Requirement of Nef for HIV-1 infectivity is biased by the expression levels of Env in the virus-producing cells and CD4 in the target cells

Tobiume, Minoru; Tokunaga, Kenzo; Kiyokawa, Etsuko; Takahoko, Mikako; Mochizuki, Naoki; Tatsumi, Masashi

doi:10.1007/s007050170060

Cited by 12 publications

(14 citation statements)

References 43 publications

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“…Since IN is important not only for the integration step of the viral DNA to the host genome but also participates during the Reverse Transcription of the viral RNA, lower concentrations of the IN would affect reverse transcription of the incoming virus impacting on viral infectivity. Our results conciliates previous data demonstrating an impairment in the HIV-1 ability to reverse transcribe the viral RNA genome in Nef-deficient viruses, which could not be explained by a role of Nef in facilitating an early step of the replication cycle as enhancement of viral capsid delivery to the cytosol of the target cell (Cavrois et al, 2004;Miller et al, 1995;Tobiume et al, 2001), trafficking of the viral cores through the cortical actin network since Pizzato et al, 2008), or capsid uncoating (Cavrois et al, 2004;Kotov et al, 1999 (Miller et al, 1997). ** A higher cleavage rate of the Nef protein was observed (Miller et al, 1997).…”

Section: Nef and Virus Maturationsupporting

confidence: 91%

Functions of the Lentiviral Accessory Protein Nef During the Distinct Steps of HIV and SIV Replication Cycle

Costa¹,

Mendonça²,

Sampaio³

2011

HIV and AIDS - Updates on Biology, Immunology, Epidemiology and Treatment Strategies

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Section: Nef and Virus Maturationsupporting

confidence: 91%

Functions of the Lentiviral Accessory Protein Nef During the Distinct Steps of HIV and SIV Replication Cycle

Costa¹,

Mendonça²,

Sampaio³

2011

HIV and AIDS - Updates on Biology, Immunology, Epidemiology and Treatment Strategies

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“…In this study, we used the SIV/macaque model to compare nef and gp120 evolution in three animals intravenously infected with identical viral swarms until progression to SAIDS. gp120 mediates viral entry through receptor-coreceptor binding, while Nef increases infectivity by enhancing the amount of Env incorporated into virus particles (11), which may be due to Nef counteracting an inhibitory effect between gp120 on the virion and CD4 expression on the target cells (12). We identified amino acid signatures in Env that closely correlated with recombination hot spots in a previous study using the model for neuroAIDS with CD8-depleted macaques infected with the same viral swarm (21).…”

Section: Discussionmentioning

confidence: 66%

“…In vitro assays have shown that Nef enhances both membrane expression and virion incorporation of env products (11). One study observed that the requirement for Nef increased as amounts of env decreased in virus-producing cells (12). In addition, recent work has demonstrated that nef can enhance macrophage tissue infiltration by altering its migratory mode (13), which may play a central role in the accumulation of macrophages residing in the CNS, the establishment of viral reservoirs, and neuropathogenesis (14).…”

mentioning

confidence: 99%

Tracking the Emergence of Host-Specific Simian Immunodeficiency Virus env and nef Populations Reveals nef Early Adaptation and Convergent Evolution in Brain of Naturally Progressing Rhesus Macaques

