AE Strains Research Articles

Molecular Evolution of the HIV-1 Thai Epidemic between the Time of RV144 Immunogen Selection to the Execution of the Vaccine Efficacy Trial

The RV144 HIV-1 vaccine trial (Thailand, 2003 to 2009), using immunogens genetically matched to the regional epidemic, demonstrated the first evidence of efficacy for an HIV-1 vaccine. Here we studied the molecular evolution of the HIV-1 epidemic from the time of immunogen selection to the execution of the efficacy trial. We studied HIV-1 genetic diversity among 390 volunteers who were deferred from enrollment in RV144 due to preexisting HIV-1 infection using a multiregion hybridization assay, full-genome sequencing, and phylogenetic analyses. The subtype distribution was 91.7% CRF01_AE, 3.5% subtype B, 4.3% B/CRF01_AE recombinants, and 0.5% dual infections. CRF01_AE strains were 31% more diverse than the ones from the 1990s Thai epidemic. Sixty-nine percent of subtype B strains clustered with the cosmopolitan Western B strains. Ninety-three percent of B/CRF01_AE recombinants were unique; recombination breakpoint analysis showed that these strains were highly embedded within the larger network that integrates recombinants from East/Southeast Asia. Compared to Thai sequences from the early 1990s, the distance to the RV144 immunogens increased 52% to 68% for CRF01_AE Env immunogens and 12% to 29% for subtype B immunogens. Forty-three percent to 48% of CRF01_AE sequences differed from the sequence of the vaccine insert in Env variable region 2 positions 169 and 181, which were implicated in vaccine sieve effects in RV144. In conclusion, compared to the molecular picture at the early stages of vaccine development, our results show an overall increase in the genetic complexity of viruses in the Thai epidemic and in the distance to vaccine immunogens, which should be considered at the time of the analysis of the trial results.

Improvement of the oligonucleotide ligation assay for detection of the M184V drug-resistant mutation in patients infected with human immunodeficiency virus type 1 subtype CRF01_AE

Methods based on genetic sequencing to monitor drug-resistance mutations in human immunodeficiency virus type 1 (HIV-1) require expensive instruments and are only capable of detecting mutant strains comprising >20% of virus populations. The National Institutes of Health's AIDS Research and Reference Reagent Program (NIH ARRRP) makes available a probe-based method, an oligonucleotide ligation assay (OLA-ARRRP), which is less expensive and more sensitive than sequencing to detect such mutations for HIV-1 subtype B.In this study, an OLA was designed to detect the Methionine to Valine mutation at codon 184 (M184V) of the reverse transcriptase (RT) gene in the circulating recombinant form AE strain of HIV-1 (HIV-1 CRF01_AE) common in Thailand, and was evaluated in Thai patients experiencing treatment failure. The subtype-specific OLA-CRF01_AE proved superior to OLA-ARRRP in detecting M184V, although this mutation existed in the genome of the multiple-drug-resistant virus at lower minimal detection levels of 3% prevalence of mutated virus, compared to 50% for OLA-ARRRP.On evaluation using clinical specimens, OLA-CRF01_AE showed excellent agreement with nucleotide sequencing (95.1% overall concordance, kappa>0.79), and the sensitivity was 100% for wild-type and 93.9% for mutant detection at codon 184. The OLA-CRF01_AE also detected M184V mutations in 2.4% (1/42) of specimens that were not detected by sequencing. The indeterminate detection by OLA-CRF01_AE was decreased, from 16.7% to 4.8%, in the samples containing mutant genotype when the strategy using unmodified- as a substitute of the modified-mutant detector probe was applied. Because of their low cost, sensitivity, and ease of use, the OLA-CRF01_AE is an attractive alternative to standard sequencing in resource-limited countries affected by this subtype of HIV-1.

