Margolis L, Shattock RSelective transmission of CCR5-utilizing HIV-1: the 'gatekeeper' problem resolved? Nat Rev Microbiol 4:312-317

National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20895, USA.
Nature Reviews Microbiology (Impact Factor: 23.57). 05/2006; 4(4):312-7. DOI: 10.1038/nrmicro1387
Source: PubMed


Understanding the mechanisms of HIV-1 transmission is crucial for the development of effective preventive microbicides and vaccine strategies, and remains one of the main goals of HIV research. Over the past decade, many studies have focused on trying to identify the 'gatekeeping' mechanism that restricts the transmission of CXCR4-utilizing HIV-1 more efficiently than CCR5-utilizing HIV-1. However, to date, no study has explained the almost perfect negative selection of the former in vivo. Here, we propose that there is no single gatekeeper and that, instead, the selective transmission of R5 HIV-1 depends on the superimposition of multiple imperfect gatekeepers.

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    • "Statistical analysis was performed using an unpaired t-test. remain unknown, we can exclude the involvement of mucosaassociated selective R5 virus transmission (see review [16] [42]) because the humanized mice were infected via the intravenous route. In addition, since the virus-specific effector functions of CD8 þ T cells are thought to be poor in HIV-1-infected humanized mice constructed via the transplantation of human HSCs alone (the exception is the BLT mouse model, which is constructed by transplanting autologous human thymus, liver and HSCs) [43e45], it is unlikely that CD8 þ T cell-mediated immunity contributed to the suppression of X4 HIV-1 infection/transmission (as observed in a macaque model [15]). "
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    ABSTRACT: CCR5-tropic (R5) immunodeficiency virus type 1 (HIV-1) strains are highly transmissible during the early stage of infection in humans, whereas CXCR4-tropic (X4) strains are less transmissible. This study aimed to explore the basis for early phase R5 and X4 HIV-1 infection in vivo by using humanized mice dually challenged with R5 HIV-1NLAD8-D harboring DsRed and X4 HIV-1NL-E harboring EGFP. Whereas R5 HIV-1 replicated well, X4 HIV-1 caused only transient viremia with variable kinetics; however, this was distinct from the low level but persistent viremia observed in mice challenged with X4 HIV-1 alone. Flow cytometric analysis of HIV-1-infected cells revealed that X4 HIV-1 infection of CCR5(+)CD4(+) T cells was significantly suppressed in the presence of R5 HIV-1. X4 HIV-1 was more cytopathic than R5 HIV-1; however, this was not the cause of restricted X4 HIV-1 infection because there were no significant differences in the mortality rates of CCR5(+) and CCR5(-) cells within the X4 HIV-1-infected cell populations. Taken together, these results suggest that restricted infection of CCR5(+)CD4(+) T cells by X4 HIV-1 (occurring via a still-to-be-identified mechanism) might contribute to the preferential transmission of R5 HIV-1 during the early phase of infection. Copyright © 2015 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.
    Full-text · Article · Mar 2015 · Microbes and Infection
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    • "R5 variants predominate during the acute phase [4], and also during the asymptomatic phase of HIV-1 infection. Whether this R5 predominance reflects a transmission bias [5] or a post-transmission amplification bias (due to a higher proportion of CCR5 + CD4+ T cells recruited during acute HIV-1 infection) [6], rather than a superior in vivo fitness of R5 strains, remains uncertain. During the course of infection, depending on the HIV-1 subtype and usually in concomitance with the earliest signs of disease progression, a proportion of patients experience the emergence of X4 variants [7]. "
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    ABSTRACT: Background Co-receptor tropism (CRT) in patients with a long history of HIV-1 infection and antiretroviral treatment has been rarely investigated to date. The aim of this study was to determine the prevalence of X4 and R5 strains in patients with a >15-year follow-up and to investigate the demographical, viral, immunological, clinical and therapeutic determinants of CRT in this population. The possible influence of CRT on the inflammation state related to chronic HIV infection was also examined. Methods A total of 118 HIV-1 infected patients with an initial HIV-1-positive test before 1997, and still on follow-up, were enrolled