Methods Very early diagnosis was explained and proposed, before and/or after delivery, to HIV positive mothers delivering at Calmette and hospitals and health centers supported by Magna Children at Risk (NMCHC, Chey Chumneas Hospital and 3 Municipality Health Centers). A first negative HIV-DNA negative DBS at day 0–day 3 was followed up by a second DBS at W6. HIV-DNA positive DBS at d0–d3, or at week 6 were followed up by a venipuncture as soon as possible for HIV-RNA quantification (Kit G2 ANRS) and CD4 count. Preliminary results Heel prick blood specimens were spotted on DBS for 272 newborns (ratio M/F = 1.3) at d0–d3. HIV DNA was detected in 3 of 272 babies (rIUT rate: 1.1%). One of them died before week 6. The two others presenting detectable HIV-1 RNA viral loads at week 6 (6.4 and 6.9 log10 copies/ ml with CD4 at 19% and 21%, respectively) started first line ARV regimen and became HIV-1 RNA undetectable after 10 and 4 months of treatment. Among the 269 HIVDNA negative newborn at d0–d3, 228 (84.5%) have been already seen at week 6 for virological confirmation, 23 are still waiting for the visit of the week 6, 14 were lost of follow up and 4 died without any AIDS clinical symptoms. 226 of 228 DBS were confirmed HIV-DNA negative at week 6 whereas 2 infants became HIV-DNA positive (PPT rate: 0.8%). Both were confirmed HIV-RNA positive two weeks later (5.8 and 6.2 log10 copies/ml with CD4 at 33% and 26%, respectively) and will soon begin their ARV treatment.
To determine the percentage of infected children for whom nevirapine (NVP) was used to prevent peripartum mother-to-child transmission (MTCT) of HIV in Yaoundé, Cameroon.The study was a prospective Public Health Pilot Program covering a 3-year period (January 2000-December 2002).Counseled and consenting HIV-1-positive pregnant women were given a single dose of NVP at the onset of labor. Babies were given 2 mg/kg NVP syrup within the first 72 hours of life. NVP-treated children were regularly followed up and examined for HIV-1 infection at 6-8 weeks and 5-6 months through plasma viral load (VL) quantification with the bDNA system.One hundred twenty-three children were diagnosed with perinatal HIV-1 infection at 6-8 weeks and 5-6 months. Thirteen children (10.6% [13/123]; 95% confidence interval, 5.1-16) were infected and presented with high VLs, in general >500,000 copies/mL. Two children had intermediate VLs (between 50 and 3500 copies/mL) at both time points. One hundred seven children (87%) were considered not infected at 6-8 weeks of age.Our results indicate that the HIV-1 MTCT rate 6-8 weeks after NVP administration was not >13% (16/123), thus demonstrating the effectiveness of NVP for lowering the risk of HIV-1 MTCT in real-life settings.
We used an ELISA to determine the prevalence of IgG antibodies specific for the Zaire subtype of Ebola virus in 790 nonhuman primates, belonging to 20 species, studied between 1985 and 2000 in Cameroon, Gabon, and the Republic of Congo. The seroprevalence rate of Ebola antibody in wild-born chimpanzees was 12.9%, indicating that (1) Ebola virus circulates in the forests of a large region of central Africa, including countries such as Cameroon, where no human cases of Ebola infections have been reported; (2) Ebola virus was present in the area before recent outbreaks in humans; (3) chimpanzees are continuously in contact with the virus; and (4) nonlethal Ebola infection can occur in chimpanzees. These results, together with the unexpected detection of Ebola-specific IgG in other species (5 drills, 1 baboon, 1 mandrill, and 1 Cercopithecus), may help to narrow the search for the reservoir of Ebola virus. They also suggest that future Ebola outbreaks may occur anywhere in the central African forest region.