Subtype CRF01_AE dominate the sexually transmitted human immunodeficiency virus type 1 epidemic in Guangxi, China

Human immunodeficiency virus type 1 (HIV-1) infection by sexual transmission in Guangxi, China had increased dramatically. However, limited information is available on the genetic characterization of the HIV-1 epidemic. In this study, HIV-1 seropositive drug-naïve patients infected by heterosexual transmission were enrolled. The full length gag and pol genes were sequenced followed by phylogenetic analysis, recombinant analysis and drug resistant analysis. Multiple subtypes were identified, including CRF01_AE (80.1%), CRF07_BC (6.4%), CRF08_BC (10.2%), subtype B (1.7%), and URFs (1.7%). In the phylogenetic tree, two large CRF01_AE clusters were identified. One cluster is originating from Vietnam strains as being reported previously in intravenous drug users. One novel cluster was identified and showed close relationship to strains from Fujian province. Inter-subtype recombination among CRF01_AE, subtype B and C was identified. Low level drug-resistance in drug-naïve heterosexually transmitted infections was found. The results suggested that multiple originating CRF01_AE strains dominated the HIV-1 epidemic in heterosexual transmission in Guangxi province.

Molecular Epidemiology of Human Immunodeficiency Virus Type 1 in Guangdong Province of Southern China

BackgroundAlthough the outbreak of human immunodeficiency virus type 1 (HIV-1) in Guangdong has been documented for more than a decade, the molecular characteristics of such a regional HIV-1 epidemic remained unknown.Methodology/Principal FindingsBy sequencing of HIV-1 pol/env genes and phylogenetic analysis, we performed a molecular epidemiologic study in a representative subset (n = 200) of the 508 HIV-1-seropositive individuals followed up at the center for HIV/AIDS care and treatment of Guangzhou Hospital of Infectious Diseases. Of 157 samples (54.1% heterosexual acquired adults, 20.4% needle-sharing drug users, 5.7% receivers of blood transfusion, 1.3% men who have sex with men, and 18.5% remained unknown) with successful sequencing for both pol and env genes, 105 (66.9%) HIV-1 subtype CRF01_AE and 24 (15.3%) CRF07_BC, 9 (5.7%) B’, 5 (3.2%) CRF08_BC, 5 (3.2%) B, 1 (0.6%) C, 3 (1.9%) CRF02_AG, and 5 (3.2%) inter-region recombinants were identified within pol/env sequences. Thirteen (8.3%) samples (3 naïves, 6 and 5 received with antiretroviral treatment [ART] 1–21 weeks and ≥24 weeks respectively) showed mutations conferring resistance to nucleoside/nonnucleoside reverse transcriptase inhibitors or protease inhibitors. Among 63 ART-naïve patients, 3 (4.8%) showed single or multiple drug resistant mutations. Phylogenetic analysis showed 8 small clusters (2–3 sequences/cluster) with only 17 (10.8%) sequences involved.Conclusion/SignificanceThis study confirms that sexual transmission with dominant CRF01_AE strain is a major risk for current HIV-1 outbreak in the Guangdong’s general population. The transmission with drug-resistant variants is starting to emerge in this region.

High prevalence of CXCR4‐using viruses in vertically HIV‐1‐infected infants in Thailand

Purpose of the studyPrevious studies evaluating the frequency of CXCR4‐using strains in HIV‐1 vertically infected children restricted mainly to patients infected with subtype B or C strains. However, the coreceptor use by non‐B or non‐C subtypes remains little known, especially in infants. In this study, we determined the HIV‐1 coreceptor usage in infants with vertically‐acquired HIV‐1 infection in Thailand, where the predominant circulating HIV‐1 strains are CRF01_AE and the minority are subtype B.MethodsC2‐V3‐C3 gp120 was amplified in a triplicate nested‐PCR and sequenced. Coreceptor usage was predicted using the geno2pheno [coreceptor] algorithm and analyzed with a false positive rate (FRP) of 10%.Summary of resultsA total of 255 sequences were obtained from viral isolates of 85 HIV‐1‐infected infants (34 male and 51 female) participating in the National AIDS Program (NAP) of the National Health Security Office (NHSO) of Thailand. All children were received ARV prophylaxis according to the Thai national guidelines. The median age was 84 days (range: 33–308). Seventy‐four children (87.1%) were infected with CRF01_AE strain and 11 (12.9%) were infected with subtype B strain. Concordance in tropism prediction for the triplicates was observed in all samples. CXCR4 coreceptor‐using strains were found in 44.7% (38 of 85) and CCR5 coreceptor‐using strains were found in 55.3% (47 of 85). No significant difference in age (p=0.34) and clinical signs of AIDS (p=0.47) were observed between these populations. CCR5Delta32 and CCR5m303 mutation genotypes that may contribute to a selective pressure of viruses to alternatively use CXCR4 as a coreceptor were not found.ConclusionsA high prevalence of HIV‐1 CXCR4‐using variants was found among HIV‐1 vertically infected infants in Thailand, indicating that a direct vertical transmission of CXCR4‐using variants or a rapid switch from CCR5‐using to CXCR4‐using viruses shortly after transmission. These observations may have implications for clinical and therapeutic aspects, especially in the early stage of HIV‐1 infection in infants and may benefits for using of CCR5‐antagonists in this population.

