None of the major drug resistance mutations was detected. The frequent minor mutations associated drug resistance observed were M36I (52%/96.3%), L10I/R/V (19%/35.2%) and L63P (7%/12.9%). The M36I mutation was widespread in all subtypes. Our result demonstrated first a significant level of viral heterogeneity and then only the presence of minor resistance associated mutations. Our study emphasizes the need of HIV sentinel survey in C?te d'Ivoire and shows that pregnant women who are candidates for receiving antiretroviral drug therapies do not contain naturally occurring or preexisting drug resistance mutations. So such drug therapies are likely to be highly effective in this setting.