The frequency of transmitted HIV drug resistance (HIVDR) was evaluated in the context of rapid scale-up of antiretroviral treatment in Thailand, Vietnam, Burkina Faso, Côte d'Ivoire, and Senegal by using an adaptation of the WHO generic protocol of the HIV Drug Resistance Threshold Survey (HIVDR-TS) for sample collection and classification. Resistance-associated mutations were interpreted using the 2009 WHO list for epidemiological surveys. We included 266 subjects from the five study sites. Of the 266 RT and PR sequences analyzed, two from Vietnam harbored virus with major drug resistance mutations (G190A in RT for one individual and M46I in PR for the second individual). Phylogenetic analysis revealed that CRF01_AE predominates (>90%) in Thailand and Vietnam. CRF02 (>65%) cocirculates with other HIV-1 variants in Senegal and Côte d'Ivoire. The prevalence of HIVDRM is scored as low (≤5%) in all the five sites for the three drug classes analyzed. A continuous population survey for HIVDRM will provide a rational basis for maintaining or changing the current first line regimen in these countries.
Simian immunodeficiency viruses (SIVs) are lentiviruses that infect an extensive number of wild African primate species. Here we describe for the first time SIV infection in a captive agile mangabey (Cercocebus agilis) from Cameroon. Phylogenetic analysis of the full-length genome sequence of SIVagi-00CM312 showed that this novel virus fell into the SIVrcm lineage and was most closely related to a newly characterized SIVrcm strain (SIVrcm-02CM8081) from a wild-caught red-capped mangabey (Cercocebus torquatus) from Cameroon. In contrast to red-capped mangabeys, no 24 bp deletion in CCR5 has been observed in the agile mangabey. Further studies on wild agile mangabeys are needed to determine whether agile and red-capped mangabeys are naturally infected with the same SIV lineage, or whether this agile mangabey became infected with an SIVrcm strain in captivity. However, our study shows that agile mangabeys are susceptible to SIV infection.
Objective: To describe the ARV resistance profiles of patients experiencing virological failure after at least 6 months on LPV /r -based 2 nd line regimen in Cambodia.Design: Retrospective analysis of resistance testing of 89 patients with detectable viral load under LPV /r -based 2 nd line regimen.Methods: Bulk sequencing of HIV-1 protease, reverse transcriptase and integrase PCR products.Results: Protease gene amplification was successful for 71/89 patients (80%).All were infected by CRF01_AE viruses.Among them, 42 did not present any resistance to PIs.A high level of resistance to PIs was observed for the 29 remaining patients.Twenty-six were resistant to LPV /r (8 possibly resistant).Twenty-eight, 21 and 20 were also found resistant to IDV, ATV/ r and FPV/ r , respectively.Twenty-six were resistant to NFV (11 possibly) and 22 to SQV/ r (9 possibly).Finally, 22/29 (75.8%) were resistant to at least 3 PIs.Interestingly, 78.6% (22/29) were found sensitive to DRV/ r .In this group, a high frequency of resistance to RTIs including ETV was also reported.No resistance to raltegravir (RAL) or elvitegravir (EVG) was observed (n=24).Detailed ARV histories documented for 15 patients revealed past exposition to multiple RTIs and PIs. Conclusion:Almost 2/3 of patients (60/89) with virological failure on LPV /r -based 2 nd line in our study were not in urgent need for treatment change.In contrast, switching treatment was clearly required for 1/3 (29/89) presenting high level of resistance to PIs and RTIs.For those patients, DRV, RAL/EVG, and potentially ETV, could be good candidates for 3 rd line ARV regimen if available.