Men who have sex with men and its relationship with HIV-1 strains prevailing in the paid blood donors from Zhengzhou city, Henan

To clarify the genetic characteristics of human immunodeficiency virus (HIV) circulated in the population of men who have sex with men (MSM) in Zhengzhou, Henan and to analyze its relationship with HIV-1 prevailing in the paid blood donors (PBDs). Thirty-one MSM who were confirmed as HIV positive individuals in 2010 together with 41 HIV-positive former PBDs were enrolled in the study. Information on related epidemiological characteristics and their plasma were collected. RT-PCR was used to amplify HIV-1 full length gag (1584 bp), pol (3147 bp) genes and partial env gene (C2V3 segment, 558 bp) followed by sequencing on those subjects. Online software available at LosAlamos HIV Database was used to identify the HIV subtypes based on the findings of the sequences. Phylogenetic tree was used to identify the possible relationship of transmission. Fifty-three full length gag, 38 full length pol and 48 partial env (C2V3) genes were collected from 72 participants. Among the 31 HIV(+) MSM individuals, 14 CRF01_AE strains, 5 CRF07_BC strains and 12 subtype B (1 subtype B and 11 B') strains were identified respectively. All of the 41 strains identified from former PBDs were infected by B' strains. The CRF01_AE strains identified in MSM showed a close relationship to those identified from both Hebei and Liaoning provinces. The CRF07_BC strains showed a close relationship with those from Shijiazhuang and Beijing cities. Among the 12 subtype B strains, 8 sequences grouped into 1 cluster with 1 sequence from the former PBDs. Two sequences grouped with 02HNseq4 suggested that B' had been prevailed in the MSM population might come from the former PBDs and were closely related to the strains identified in the MSM population. Complicated genetic background and multiple introductions of HIV in the MS population in Zhengzhou, were found. This was also the first report which noticed that the subtype B epidemic among Zhengzhou MSM was mainly originated from the B' among the former PBDs.

Fusion of CTA and CTB gene to immunogen significantly enhances the immunogenicity of DNA vaccine

Background Cholera toxin and its two subunits (CTA,CTB) have been intensively investigated as mucosal adjuvants for protein based vaccine. In this study we evaluated the adjuvanticity of CTA and CTB in modality of either mixing their encoding plasmids with DNA vaccine or fusing their encoding genes to immunogen encoding gene. Methods DNA and recombinant vaccinia vaccines expressing HIV-1 AE strain tat, rev, intergrase(C-half), vif, nef fusion gene (designated as TRIVN) have been constructed. For the construction of fusion gene of CTA/CTB to TRIVN, overlapping PCR was employed to link CTA/CTB and TRIVN gene, the fused genes(TRIVN-CTA and TRIVN-CTB)were cloned into eukaryotic expression plasmid vector(pSV1.0). Six groups of female BALB/c mice were immunized with mock control, pSV-TRIVN, pSV-TRIVN-CTA, pSVTRIVN-CTB, pSV-TRIVN mixed with CTA or with CTB respectively in a DNA priming-recombinant vaccinia boosting regimen. Two weeks after the final injection, mice splenocytes were collected and IFN-g ELISPOT assay were used as readout for specific T cell response. Statistical analysis was performed by using Prism5.0 software. Results Our data showed that all constructed plasmids are capable of efficiently expressing their inserted genes. All groups immunized with vaccines raised significant more T-cell response than mock control. T-cell responses elicited by pSV-TRIVN-CTB(1548±330SFCs/106splenocytes) and pSV-TRIVN-CTA (1642±514SFCs/106splenocytes) were significantly higher than that by pSV1.0-TRIVN (520±150SFCs/106splenocytes), pSV1.0-TRIVN mixed with CTA (692±220SFCs/106splenocytes) and pSV1.0TRIVN mixed with CTB (734±240SFCs/106splenocytes). Though TRIVN-CTA and TRIVN-CTB fusion vaccines mounted comparable level of total IFN-g+ T-cell responses, only TRIVN-CTB elicits significantly T-cell responses against Tat, which is a subdominant component in the fusion immunogen. No significant differences were observed among groups inoculated with TRIVN alone or adjuvanted by CTA/CTB subunit proteins. Conclusion CTA and CTB could serve as potent adjuvants for DNA vaccine in immunogen-CTA/CTB fusion modality. Compared with CTA, CTB may enhance T-cell responses against subdominant epitopes in the immunogen and broaden the T-cell immune responses.

