The X4 Phenotype of HIV Type 1 Evolves from R5 in Two Children of Mothers, Carrying X4, and Is Not Linked to Transmission

Microbiology and Tumor Biology Center, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
AIDS Research and Human Retroviruses (Impact Factor: 2.33). 06/2005; 21(5):371-8. DOI: 10.1089/aid.2005.21.371
Source: PubMed


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.

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    • "In the absence of such work, it was widely believed that the gatekeeping mechanisms of vertical transmission are as tight as those of horizontal transmission. When the phylogenic analysis of the mother-to child transmitted variants has been performed it was found that X4 variants always evolves from the transmitted R5 HIV-1 [164]. "
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    ABSTRACT: To enter target cells HIV-1 uses CD4 and a coreceptor. In vivo the coreceptor function is provided either by CCR5 (for R5) or CXCR4 (for X4 HIV-1). Although both R5 and X4 HIV-1 variants are present in body fluids (semen, blood, cervicovaginal and rectal secretions), R5 HIV-1 appears to transmit infection and dominates early stages of HIV disease. Moreover, recent sequence analysis of virus in acute infection shows that, in the majority of cases of transmission, infection is initiated by a single virus. Therefore, the existence of a "gatekeeper" that selects R5 over X4 HIV-1 and that operates among R5 HIV-1 variants has been suggested. In the present review we consider various routes of HIV-transmission and discuss potential gatekeeping mechanisms associated with each of these routes. Although many mechanisms have been identified none of them explains the almost perfect selection of R5 over X4 in HIV-1 transmission. We suggest that instead of one strong gatekeeper there are multiple functional gatekeepers and that their superimposition is sufficient to protect against X4 HIV-1 infection and potentially select among R5 HIV-1 variants. In conclusion, we propose that the principle of multiple barriers is more general and not restricted to protection against X4 HIV-1 but rather can be applied to other phenomena when one factor has a selective advantage over the other(s). In the case of gatekeepers for HIV-1 transmission, the task is to identify them and to decipher their molecular mechanisms. Knowledge of the gatekeepers' localization and function may enable us to enhance existing barriers against R5 transmission and to erect the new ones against all HIV-1 variants.
    Journal of Translational Medicine 01/2011; 9 Suppl 1(Suppl 1):S6. DOI:10.1186/1479-5876-9-S1-S6 · 3.93 Impact Factor
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    • "Another interesting observation comes from the study by Casper et al. [1], which shows that in HIV-1 infected children the emergence of the X4 phenotype during disease progression occurs when the mother carried an X4 virus. The same group was able to demonstrate that in these two children the X4 virus developed from their own R5 population, and not from a transmitted maternal X4 variant [24]. It is tempting to speculate that the transmitted virus has an intrinsic propensity to evolve to CXCR4 usage or that the similar genetic background of the mother and the child may favor such evolution. "
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    ABSTRACT: Viral CCR5 usage is not a predictive marker of mother to child transmission (MTCT) of HIV-1. CXCR4-using viral variants are little represented in pregnant women, have an increased although not significant risk of transmission and can be eventually also detected in the neonates. Genetic polymorphisms are more frequently of relevance in the child than in the mother. However, specific tissues as the placenta or the intestine, which are involved in the prevalent routes of infection in MTCT, may play an important role of selective barriers. The virus phenotype of the infected children, like that of adults, can evolve from R5 to CXCR4-using phenotype or remain R5 despite clinical progression to overt immune deficiency. The refined classification of R5 viruses into R5narrow and R5broad resolves the enigma of the R5 phenotype being associated with the state of immune deficiency. Studies are needed to address more in specific the relevance of these factors in HIV-1 MTCT and pediatric infection of non-B subtypes.
    Journal of Translational Medicine 01/2011; 9 Suppl 1(Suppl 1):S10. DOI:10.1186/1479-5876-9-S1-S10 · 3.93 Impact Factor
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    • "X4 HIV strains are rarely, if ever, transmitted, even when the donor predominantly carries X4 virus. Clevestig [3] found that in children, the X4 virus developed from their own R5 population, and was not caused by transmission from the mother. CXCR4 is expressed on a majority of CD4+ T cells and thymocytes, whereas only about 5 to 25% of mature T cells and 1 to 5% of thymocytes express detectable levels of CCR5 on the cell surface [4]. "
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    ABSTRACT: During the HIV infection several quasispecies of the virus arise, which are able to use different coreceptors, in particular the CCR5 and CXCR4 coreceptors (R5 and X4 phenotypes, respectively). The switch in coreceptor usage has been correlated with a faster progression of the disease to the AIDS phase. As several pharmaceutical companies are starting large phase III trials for R5 and X4 drugs, models are needed to predict the co-evolutionary and competitive dynamics of virus strains. We present a model of HIV early infection which describes the dynamics of R5 quasispecies and a model of HIV late infection which describes the R5 to X4 switch. We report the following findings: after superinfection (multiple infections at different times) or coinfection (simultaneous infection by different strains), quasispecies dynamics has time scales of several months and becomes even slower at low number of CD4+ T cells. Phylogenetic inference of chemokine receptors suggests that viral mutational pathway may generate a large variety of R5 variants able to interact with chemokine receptors different from CXCR4. The decrease of CD4+ T cells, during AIDS late stage, can be described taking into account the X4-related Tumor Necrosis Factor dynamics. The results of this study bridge the gap between the within-patient and the inter-patients (i.e. world-wide) evolutionary processes during HIV infection and may represent a framework relevant for modeling vaccination and therapy.
    BMC Evolutionary Biology 02/2007; 7 Suppl 2(Suppl 2):S5. DOI:10.1186/1471-2148-7-S2-S5 · 3.37 Impact Factor
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