Frequency of subtype B and F1 dual infection in HIV-1 positive, Brazilian men who have sex with men
- Ana Carolina Soares de Oliveira1, 2,
- Rodrigo Pessôa de Farias2,
- Antonio Charlys da Costa1, 2,
- Mariana Melillo Sauer3,
- Katia Cristina Bassichetto4,
- Solange Maria Santos Oliveira4,
- Priscilla Ramos Costa3,
- Claudia Tomiyama3,
- Helena Tomoko Iwashita Tomiyama3,
- Ester Cerdeira Sabino5,
- Esper Georges Kallas3 and
- Sabri Saeed Sanabani6, 7Email author
© Soares de Oliveira et al.; licensee BioMed Central Ltd. 2012
Received: 20 April 2012
Accepted: 27 September 2012
Published: 29 September 2012
Because various HIV vaccination studies are in progress, it is important to understand how often inter- and intra-subtype co/superinfection occurs in different HIV-infected high-risk groups. This knowledge would aid in the development of future prevention programs. In this cross-sectional study, we report the frequency of subtype B and F1 co-infection in a clinical group of 41 recently HIV-1 infected men who have sex with men (MSM) in São Paulo, Brazil.
Proviral HIV-1 DNA was isolated from subject's peripheral blood polymorphonuclear leukocytes that were obtained at the time of enrollment. Each subject was known to be infected with a subtype B virus as determined in a previous study. A small fragment of the integrase gene (nucleotide 4255–4478 of HXB2) was amplified by nested polymerase chain reaction (PCR) using subclade F1 specific primers. The PCR results were further confirmed by phylogenetic analysis. Viral load (VL) data were extrapolated from the medical records of each patient.
For the 41 samples from MSM who were recently infected with subtype B virus, it was possible to detect subclade F1 proviral DNA in five patients, which represents a co-infection rate of 12.2%. In subjects with dual infection, the median VL was 5.3 × 104 copies/ML, whereas in MSM that were infected with only subtype B virus the median VL was 3.8 × 104 copies/ML (p > 0.8).
This study indicated that subtype B and F1 co-infection occurs frequently within the HIV-positive MSM population as suggested by large number of BF1 recombinant viruses reported in Brazil. This finding will help us track the epidemic and provide support for the development of immunization strategies against the HIV.
Mutation and recombination are the two main evolutionary forces that generate genetic variation in HIV-1. Like other human positive-sense RNA viruses, human immunodeficiency virus (HIV-1) has a high mutation rate, which in its case is due to the error-prone nature of the viral reverse transcriptase (3 × 10-5 mutations per nucleotide per replication cycle) [1, 2]. This high rate of mutation, coupled with a high replication rate (10.3 × 109 particles per day) , allows for the generation and fixation of a variety of advantageous mutations in a virus population. These changes are selected in response to the host immune pressure to enable the virus to resist the host defense. Recombination is another potential source of genetic variation that contributes significantly to the genetic diversification of HIV and could potentially produce more virulent viruses, drug resistant viruses, or viruses with altered cell tropism that may reduce the effectiveness of antiretroviral therapy and may present major challenges for the design of vaccines . It has been reported that recombinant viruses including the unique recombinant forms (URF) and circulating recombinant forms (CRF), may account for at least 20% of all HIV infections . The existence of recombinant viruses is an evidence of simultaneous infection of multiple viruses during a single transmission event (co-infection) or from the sequential infection of viruses during multiple transmission events (superinfection). Co-infection has been well documented in individuals that are infected with both HIV-1 and HIV-2 [6, 7], and individuals infected with viruses from different HIV-1 groups , and individuals infected with different subtypes or recombinant variants [9–16], and with divergent variants of the same subtype from different sources [17–23]. The consequence of co-infection has significant implications on antiretroviral resistance and vaccine development. Furthermore, it could lead to immunologic escape and subsequent disease progression [21, 24]. Thus, determining the frequency of dual infections is of great interest for the clinical management of HIV infection.
Unpublished data from our laboratory found evidence of an HIV-1 subtype B and F1 dual infected homosexual patient. Therefore, we attempted to retrospectively evaluate the frequency of HIV-1 subclade F1 and subtype B dual infections in Brazilian recently HIV-1-infected men who have sex with men (MSM).