Reconstituting the Epidemic History of HIV Strain CRF01_AE among Men Who Have Sex with Men (MSM) in Liaoning, Northeastern China: Implications for the Expanding Epidemic among MSM in China

HIV CRF01_AE accounted for 84% of the recent infections among men who have sex with men (MSM) in Liaoning Province of northeastern China. CRF01_AE strains were grouped into two distinct clusters (designated clusters 1 and 2) that were also detected in other regions in China. Phylodynamics study revealed that these two CRF01_AE strains were independently introduced into the population of MSM in China in the early and mid-1990s. Our study elucidated unique features of dynamics and interrelationships of MSM epidemics in China.

Profiles of neutralizing antibody response in chronically human immunodeficiency virus type 1 clade B′-infected former plasma donors from China naïve to antiretroviral therapy

Broadly neutralizing antibodies (NAbs) such as those generated in chronic human immunodeficiency virus type 1 (HIV-1) infection are considered a key component for an effective HIV-1 vaccine. Here, we measured NAb responses using a panel of 25 Env-pseudotyped viruses, including clade B, C, A, CRF07_BC and CRF01_AE strains, against plasma samples from 103 subjects in a former plasma donor cohort in central China, who were infected with HIV-1 clade B' for at least 10 years and naïve to antiretroviral therapy at the time of sampling. We found that 64 % of samples (n = 66) neutralized at least half of the viruses tested and 2 % (n = 2) neutralized all of the viruses, while 5 % (n = 5) neutralized none of the viruses tested. Strikingly, 29 % of plasma samples (n = 30) neutralized >80 % of the viral strains tested, indicating the presence of broadly reactive NAbs in these patients. When the magnitude (geometric mean ID(50) titres, GMTs) or breadth of neutralization was assessed for correlation with CD4 count or plasma viral load, the only significant positive correlations were observed between viral load and neutralization magnitude (r = 0.2189, P = 0.0263) and between viral load and neutralization breadth (r = 0.1970, P = 0.0461). A moderate difference between progressors and long-term non-progressors was observed in both the breadth (P = 0.0316) and the potency (P = 0.0300). A significant difference was found in the GMTs between intra-clade and inter-clade strains (P<0.001). Heat-map analysis based on k-means clustering of plasma determined a statistically stable cluster of plasma with cross-reactive and potent neutralizing reactivity. These samples could provide physical biomaterials for further virological and serological studies from which useful insights into rational HIV-1 vaccine development and therapeutic design might be derived.

