HIV-1 with Multiple CCR5/CXCR4 Chimeric Receptor Use Is Predictive of Immunological Failure in Infected Children

Viral Evolution and Transmission Unit, DIBIT, Fondazione Centro San Raffaele, Milan, Italy.
PLoS ONE (Impact Factor: 3.23). 02/2008; 3(9):e3292. DOI: 10.1371/journal.pone.0003292
Source: PubMed


HIV-1 R5 viruses are characterized by a large phenotypic variation, that is reflected by the mode of coreceptor use. The ability of R5 HIV-1 to infect target cells expressing chimeric receptors between CCR5 and CXCR4 (R5(broad) viruses), was shown to correlate with disease stage in HIV-1 infected adults. Here, we ask the question whether phenotypic variation of R5 viruses could play a role also in mother-to-child transmission (MTCT) of HIV-1 and pediatric disease progression.
Viral isolates obtained from a total of 59 HIV-1 seropositive women (24 transmitting and 35 non transmitting) and 28 infected newborn children, were used to infect U87.CD4 cells expressing wild type or six different CCR5/CXCR4 chimeric receptors. HIV-1 isolates obtained from newborn infants had predominantly R5(narrow) phenotype (n = 20), but R5(broad) and R5X4 viruses were also found in seven and one case, respectively. The presence of R5(broad) and R5X4 phenotypes correlated significantly with a severe decline of the CD4+ T cells (CDC stage 3) or death within 2 years of age. Forty-three percent of the maternal R5 isolates displayed an R5(broad) phenotype, however, the presence of the R5(broad) virus was not predictive for MTCT of HIV-1. Of interest, while only 1 of 5 mothers with an R5X4 virus transmitted the dualtropic virus, 5 of 6 mothers carrying R5(broad) viruses transmitted viruses with a similar broad chimeric coreceptor usage. Thus, the maternal R5(broad) phenotype was largely preserved during transmission and could be predictive of the phenotype of the newborn's viral variant.
Our results show that R5(broad) viruses are not hampered in transmission. When transmitted, immunological failure occurs earlier than in children infected with HIV-1 of R5(narrow) phenotype. We believe that this finding is of utmost relevance for therapeutic interventions in pediatric HIV-1 infection.

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Available from: Gabriella Scarlatti
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    • "EMBO Mol Med (2013) 5, 1–19 to transmit in trans the virus to lymphocytes (Shen et al, 2010). Thus, some of the described mechanisms support a preferential transmission of CCR5-using viruses, which reflect the in vivo prevalence of R5 variants during the acute infection (Cavarelli et al, 2008; Koot et al, 1993; Scarlatti et al, 1997), others instead provided evidence of the transmission of X4 viruses as well. "
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    • "Increasing evidences are emerging showing that the classical dichotomy of the viral phenotype into R5 and X4 is not sufficient to explain the large phenotypic variation of HIV-1 [5]. Further classification of R5 viruses into R5narrow and R5broad permitted to explain why some children progress more rapidly than others, despite the early presence of an R5 phenotype close to birth [6]. Our recent study performed on 28 infected newborns demonstrated that the presence of viruses with R5broad phenotype close to birth was significantly associated with a fast progression to severe immunological failure within 3 years of age (Figure 1). "
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    • "However, accumulating evidence indicates that in spite of their ''monogamous'' CCR5 use late isolates from these patients are inherently more pathogenic [126] and RANTES-resistant than early isolates [127,128]. In line with these observation is the ability of late-stage CCR5-restricted HIV-1 variants to use chimeric coreceptors in which parts of CCR5 have been replaced with segments of CXCR4 (R5 broad), whilst early CCR5-using HIV-1 variants are restricted to the use of wild-type CCR5 (R5 narrow) [127,129,130]. "
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    ABSTRACT: The identification of phenotypically distinct HIV-1 variants with different prevalence during the progression of the disease has been one of the earliest discoveries in HIV-1 biology, but its relevance to AIDS pathogenesis remains only partially understood. The physiological basis for the phenotypic variability of HIV-1 was elucidated with the discovery of distinct coreceptors employed by the virus to infect susceptible cells. The role of the viral phenotype in the variable clinical course and treatment outcome of HIV-1 infection has been extensively investigated over the past two decades. In this review, we summarize the major findings on the clinical significance of the HIV-1 coreceptor usage.
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