Materials and methods
Characteristics of the 41 study MSM subjects
Median age. years (range)
Median CD4 count . cells/mm3 (range)
Median viral load. log HIV RNA copies/mL (range)
4.3 X 104 (< 400–39 X104)
Serologies (% positive)*
HHV8 ( LANA)
Proviral DNA extraction and amplification
Details of PCR primer combinations
Combinations of Primers
Product size bp
Isolates that were characterized as subclade F1 by PCR amplification and DNA sequencing of the pol-IN fragment but failed to be amplified by PCR using the L-pol specific primers suggested that these isolates may be recombinant viruses. To address this issue, forward primers were used to amplify a 727-bp product (denoted as M-pol). These primers were able to amplify a broad range of HIV-1 variants including subtype B and F1. These primers were used in combination with the reverse pol-IN primers in a nested PCR assay, using the same conditions described for the pol-IN PCR assay except for an annealing temperature at 55°C and a 2 minute extension time. Both PCR assays, L-pol and M-pol, had a sensitivity of 25 and 15 copies per reaction, respectively. All assays were performed in duplicate for each fragment using the primer combinations shown in Table 2. Positive and negative controls (healthy donor PMNs) were included in each assay. Strict laboratory precautions were taken to avoid cross contamination. Specimens that had a clear amplification in each duplicate reaction were considered to be positive.
Sequencing and phylogenetic analysis
The amplified DNA fragments were purified using a QIAquick PCR Purification Kit (Qiagen, Hilden, Germany) and directly sequenced using second-round primers and the PRISM Big Dye Terminator Cycle Sequencing Ready Reaction Kit (Applied Biosystems/Perkin-Elmer, Foster City, CA) on an automated sequencer (ABI 3130, Applied Biosystems). After excluding the primer regions, each amplicon was assembled into a contiguous sequence alignment and edited with the Sequencher program 4.7 (Gene Code Corp., Ann Arbor, MI). The alignment of multiple sequences, including the reference sequences for subtypes A–D, F–H, J and K (http://hiv-web.lanl.gov), was performed using the CLUSTAL X program  and followed by manual editing using the BioEdit Sequence Alignment Editor program version 5.0.7 . Gaps and ambiguous positions were removed from the final alignment. The phylogenetic relationships were determined by two methods: the neighbor-joining (NJ) algorithm of MEGA version 5.0 software  and maximum likelihood (ML) using PHYML v.2.4.4 . For the NJ method, trees were constructed under the maximum composite likelihood substitution model and bootstrap re-sampling was carried out 1000 times. For the ML method, phylogentic trees were constructed using the GTR + I + G substitution model and a BIONJ starting tree. Heuristic tree searches under the ML optimality criterions were performed using the nearest-neighbor interchange (NNI) branch-swapping algorithm. The approximate likelihood ratio test (aLRT) based on a Shimodaira-Hasegawa-like procedure was used as a statistical test to calculate branch support. Trees were displayed using the MEGA v.5 package.
Nucleotide sequence accession numbers
The sequences described here have been deposited (accession numbers pending)
Having verified the sensitivity and specificity of the pol-IN primers, we wanted to establish the conditions and reliability of the L-pol and M-pol primers in amplifying their specific PCR fragments (see Table 2). Thus, the latter primers were tested against a range of previously published HIV-1 subtype B, F1 and BF1 proviral variants [27, 28, 34–37]. The L-pol primers amplified a clear product from only subclade F1 isolates (Figure 2C). Similarly, the M-pol primers amplified a fragment of the correct size from all BF1 and subclade F1 variants, but no or weak amplification of multiple products was observed when the primers were used to assay subtype B variants (Figure 2D). All products were sequenced to determine the specific subtype.
Despite various attempts, amplification of the L-pol fragment in subclade F1 positive samples was unsuccessful. These results suggested that the 5 MSM were co-infected with a BF1 recombinant virus. To address this question, proviral DNA from the samples that were positive for the pol-IN fragment were subjected to amplification and sequencing of M-pol. We used a combination of primers that specifically amplified the M-pol fragment that contained subclade F1 sequence at the 3' end if these patients were infected with recombinant virus. This reaction produced either no amplification or resulted in the amplification of multiple weak fragments with insufficient yield to perform sequencing. Overall, these results indicated that the 5 MSM patients are likely infected with both subtype B and F1 HIV-1. The failure to amplify L-pol and M-pol fragments is likely a result of the low frequency of subclade F1 proviral DNA.