Rising Epidemic of HIV-1 Infections Among General Populations in Fujian, China

HIV-1 infections have increased significantly with a doubled number of cases identified between 2006-2007 and 2008-2009 in Fujian, a southeastern province of China. No study has investigated the cause and the evolving epidemic there. In a province-wide study of recently identified infections from 2006 to 2009, we sought to investigate the rising epidemic of HIV-1 infections among general populations and conducted a molecular epidemiology study to determine the new trends of HIV-1 evolution there. About 915,830 and 2,152,658 specimens collected in 2006-2007 and 2008-2009 were tested for HIV-1 infection. We found that the overall prevalence of infections elevated from 0.064% in 2006-2007 to 0.074% in 2008-2009 (P = 0.003). A high frequency of HIV-1 infections was consistently related to unprotected heterosexual transmissions compared with other risk groups such as intravenous drug users. Critically, the prevalence rate had significantly increased in recent years among general populations such as voluntary blood donors (P < 0.001), recipients of blood transfusion (P < 0.001) and people during presurgery screening (P < 0.001). Besides CRF01_AE as the major circulating subtype (61/86, 70.9%), 25 non-CRF01_AE strains were found contributing to increased HIV-1 genetic diversity including C/CRF07_BC/CRF08_BC (5.8%), B/B' (15.1%), unique recombinant forms (8.1%), and some minor drug-resistant variants. Increased prevalence of HIV-1 infections among general populations likely accounts for the rising epidemic in recent years in Fujian. The epidemic was no longer dictated by CRF01_AE but rather by multisubtype viruses. Our findings call for an enhanced surveillance system and have implications to strategic prevention programs among general populations.

Primary drug resistance of HIV-1 infected men who have sex with men in Shenzhen, China

To evaluate the status of drug resistance among treat-naive HIV-1 infected men who have sex with men (MSM) in Shenzhen during the period of 2008 - 2010. Plasma samples of 227 treatment-naive HIV-1 infected MSM were collected in Shenzhen. HIV-1 pol genes (RT and PR) were amplified by nested-polymerase chain reaction (PCR) from RNA. Phylogenetic and drug resistance analyses were performed on the nucleotide sequence data. A total of 164 pol gene sequences were amplified. The prevalence of primary genotypic drug resistance was 14.6%. The overall prevalence of drug-resistant mutations was 22.6%, corresponding to 8.54% for protease inhibitors (PI) minor drug resistance mutation, 1.22% for nucleotide reverse transcriptase inhibitors (NRTI) drug resistance mutation and 13.41% for non-nucleotide reverse transcriptase inhibitors (NNRTI) drug resistance mutation. The prevalence of drug-resistant mutations was 30.88% for CRF01_AE strain and 19.23% for B strain. The prevalence of drug resistance is relatively moderate in the treat-naive HIV-1 infected MSM in Shenzhen. The prevalence of drug-resistant HIV-1 among MSM in Shenzhen should raise a high alert.

Emergence of a New HIV Type 1 CRF01_AE Variant in Guangxi, Southern China

The distribution of HIV-1 subtypes and genetic characterization of CRF01_AE in Guangxi, southern China were identified. The distribution of HIV-1 genotypes based on gag, pol, and partial env sequences (n=349) was as follows: CRF01_AE (66.5%), CRF08_BC (19.2%), CRF07_BC (7.2%), URF (4.6%), subtype B (1.7%), and subtype B' (0.9%). CRF01_AE predominated in all geographic regions and risk populations and there were multiple introductions of CRF01_AE strains in Guangxi. We found a peculiar CRF01_AE monophyletic lineage distinct from other CRF01_AE viruses, and we designated it "CRF01_AE-v" for convenience. CRF01_AE-v circulating in both heterosexuals and injecting drug users (IDUs) had accounted for 39.7% of CRF01_AE. It showed a selective advantage in the Guangxi population and formed its own characteristic compared with all the CRF01_AE references. Our results suggested that CRF01_AE-v was a new variant of CRF01_AE and it might lead to a new epidemic in Guangxi.

Increasing Diversity of Human Immunodeficiency Virus Type 1 Subtypes Circulating in Australia

Characterization of HIV subtypes can provide a more comprehensive understanding of the epidemic within a distinct region, and when combined with notification data, may also be helpful in enhancing current HIV prevention strategies. In this study, we characterized 1056 HIV-positive individuals (948 males and 108 females) living in Victoria and whose infection was detected for the first time between 2005 and 2010 inclusive. HIV-1 strains were subtyped based on pol gene sequence. Phylogenetic analysis was performed on all non-B subtype sequences identified. Of the 1056 sequences analyzed, 825 were subtype B and 231 were non-B. Overall 6 HIV-1 subtypes, 6 circulating recombinant forms (CRFs), and 12 unique recombinant forms (URFs) were identified. Regardless of gender, the majority of individuals were infected with a subtype B virus (78%). Subtype B was dominant in males (n=806, 85%). In contrast, the majority of females were infected with non-B subtypes (n=89, 82%), in particular subtype C (n=48, 45%). Phylogenetic analysis of the non-B subtypes revealed that the majority of clustering, and thereby transmission, occurred with CRF01_AE strains. Despite the relatively high numbers identified in females there was very little clustering of subtype C viruses. Subtypes C and A1 both historically associated with heterosexual transmission, and CRF01_AE often associated with IVDU, were also associated with transmission within the MSM population, demonstrating the potential for non-B subtypes to expand into the MSM population. The observation of increasing numbers of females and heterosexual males infected with non-subtype B viruses, the majority imported through migration and travel to countries where there is a high prevalence of HIV, suggests a targeted public health message may be required to prevent further increases within these two groups.