To the Editor: A recent demographic and health survey was performed in Cameroon in 2004 that showed an HIV-1 seroprevalence rate of 5.5% in the general population.1 In Yaoundé, the capital city of Cameroon, HIV-1 prevalence is as high as 10% among pregnant women attending antenatal centers.2 Since the year 2000, a public health pilot program for the prevention of mother-to-child transmission started providing a single dose of the nonnucleoside reverse transcriptase (RT) inhibitor, nevirapine (NVP), to pregnant women who were diagnosed as HIV-1 positive in a maternity ward in Yaoundé.2 This program is now scaled to at least 60% of health districts of the country.3 One of the main portals of antiretroviral (ARV) entry in Cameroon is via the HIV-1 prevention of mother-to-child transmission program. To date, no information is available on ARV resistance in this sentinel population. The present study aimed to investigate whether genetic polymorphisms were present in RT and protease (PR) of HIV-1 genes at positions affecting the susceptibility to ARV and to evaluate baseline drug resistance among HIV-1-infected pregnant women, naive to NVP in Yaoundé, Cameroon, where HIV-1 non-B subtypes predominate. After informed consent was obtained, HIV-1-positive pregnant women who were willing to participate in the study were included and interviewed for ARV history. Blood samples (2 × 5 mL) were drawn by venous puncture on EDTA-treated tubes. CD4+ T-lymphocyte enumeration was performed by flow cytometry with a FACSCount (Becton-Dickinson, San Jose, CA) and plasma viral load was quantitated by bDNA (Bayer Diagnostics, Paris, France). Viral RNA for the genotypic resistance study was extracted from 1 mL of plasma by using the Qiagen viral RNA extraction mini kit (Qiagen, Inc., Chatsworth, CA) as recommended by the manufacturer. The RT gene (codons 1-255) and PR gene (codons 1-99) were amplified by using the primers MJ3/MJ4 and Prot1FW/Prot1RV,4-6 respectively. These first polymerase chain reaction (PCR) were followed by nested PCR with primers A35/NE1 for RT and Prot2FW/Prot2Rev 4,7 for PR. PCR products were sequenced on both strands by Genome Express (Meylan, France) using the BigDye Terminator v3.1 Cycle Sequencing Kit on a 3730xl DNA analyzer (Applied Biosystems, Foster City, CA). Prot2FW/Prot2Rev and A35/NE1 primer sets were used for the PR and RT, respectively. Sequences were manually corrected by using the Ceq2000 (Beckman Coulter) software using the HIV-1 HXB2 (GenBank Acc. Number: K03455) sequence as template. Genotypic drug resistance interpretation was performed according to the latest version (September 2005) of the French Agence Nationale de Recherche contre le Sida et les Hépatites algorithm (http://www.hivfrenchresistance.org/). Between 2001 and 2004, a total of 110 HIV-1-positive pregnant women consented to participate in the study. They were all ARV therapy-naive before the index pregnancy. One hundred ten amino acid sequences were obtained in the PR gene and 109 in the RT gene. In this report, we considered only samples with complete sequences for both strands in the PR and RT genes. Overall, 96 ARV therapy-naive pregnant women whose HIV-1 were full-length sequenced in both PR and RT genes were analyzed. Age at inclusion was 27 years on average (range, 16-41 years). HIV-1 status was known for an average of 7 months (range, 3-12 months). The mean T-lymphocyte count was 365 (range, 9-962 cells/μL) and viral load was, on average, 4.8 log10 RNA copies/mL (range, 1.7-5.7 log10 RNA copies/mL). Phylogenetic analysis of the 96 PR and RT sequences, together with Basic Local Alignment Search Tool search, revealed a high genetic diversity in both genes. Almost all known HIV-1 subtypes were found, with CRF02-AG representing, however, 63 of 96 (65.6%) sequences in PR and 56 of 96 (58.3%) in RT genes. Other circulating recombinant forms were marginally found: CRF11 (6.2% in PR and 5.2% in RT), CRF14 (5.2% in PR), and other subtypes represent 14 of 96 sequences in PR and 22 of 96 sequences in RT. Complex recombinant forms were encountered more often in the RT genes, where they represent up to 26% (25/96). Sequence analysis for genotypic drug resistance in the RT gene revealed no major mutations associated with HIV-1 ARV resistance. One sample (M4587N, HIV-1/F2 Beckman-Coulter, Nyon, Switzerland) presented the L210W and T215S amino acid mutations. These mutations confer a possible resistance to the nucleoside RT inhibitors, zidovudine and stavudine, and to the nucleotide analog RT inhibitor, tenofovir. In the PR gene, all of the 96 sequences analyzed harbored 2 mutations or more at positions associated with a lower susceptibility to PR inhibitors in subtype B HIV-1 strains (Fig. 1). More than 87% of the sequences harbored 5 to 9 mutations. Minor amino acid substitutions K20I, M36I, R41K, and H69K were found at 79%, 99%, 86%, and 95% frequencies, respectively. One sample (M3988N) showed the mutation N88S, conferring resistance to the PR inhibitor nelfinavir. Overall, 1 (M3988N, 1.04%) of 96 