and consecutively submitted to blood sampling. Of these, 111 were on antiretroviral therapy and 89/111 (80.2%) had a plasma viral load (pVL) <25 copies/ml at testing. HIV-1 DNA was extracted and amplified from PBMCs for env gp120 sequencing. CRT was assigned by using geno2pheno and isolates were classified as X4 (FPR ≤20%) or R5 (FPR >20%). Level of serological inflammation biomarkers including IL-6, hsPCR, and D-dimers were measured. Results An X4 virus was evidenced in HIV-1 proviral DNA of 50 patients (42%) while the remaining 68 patients were classified as R5. The median follow-up was 19 years (range 15–25). No association was observed between CRT and sex, age, nationality, subtype, HIV risk factor, HBV/HCV co-infection, baseline CD4+ cell count and pVL, overall duration of antiretroviral therapy, past exposure to mono-or dual therapies, and duration of NNRTI or PI-based therapy. The presence of an X4 strain was associated with CD4 nadir (p = 0.005), CD4 absolute count over time (p < 0.001), and cumulative positive (copy/years) viremia (p <0.001) during the whole patient history. No differences were found between R5 and X4 patients regarding inflammation marker levels including Il-6, hsPCR and D-dimers. Conclusions An archived X4 virus was demonstrated in 42% of patients with a >15-year-history of HIV infection. This presence was clearly associated with a greater exposure to positive viremia and a poorer CD4 trend over time compared to R5, independent of type and duration of antiretroviral treatment. CRT does not seem to influence the inflammation rate of patients aging with HIV.
    Full-text · Article · May 2013 · BMC Infectious Diseases
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    • "V3-loop). The C2-V4 region contains the Env third variable loop (V3), a major determinant of cell tropism, coreceptor usage, and transmission [51]–[55]. Based on its important role in Env function, it is not surprising that V3-loop polymorphisms have been associated with changes in viral fitness, that antibodies targeting V3 can neutralize viral infectivity, and that the V3-loop determines susceptibility to entry inhibitors [28], [56]–[59]. Previously, we showed that the V3-loop sequences from a treatment naïve, subtype C-infected, slow-progressor, Zambian infant diverged extensively from birth to 67 months of age. "
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    ABSTRACT: Human immunodeficiency virus type-1 (HIV-1) fitness has been associated with virus entry, a process mediated by the envelope glycoprotein (Env). We previously described Env genetic diversification in a Zambian, subtype C infected, slow-progressor child (1157i) in parallel with an evolving neutralizing antibody response. Because of the role the Variable-3 loop (V3) plays in transmission, cell tropism, neutralization sensitivity, and fitness, longitudinally isolated 1157i C2-V4 alleles were cloned into HIV-1NL4-3-eGFP and -DsRed2 infectious molecular clones. The fluorescent reporters allowed for dual-infection competitions between all patient-derived C2-V4 chimeras to quantify the effect of V3 diversification and selection on fitness. 'Winners' and 'losers' were readily discriminated among the C2-V4 alleles. Exceptional sensitivity for detection of subtle fitness differences was revealed through analysis of two alleles differing in a single synonymous amino acid. However, when the outcomes of N = 33 competitions were averaged for each chimera, the aggregate analysis showed that despite increasing diversification and divergence with time, natural selection of C2-V4 sequences in this individual did not appear to be producing a 'survival of the fittest' evolutionary pattern. Rather, we detected a relatively flat fitness landscape consistent with mutational robustness. Fitness outcomes were then correlated with individual components of the entry process. Env incorporation into particles correlated best with fitness, suggesting a role for Env avidity, as opposed to receptor/coreceptor affinity, in defining fitness. Nevertheless, biochemical analyses did not identify any step in HIV-1 entry as a dominant determinant of fitness. Our results lead us to conclude that multiple aspects of entry contribute to maintaining adequate HIV-1 fitness, and there is no surrogate analysis for determining fitness. The capacity for subtle polymorphisms in Env to nevertheless significantly impact viral fitness suggests fitness is best defined by head-to-head competition.
    Preview · Article · Apr 2013 · PLoS ONE
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