Study on the molecular-epidemiological characteristics of HIV-1 in Shenzhen, 1992-2008

To investigate the epidemiological characteristics of HIV-1 subtype in Shenzhen from 1992 to 2008. 489 HIV-1 positive plasma samples were collected from 1992 to 2008 in Shenzhen. HIV-1 env genes were amplified by nested-PCR from RNA. Phylogenetic analysis was performed on data regarding the nucleotide sequence. A total of 464 sequences were amplified and genotyped. Data from this study revealed that CRF01_AE was a predominant HIV-1 subtype in Shenzhen (64.4%, 299/464), followed by subtypes CRF_BC (17.5%, 81/464), B' (14.7%, 68/464) and B (2.4%, 11/464). Subtype C (0.4%, 2/464), A1 (0.2%, 1/464), CRF02_AG (0.2%, 1/464) and CRF06_cpx (0.2%, 1/464) were also prevalent in Shenzhen. CRF01_AE and CRF_BC were predominant among heterosexuals, homosexuals and injection drug users, while B' was predominant among blood donors. Results from phylogenetic tree analysis showed that some of the HIV-1 clusters had been defined in CRF01_AE strains at different time or groups with different transmission routes. Cross-infections were also seen. CRF01_AE was the predominant HIV-1 subtype in Shenzhen while CRF_BC, B, B', C, A1, CRF02_AG and a small amount of CRF06_cpx or recombinant subtypes were prevalent in this city. Different subtypes showed great variation in the process of epidemics.

Screening and evaluation of potential volunteers for a phase III trial in Thailand of a candidate preventive HIV vaccine (RV148)

Screening for the community-based, phase III, prime-boost HIV vaccine trial conducted in Thailand (also referred to as “RV144”) began in September 2003 and concluded in December 2005 in Rayong and Chon Buri provinces. During this period 26,676 persons were consented and screened for vaccine trial eligibility in a separate protocol (“RV148”) at 47 screening sites, of which 26,548 were tested for HIV, and 16,402 were ultimately enrolled in RV144 and received at least one vaccination or corresponding placebo injection. Fifty-eight percent of those enrolled in RV148 were men and roughly half of the men and women were married. A slight majority was born in the provinces in which the study was conducted. The median age was 23 (IQR 20–26) and most had achieved a level of education that was higher than grade 9, which is compulsory for Thai citizens. The prevalence of confirmed HIV infection was 1.6%; among persons who did not return for confirmatory testing, it was 2.0%. Eighty-three percent were infected with CRF01_AE strains (formerly subtype E) as determined by serological typing. The estimated incidence of HIV infection using a capture EIA assay was 0.19 per 100 person-years. Female sex, older age, single marital status, and lower educational attainment were associated with HIV infection. Persons who reported working in the fishing or sex-work industries were more frequently infected (2.4% and 4.1%, respectively), but accounted for a small percent of the tested population in RV148 (0.7% and 0.6%, respectively), reflecting the overall low-risk of HIV in this study. Those screened for eligibility but did not participate in the vaccine trial were not substantially different from enrolled vaccine trial subjects.