samples we analyzed in the RT and PR presented a major HIV-1 drug resistance mutation in the PR gene (N88S) that confers resistance to the PR inhibitor, nelfinavir. In the present study, we have shown that HIV-1 genetic diversity in both PR and RT genes is very high in viruses circulating in seropositive pregnant women in Yaoundé, confirming previous findings from the same country but targeting a mixed population of men and women.8,9 Genotypic drug resistance analysis of the pol gene uncovered no major drug resistance mutation but one (M3988N) in both RT and PR, despite the great genetic diversity observed. This lack of major drug resistance mutation is consistent with an ARV-naive population, in an area like Cameroon, where mass anti-HIV-1 drugs are of relatively recent introduction. In the PR gene, the high genetic diversity observed seems to be correlated to a high degree of polymorphism at positions known to be associated with drug resistance in subtype B HIV-1. This observation was repeatedly reported in various studies on samples obtained from Africa and, to a lesser extent, from southeast Asia.10,11 The implication of these polymorphisms at key amino acid positions in the PR gene remains a concern for long-course anti-PR treatment of HIV-1-infected patients in southern countries. In the course of the present study, a small group of 10 women who already experienced NVP in a previous pregnancy was screened as well. Analysis of corresponding samples did not reveal either the presence of NVP-related mutations or related to other ARV. It should be mentioned, however, that the time between the 2 pregnancies was always greater than 20 months for the 10 women. Hence, single-dose NVP-associated mutations fade up in the plasma by approximately 18 months after drug application, as previously reported.12,13 These findings also emphasize the urgent need for genotypic drug resistance interpretation algorithms adapted to nonsubtype B HIV-1 strains. Our present data indicate that less than 1% of HIV-1-positive, ARV-naive pregnant women in Yaoundé carried viruses with major genotypic drug resistance mutations. It would be very informative to repeat such a study to evaluate the incidence of HIV-1 drug resistance mutations among ARV-naive and ARV-experienced pregnant women in Cameroon and the impact of a greater availability of ARV to other subpopulations.FIGURE 1: HIV-1 PR gene polymorphism at position associated with drug resistance in non-B subtypes. HIV-1 PR gene (codons 1-99) were amplified and sequenced, and the corresponding amino acid sequence deduced. The figure shows the frequency of amino acids at indicated positions, different from the reference sequence of HIV-1 subtype B (HXB2). Black bars represent any amino acid different from that of HXB2. Dashed bars represent resistance-associated mutations if present in a subtype B HIV-1. The black arrow indicates the unique major drug resistance mutation found in our sample.Aurélia Vessière, MSc* Eric Nerrienet, PhD*† Anfumbom Kfutwah, MSc* Elisabeth Menu, PhD‡ Mathurin Tejiokem, MD* Patricia Pinson-Recordon, PhD‡ Françoise Barré-Sinoussi, PhD‡ Hervé Fleury, MD§ Ahidjo Ayouba, PhD*‡ *Centre Pasteur du Cameroun BP 1274 Yaoundé, Cameroun †Laboratoire VIH/Hépatites Institut Pasteur du Cambodge BP 983 Phnom Penh Kingdom of Cambodia ‡Institut Pasteur de Paris Unité Régulation des Infections Rétrovirales, Paris, France and §Laboratoire de Virologie EA2968 Université Victor Segalen Bordeaux, France
ABSTRACT Nef is a multifunctional accessory protein of primate lentiviruses. Recently, it has been shown that the ability of Nef to downmodulate CD4, CD28, and class I major histocompatibility complex is highly conserved between most or all primate lentiviruses, whereas Nef-mediated downregulation of T-cell receptor-CD3 was lost in the lineage that gave rise to human immunodeficiency virus type 1 (HIV-1). Whether or not other Nef activities are preserved between different groups of primate lentiviruses remained to be determined. Here, we show that nef genes from a large variety of HIVs and simian immunodeficiency viruses (SIVs) enhance virion infectivity and stimulate viral replication in human cells and/or in ex vivo infected human lymphoid tissue (HLT). Notably, nef alleles from unpassaged SIVcpz and SIVsmm enhanced viral infectivity, replication, and cytopathicity in cell culture and in ex vivo infected HLT as efficiently as those from HIV-1 and HIV-2, their human counterparts. Furthermore, nef genes from several highly divergent SIVs that have not been found in humans were also highly active in human cells and/or tissues. Thus, most primate lentiviral Nefs enhance virion infectivity and stimulate viral replication. Moreover, our data show that SIVcpz and SIVsmm Nefs do not require adaptive changes to perform these functions in human cells or tissues and support the idea that nef alleles from other primate lentiviruses would also be capable of promoting efficient virus spread in humans.
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