Lamers¹,

Nolan

Rife

et al. 2015

J Virol

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While a clear understanding of the events leading to successful establishment of host-specific viral populations and productive infection in the central nervous system (CNS) has not yet been reached, the simian immunodeficiency virus (SIV)-infected rhesus macaque provides a powerful model for the study of human immunodeficiency virus (HIV) intrahost evolution and neuropathogenesis. The evolution of the gp120 and nef genes, which encode two key proteins required for the establishment and maintenance of infection, was assessed in macaques that were intravenously inoculated with the same viral swarm and allowed to naturally progress to simian AIDS and potential SIV-associated encephalitis (SIVE). Longitudinal plasma samples and immune markers were monitored until terminal illness. Single-genome sequencing was employed to amplify full-length env through nef transcripts from plasma over time and from brain tissues at necropsy. nef sequences diverged from the founder virus faster than gp120 diverged. Host-specific sequence populations were detected in nef (ϳ92 days) before they were detected in gp120 (ϳ182 days). At necropsy, similar brain nef sequences were found in different macaques, indicating convergent evolution, while gp120 brain sequences remained largely host specific. Molecular clock and selection analyses showed weaker clock-like behavior and stronger selection pressure in nef than in gp120, with the strongest nef selection in the macaque with SIVE. Rapid nef diversification, occurring prior to gp120 diversification, indicates that early adaptation of nef in the new host is essential for successful infection. Moreover, the convergent evolution of nef sequences in the CNS suggests a significant role for nef in establishing neurotropic strains. IMPORTANCEThe SIV-infected rhesus macaque model closely resembles HIV-1 immunopathogenesis, neuropathogenesis, and disease progression in humans. Macaques were intravenously infected with identical viral swarms to investigate evolutionary patterns in the gp120 and nef genes leading to the emergence of host-specific viral populations and potentially linked to disease progression. Although each macaque exhibited unique immune profiles, macaque-specific nef sequences evolving under selection were consistently detected in plasma samples at 3 months postinfection, significantly earlier than in gp120 macaque-specific sequences. On the other hand, nef sequences in brain tissues, collected at necropsy of two animals with detectable infection in the central nervous system (CNS), revealed convergent evolution. The results not only indicate that early adaptation of nef in the new host may be essential for successful infection, but also suggest that specific nef variants may be required for SIV to efficiently invade CNS macrophages and/or enhance macrophage migration, resulting in HIV neuropathology. Aclear understanding of the events leading to the establishment of human immunodeficiency virus type 1 (HIV-1) infection in a new host, including the central nervous system (C...

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“…This experimental approach enhances inhibitory effects on infectivity when Env amounts are limiting (48,49,53) and allowed us to enhance a phenotype that otherwise might not be revealed in in vitro experiments. The majority of the target cells in vivo are CD4-positive lymphocytes expressing levels of CD4 high enough to make the virus susceptible to CD4-inhibitory effects.…”

Section: Discussionmentioning

confidence: 99%

Enhanced CD4 Down-modulation by Late Stage HIV-1 nef Alleles Is Associated with Increased Env Incorporation and Viral Replication

Argañaraz

Schindler

Kirchhoff

et al. 2003

Journal of Biological Chemistry

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Three viral proteins participate in the down-modulation of CD4 in human immunodeficiency virus type 1 (HIV-1)-infected cells. The underlying mechanisms have been extensively investigated. However, the physiological relevance of this phenomenon remains poorly understood. To address the role of CD4 down-modulation in HIV-1 pathogenesis in vivo, we have characterized the functional properties of nef alleles isolated from seven HIV-1-infected patients at either the stage of AIDS (late alleles) or during the asymptomatic phase of infection (early alleles). HIV-1 variants carrying these nef alleles showed striking differences in CD4 down-modulation, virus infectivity, and replication properties. Infection of T cells with late strains resulted in production of viral particles with enhanced infectivity, as compared with variants carrying early nef alleles. These differences in infectivity were observed only when viruses were produced in cells with high levels of the viral receptor, suggesting a functional link between CD4 levels and the ability of Nef to down-modulate CD4 and to enhance viral infectivity. Similarly, late nef alleles were substantially more active than early nef genes in stimulating HIV-1 replication in high CD4-positive cells, including primary lymphocytes, but not in cells expressing low levels of the CD4 receptor. Single-round assays showed that differences in infectivity between late and early strains are largely reduced when evaluated in target cells with high levels of CD4, suggesting that the inhibitory effect occurs at the entry step. Supporting this, enhanced CD4 down-modulation by late nef alleles was associated with higher levels of envelope incorporation into viral particles, a phenomenon that likely accounted for the augmented infectivity. Our data suggest a mechanistic link between the Nef-mediated CD4 down-modulation and the enhancement of replication in CD4-positive lymphocytes. As progression to disease occurs, HIV-1 Nef variants with enhanced ability to down-modulate CD4 are selected. These strains efficiently overcome the deleterious effects of CD4 and replicate more aggressively in CD4-positive primary lymphocytes. These results highlight the importance of the virus-induced CD4 down-modulation in HIV-1 pathogenesis.

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Requirement of Nef for HIV-1 infectivity is biased by the expression levels of Env in the virus-producing cells and CD4 in the target cells

Cited by 12 publications

References 43 publications

Functions of the Lentiviral Accessory Protein Nef During the Distinct Steps of HIV and SIV Replication Cycle

Functions of the Lentiviral Accessory Protein Nef During the Distinct Steps of HIV and SIV Replication Cycle

Tracking the Emergence of Host-Specific Simian Immunodeficiency Virus env and nef Populations Reveals nef Early Adaptation and Convergent Evolution in Brain of Naturally Progressing Rhesus Macaques

Enhanced CD4 Down-modulation by Late Stage HIV-1 nef Alleles Is Associated with Increased Env Incorporation and Viral Replication

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