Genetic Characterization of 13 Subtype CRF01_AE Near Full-Length Genomes in Guangxi, China

Guangxi is an important transit area for HIV transmission in South China. Characterization of the full-length genome of HIV-1 prevalent in the area is important for phylogenetic analysis and vaccine development. CRF01_AE is one of the most rapidly spreading subtypes in Guangxi. In this study, we reported thirteen near full-length CRF01_AE genomes from Guangxi, China. The nearly full-length genome was reverse transcripted and amplified in two halves with the 1-kb overlap regions. The PCR products were sequenced directly. The sequence analysis showed that all of 13 strains were CRF01_AE recombinant subtypes. Two clusters were set up with all of the sequences that grouped separately with sequences from Vietnam and Fujian, China, which strongly suggested multiple introductions of CRF01_AE strains into Guangxi province. The results will improve our understanding on the phylogenetic relationship of CRF01_AE strains in South China and also help in the development of a successful HIV vaccine.

Patients Infected with HIV Type 1 Subtype CRF01_AE and Failing First-Line Nevirapine- and Efavirenz-Based Regimens Demonstrate Considerable Cross-Resistance to Etravirine

AIDS Research and Human RetrovirusesVol. 26, No. 6 Letter to the EditorPatients Infected with HIV Type 1 Subtype CRF01_AE and Failing First-Line Nevirapine- and Efavirenz-Based Regimens Demonstrate Considerable Cross-Resistance to EtravirineWeerawat Manosuthi, David M. Butler, Wasun Chantratita, Chonlaphat Sukasem, Douglas D. Richman, and Davey M. SmithWeerawat ManosuthiBamrasnaradura Infectious Diseases Institute, Ministry of Public Health, Nonthaburi, Thailand.Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.Search for more papers by this author, David M. ButlerUniversity of California San Diego, La Jolla, California.Search for more papers by this author, Wasun ChantratitaFaculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.Search for more papers by this author, Chonlaphat SukasemFaculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.Search for more papers by this author, Douglas D. RichmanUniversity of California San Diego, La Jolla, California.Veterans Affairs San Diego Healthcare System, San Diego, California.Search for more papers by this author, and Davey M. SmithUniversity of California San Diego, La Jolla, California.Veterans Affairs San Diego Healthcare System, San Diego, California.Search for more papers by this authorPublished Online:20 Jun 2010https://doi.org/10.1089/aid.2009.0107AboutSectionsView articleView Full TextPDF/EPUB ToolsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail View articleFiguresReferencesRelatedDetailsCited ByGlobal Comparison of Drug Resistance Mutations After First-Line Antiretroviral Therapy Across Human Immunodeficiency Virus-1 Subtypes3 November 2015 | Open Forum Infectious Diseases, Vol. 3, No. 2High prevalence of PI resistance in patients failing second-line ART in Vietnam11 December 2015 | Journal of Antimicrobial Chemotherapy, Vol. 71, No. 3A simian-human immunodeficiency virus carrying the rt gene from Chinese CRF01_AE strain of HIV is sensitive to nucleoside reverse transcriptase inhibitors and has a highly genetic stability in vivoMicrobes and Infection, Vol. 16, No. 6Extensive Drug Resistance in HIV-Infected Cambodian Children Who Are Undetected as Failing First-Line Antiretroviral Therapy by WHO 2010 Guidelines Mia Coetzer, Benjamin Westley, Allison DeLong, Chhraing Tray, Dim Sophearin, Eric Nerrienet, Leeann Schreier, and Rami Kantor13 June 2013 | AIDS Research and Human Retroviruses, Vol. 29, No. 7The Potential Cost and Benefits of Raltegravir in Simplified Second-Line Therapy among HIV Infected Patients in Nigeria and South Africa15 February 2013 | PLoS ONE, Vol. 8, No. 2High Plasma Efavirenz Concentration and CYP2B6 Polymorphisms in Thai HIV-1 InfectionsDrug Metabolism and Pharmacokinetics, Vol. 28, No. 5Unusual Insertion and Deletion at Codon 67 and 69 of HIV Type 1 Subtype C Reverse Transcriptase Among First-Line Highly Active Antiretroviral Treatment-Failing South Indian Patients: Association with Other Resistance Mutations Shanmugam Saravanan, Vidya Madhavan, Rami Kantor, Sathasivam Sivamalar, Selvamurthi Gomathi, Sunil S. 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Butler, Wasun Chantratita, Chonlaphat Sukasem, Douglas D. Richman, and Davey M. Smith.Patients Infected with HIV Type 1 Subtype CRF01_AE and Failing First-Line Nevirapine- and Efavirenz-Based Regimens Demonstrate Considerable Cross-Resistance to Etravirine.AIDS Research and Human Retroviruses.Jun 2010.609-611.http://doi.org/10.1089/aid.2009.0107Published in Volume: 26 Issue 6: June 20, 2010Online Ahead of Print:May 27, 2010PDF download