A comparison of the VLs between single and dual infected MSM was performed. In subjects with dual infection, the median VL was 5.3 × 104 and ranged from 1.5 × 104 to 12.5 × 104 copies/mL. In MSM that were infected only with subtype B, the median VL was 3.8 × 104 copies/mL and ranged from undetectable (<400 copies/mL) to 39.3 × 104 copies/mL. As observed in other studies, there results indicated that the VL are statistically the same .
This study describes the prevalence of HIV-1 subtype B and F1 dual infections in recently infected Brazilian MSM. Among the 41 subjects studied, 12.2% were positive for both subtypes B (from previous study) and F1 proviral DNA (current study). These results are not surprising because both viral subtypes and recombinants are widely circulating in Brazil, which is a country that offers an excellent setting for such studies. It is probable that our results have underestimated the true rate of dual infection in this group. The most likely explanation for underestimation is that some isolates could have been undetected by our specific PCR screening method because of a mismatch at the primer binding sites, low proviral load, or that the subclade F1 isolates were maintained in another reservoir other than the CD4-positive compartment that was sampled in the peripheral blood. Additionally, our method only detects dual infection of subtypes B and F1 when the pol-IN region is subclade F1. We could have missed some instances of co-infection if recombination had happened, and the pol-IN fragment is not subclade F1. Therefore, it is possible that the dual infection in this group may be higher than what was observed if we had sequenced a larger region or sequenced other regions of the viral genome. Our attempts to amplify larger fragments to determine if recombination had occurred were unsuccessful, probably because these subjects were co-infected and maintained low proviral loads of subclade F1 compared to the subtype B viral population. However, because most of the HIV-1 subclade F1 strains circulating in Brazil contain recombinant genomes and particularly with recombination with subtype B [27, 34, 39], we cannot rule out the possibility of F1 recombination in the present study. Our findings also may not be generalizable. This retrospective study focused on a select, relatively small group of recently HIV infected MSM that were known to be infected with subtype B virus. Consequently, the dual infection rates reported cannot necessarily be extrapolated to other populations of HIV-infected MSM. In spite of these caveats, we have been able to identify five cases of dual infection by studying only one genomic region of the HIV genome, similar to the Kenyan study . In the Kenyan study, the authors observed seven cases of HIV-1 superinfection among 36 high-risk women and only five cases of superinfection were detected by differences in only one gene. Unexpectedly, a lack of detectable HIV-1 dual infections has recently been reported in a retrospective study of 83 samples from chronically infected patients on antiretroviral treatment throughout the KwaZulu-Natal region that has a high HIV prevalence . The lack of dual infections in this study was explained by the ability of the immune system to evolve overtime to eliminate or prevent a second viral infection during chronic infection [40, 41].
Despite a large body of literature, the true prevalence and the timing of immune selection in HIV co/superinfection cases have not yet been substantiated by robust clinical studies and the limited data that do exist have yielded inconclusive or contradictory findings that partially contribute to the controversies surrounding the challenge and implications of HIV co/superinfection for efficient vaccine design [38, 42, 43]. Our estimates of subtype B and F1 dual infection rates are not directly comparable to other published studies as each study group has used different research designs, methodologic approaches, and different target population for the search of different HIV-1 subtypes [8, 16, 44–52]. All together, these data lend further support to the conclusions that dual infections are an integral part of the HIV/AIDS epidemic, particularly in countries where multiple subtypes are circulating in the population .
In summary, our data adds to the knowledge of the prevalence of HIV-1 dual infections caused by HIV-1 subtype B and F1 viruses in MSM subjects and provides data from a country where such a phenomenon is rarely documented. Furthermore, these data agree with the consensus that the presence of two or more HIV-1 subtypes within an infected individual is relatively frequent [53, 54]. Thus, testing for co-infection and superinfection and the implementation of effective preventative measures in the MSM population remains relevant issue.
This study was supported with funding from the Brazilian Program for STD and AIDS, Ministry of Health (914/BRA/3014-UNESCO/Kallas), the São Paulo City Health Department (2004–0.168.922-7/Kallas), and the Fundação de Amparo a Pesquisa do Estado de São Paulo (04/15856-9/Sabino & Kallas).
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