Drug-resistant variants are frequently present in both recently and chronically infected therapy-naive patients. Drug-resistant variants are most commonly seen in patients infected with subtype B virus, probably because of longer exposure of these viruses to drugs. However, an increase in baseline resistance in non-B viruses is observed. These data argue for testing all drug-naive patients and are of relevance when guidelines for management of postexposure prophylaxis and first-line therapy are updated.
Based on the calculated genetic barrier, the rate of drug resistance development may be similar for different HIV-1 subtypes. Because of differences in minor protease substitutions, protease inhibitor resistance could be enhanced in particular subtypes once the relevant major substitutions are selected.
Previously, we found that emergence of the X4 viral phenotype in HIV-1-infected children was related to the presence of X4 in their mothers (C.H. Casper et al., J Infect Dis 2002; 186:914-921). Here, we investigated the origin of the X4 phenotype in the child, analyzing two mother-child pairs (Ma-Ca, Mb-Cb) where the mothers carried X4 and their children developed X4 after an initial presence of R5. We used nested polymerase chain reaction of the env V3 region to generate 203 HIV-1 clones for sequencing (Ma, n = 44; Ca, n = 73; Mb, n = 61; Cb, n = 25) from DNA of peripheral blood mononuclear cell (PBMC) lysates, altogether 167 clones, or from cDNA of plasma RNA, 36 clones. PBMC and plasma isolate sequences from each time point enabled us to assign the probable phenotype to clone sequences in a phylogenetic tree. The transmission and evolution were reconstructed using the maximum likelihood method. In mother-child pair Ma-Ca, one maternal R5 isolate clustered with the child's R5 sequences, at the earliest time when R5 was isolated in the child, confirming this as a likely source of the transmitted R5 phenotype. At age 3, an X4 population was present in the child that had evolved from the child's own R5-associated population, clearly distinct from the maternal X4 sequences. The second mother-child pair (Mb-Cb) displayed a similar pattern. Amino acid substitution patterns corroborated the conclusions from the phylogenetic tree. Thus, in both children, the X4 virus developed from their own R5 population, and was not caused by transmission of X4.
To investigate the molecular epidemiology of HIV-1 among intravenous drug users (IDUs) in Hanoi we collected 17 samples from individuals living in 12 locations in and around Hanoi. The HIV-1 env V3 and gag p17 regions were directly sequenced from the proviral PBMC population. The majority of the IDUs were infected with HIV-1 CRF01_AE and one individual carried a p17/V3 CRF01/subtype C recombinant. The CRF01 viruses found among these individuals did not seem to be directly epidemiologically linked to each other. The sequences were, however, related to previously reported CRF01 sequences from Vietnam and China. Thus, IDUs in Hanoi seem to have derived their infections in Vietnam, but not from the same source. The discovery of the CRF01/C recombinant shows that new viral forms easily can be generated in IDU transmission chains.
The prevalence of genetic drug resistance in newly diagnosed HIV-1 cases and potential subtype-specific mutation patterns were studied. Samples from 100 newly diagnosed patients were randomly chosen from three HIV clinics in Sweden, prospectively collected during the period June 1998 to August 2001. Viral RNA was extracted from plasma and an approximately 2000-bp fragment covering the protease (PR) and reverse transcriptase (RT) genes was sequenced. Subtypes A, B, C, D, G, U, and CRF01_AE were found. All 100 sequences had mutations reported to be involved in some drug resistance, revealing naturally occurring subtype-specific amino acid patterns. Such patterns may be important to consider when treating patients infected with nonsubtype B viruses. While many drug resistance mutations seem to be naturally occurring, 9% of the newly detected patients in Sweden may have been infected with virus from antiviral-treated patients. Among the individuals infected with resistant virus, the majority were infected with subtype B virus and belonged to the homosexual risk group. It may be important to routinely test for resistance in newly infected cases to improve the choice of drugs for treatment because the virus may revert and resistant forms can become latent.
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