High genetic diversity of HIV-1 viruses in Macao, China

To investigate the molecular epidemiology of recently diagnosed HIV-1 infection in Macao for better understanding the epidemiology in this Chinese city, in context of its relationship with other countries in Asia and the rest of the world. Serum samples of HIV positive cases reported between 2005 and 2007 were collected from the Macao Public Health Laboratory. HIV genotype was determined by phylogenetic analysis of sequences from gag, RT, and env regions. A total of 30 HIV positive samples were genotyped. The HIV-1 viruses circulating in Macao were characterized by their relatively high genetic diversity. CRF01_AE was predominant (56%), followed by subtype B (13%), CRF12_BF (10%), G/CRF12_BF, A1/CRF10_AD and CRF07_BC, of which CRF12_BF and G/CRF12_BF were first reported in Southeast Asia. Phylogenetic analysis showed that there was no clear clustering of CRF01_AE strains but a distinct CRF12_BF cluster associated with injection drug use could be delineated. The results suggested that there were multiple introductions of HIV strains in Macao that have been circulating for an extended period of time, superimposed by an outbreak in injection drug users.

Distinct Circulating Recombinant HIV-1 Strains Among Injecting Drug Users and Sex Workers in Afghanistan

Little information is available regarding a circulating HIV genotype among high-risk groups in Afghanistan; we describe HIV genotypes among injecting drug users (IDUs) and sex workers (SWs) in four Afghan cities. Participants completed behavioral questionnaires and HIV testing. Western blot-confirmed specimens had peripheral mononuclear blood cells isolated for genotyping. Analysis of recombinants was done by bootscanning and manual sequence alignment. The single SW sample harbored a CRF01_AE strain. Of 10 IDUs available for analysis, all were CRF35_AD and from Hirat. Analyzed subregions (gag p17 and env C1-C5) revealed close homology between the Hirat specimens. Three distinct subclusters comprising two or three strains were identified, whereas two other strains were generally equidistant from previously identified Kabul strains. Results suggest that the nascent HIV epidemic among IDUs in Hirat is largely, if not entirely, subtype CRF35_AD, and the close homology suggests recent infection; harm reduction should be supported to avert further transmission.

Neutralization of genetically diverse HIV-1 strains by IgA antibodies to the gp120–CD4-binding site from long-term survivors of HIV infection

To identify an HIV epitope suitable for vaccine development. Diverse HIV-1 strains express few structurally constant regions on their surface vulnerable to neutralizing antibodies. The mostly conserved CD4-binding site (CD4BS) of gp120 is essential for host cell binding and infection by the virus. Antibodies that recognize the CD4BS are rare, and one component of the CD4BS, the 421-433 peptide region, expresses B-cell superantigenic character, a property predicted to impair the anti-CD4BS adaptive immune response. IgA samples purified from the plasma of patients with HIV infection were analyzed for the ability to bind synthetic mimetics containing the 416-433 gp120 region and full-length gp120. Infection of peripheral blood mononuclear cells by clinical HIV isolates was measured by p24 ELISA. IgA preparations from three patients with subtype B infection for 19-21 years neutralized heterologous, coreceptor CCR5-dependent subtype A, B, C, D, and AE strains with exceptional potency. The IgAs displayed specific binding of a synthetic 416-433 peptide mimetic dependent on recognition of the CD4-binding residues located in this region. Immunoadsorption, affinity chromatography, and mutation procedures indicated that HIV neutralization occurred by IgA recognition of the CD4BS. These observations identify the 421-433 peptide region as a vulnerable HIV site to which survivors of infection can produce powerful neutralizing antibodies. This indicates that the human immune system can bypass restrictions on the adaptive B cell response to the CD4BS, opening the route to targeting the 421-433 region for attaining control of HIV infection.