Role of the Human Immunodeficiency Virus Type 1 Envelope Gene in Viral Fitness

Department of Virology, Lerner Research Institute, Cleveland Clinic Foundation, OH 44195, USA.
Journal of Virology (Impact Factor: 4.44). 09/2003; 77(16):9069-73. DOI: 10.1128/JVI.77.16.9069-9073.2003
Source: PubMed


A human host offers a variety of microenvironments to the infecting human immunodeficiency virus type 1 (HIV-1), resulting in various selective pressures, most of them directed against the envelope (env) gene. Therefore, it seems evident that the replicative capacity of the virus is largely related to viral entry. In this study we have used growth competition experiments and TaqMan real-time PCR detection to measure the fitness of subtype B HIV-1 primary isolates and autologous env-recombinant viruses in order to analyze the contribution of wild-type env sequences to overall HIV-1 fitness. A significant correlation was observed between fitness values obtained for wild-type HIV-1 isolates and those for the corresponding env-recombinant viruses (r = 0.93; P = 0.002). Our results suggest that the env gene, which is linked to a myriad of viral characteristics (e.g., entry into the host cell, transmission, coreceptor usage, and tropism), plays a major role in fitness of wild-type HIV-1. In addition, this new recombinant assay may be useful for measuring the contribution of HIV-1 env to fitness in viruses resistant to novel antiretroviral entry inhibitors.


Available from: Miguel E Quinones-Mateu
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    • "More importantly, env recombinant viruses duplicated the fitness stratification, suggesting that HIV-1 fitness, in the absence of drug selection, was a function of Env-mediated processes. Subsequent reports verified these observations with alternative approaches and patient samples [43], [44], [46], [47]. Troyer et al. investigated temporal relationships in the V3-loop region of HIV-1 in subtype B infected adults and reported a modest correlation between Env diversification and fitness, as well as the anticipated higher fitness of X4- versus R5-tropic strains in individuals who underwent a coreceptor switch. "
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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.
    PLoS ONE 04/2013; 8(4):e63094. DOI:10.1371/journal.pone.0063094 · 3.23 Impact Factor
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    • "These signature sequences are lost during chronic infection under selective pressure from the adaptive immune response [51], [52]. Ex vivo assays of primary HIV-1 isolates revealed that fitness mapped to the env gene and was controlled predominantly during the early stages of viral replication [53], [54]. For example, some type C HIV-1 envs displayed reduced fitness in comparison with those of type B isolates and this was associated with weak cell surface binding, inefficient entry, and an increased sensitivity to CCR5 antagonists and fusion inhibitors [55]. "
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    ABSTRACT: Following long-term infection with virus derived from the pathogenic GL8 molecular clone of feline immunodeficiency virus (FIV), a range of viral variants emerged with distinct modes of interaction with the viral receptors CD134 and CXCR4, and sensitivities to neutralizing antibodies. In order to assess whether this viral diversity would be maintained following subsequent transmission, a synthetic quasispecies was reconstituted comprising molecular clones bearing envs from six viral variants and its replicative capacity compared in vivo with a clonal preparation of the parent virus. Infection with either clonal (Group 1) or diverse (Group 2) challenge viruses, resulted in a reduction in CD4+ lymphocytes and an increase in CD8+ lymphocytes. Proviral loads were similar in both study groups, peaking by 10 weeks post-infection, a higher plateau (set-point) being achieved and maintained in study Group 1. Marked differences in the ability of individual viral variants to replicate were noted in Group 2; those most similar to GL8 achieved higher viral loads while variants such as the chimaeras bearing the B14 and B28 Envs grew less well. The defective replication of these variants was not due to suppression by the humoral immune response as virus neutralising antibodies were not elicited within the study period. Similarly, although potent cellular immune responses were detected against determinants in Env, no qualitative differences were revealed between animals infected with either the clonal or the diverse inocula. However, in vitro studies indicated that the reduced replicative capacity of variants B14 and B28 in vivo was associated with altered interactions between the viruses and the viral receptor and co-receptor. The data suggest that viral variants with GL8-like characteristics have an early, replicative advantage and should provide the focus for future vaccine development.
    PLoS ONE 01/2013; 8(1):e54871. DOI:10.1371/journal.pone.0054871 · 3.23 Impact Factor
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    • "For subjects who harbor only CCR5-using (R5) viruses throughout their disease, a large body of evidence indicates the relative efficiency by which HIV-1 uses CD4 and CCR5 correlates with the pathogenic potential of the virus (Duenas- Decamp et al., 2010; Gorry and Ancuta, 2011). For patients with R5 viruses, HIV disease progression has been associated with enhanced macrophage (M)-tropism (Blaak et al., 2000; Li et al., 1999; Trkola et al., 1996), the increased ability to use low levels of CCR5 (Gray et al., 2005; Li et al., 1999; Smit et al., 2001; Tuttle et al., 2002), and the increasing relative entry efficiency of the infecting virus (Marozsan et al., 2005; Rangel et al., 2003). Neurovirulence is also correlated with an isolates ability to use low levels of CD4 and/or CCR5 present on microglial cells (Gorry et al., 2002; Smit et al., 2001). "
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    ABSTRACT: HIV-1 envelope (Env) uses CD4 and a coreceptor (CCR5 and/or CXCR4) for viral entry. The efficiency of receptor/coreceptor mediated entry has important implications for HIV pathogenesis and transmission. The advent of CCR5 inhibitors in clinical use also underscores the need for quantitative and predictive tools that can guide therapeutic management. Historically, measuring the efficiency of CD4/CCR5 mediated HIV entry has relied on surrogate and relatively slow throughput assays that cannot adequately capture the full spectrum of Env phenotypes. In this review, we discuss the details of the Affinofile receptor affinity profiling system that has provided a quantitative and higher throughput method to characterize viral entry efficiency as a function of CD4 and CCR5 expression levels. We will then review how the Affinofile system has been used to reveal the distinct pathophysiological properties associated with Env entry phenotypes and discuss potential shortcomings of the current system.
    Virology 01/2013; 435(1):81-91. DOI:10.1016/j.virol.2012.09.043 · 3.32 Impact Factor
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