Nef Induces Multiple Genes Involved in Cholesterol Synthesis and Uptake in Human Immunodeficiency Virus Type 1-Infected T Cells

Wout, Angélique B. van ′t; Swain, J. Victor; Schindler, Michael; Rao, Ushnal; Pathmajeyan, Melissa; Mullins, James I.; Kirchhoff, Frank

doi:10.1128/jvi.79.15.10053-10058.2005

Cited by 91 publications

(86 citation statements)

References 24 publications

(25 reference statements)

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“…One mechanism by which Nef controls viral infectivity is through increasing cholesterol content of lipid rafts ( 8 ). Nef induces a number of genes involved in cholesterol synthesis ( 8,9 ) and can facilitate cholesterol delivery to lipid rafts ( 8,10 ). This activity is consistent with membrane localization of Nef due to myristoylation ( 8,11,12 ); nonmyristoylated Nef did not affect lipid rafts ( 8 ).…”

Section: Lipid Raft Cholesterol Content Analysissupporting

confidence: 63%

HIV-1 Nef mobilizes lipid rafts in macrophages through a pathway that competes with ABCA1-dependent cholesterol efflux

Cui

Grant

Mukhamedova

et al. 2012

Journal of Lipid Research

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This article is available online at http://www.jlr.org Supplementary key words cholesterol metabolism • cholesterol traffi cking • ATP binding cassette transporter A1 • human immunodeficiency virus Impairment of cholesterol metabolism plays a key role in pathogenesis of many disorders, most importantly cardiovascular and neurodegenerative diseases. Many infectious agents, from prions to parasites, affect cholesterol metabolism of the host. Microorganisms modify host cholesterol metabolism for two main reasons: to satisfy their own requirements for cholesterol at different stages of their life cycle, and to weaken the immune response of the host. These modifi cations may cause "unintended" consequences, triggering development of diseases that are not directly related to infection. This situation is exemplifi ed by the increased risk of atherosclerosis coincident with HIV infection. Targeting cholesterol metabolism for antimicrobial intervention, while at the same time correcting metabolic consequences of the infection, is a tempting possibility limited by the lack of knowledge about mechanisms of interaction between microorganisms and pathways of cholesterol metabolism in host cells.

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Section: Lipid Raft Cholesterol Content Analysissupporting

confidence: 63%

HIV-1 Nef mobilizes lipid rafts in macrophages through a pathway that competes with ABCA1-dependent cholesterol efflux

Cui

Grant

Mukhamedova

et al. 2012

Journal of Lipid Research

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“…Based on our results, however, we feel that it is more likely that HIV-1 Nef interferes with superinfection by a yet-to-be-identified mechanism that does not involve down-modulation of both X4 and CD4. Several known effects of Nef could potentially affect superinfection resistance, i.e., Nef modifies the composition of the host cell membrane (65,71), induces changes of the cytoskeleton (11,22), and alters intracellular trafficking pathways (21,37).…”

Section: Discussionmentioning

confidence: 99%

Contribution of Vpu, Env, and Nef to CD4 Down-Modulation and Resistance of Human Immunodeficiency Virus Type 1-Infected T Cells to Superinfection

Wildum

Schindler

Münch

et al. 2006

J Virol

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Human immunodeficiency virus type 1 (HIV-1) utilizes Vpu, Env, and Nef to down-modulate its primary CD4 receptor from the cell surface, and this function seems to be critical for the pathogenesis of AIDS. The physiological relevance of CD4 down-modulation, however, is currently not well understood. In the present study, we analyzed the kinetics of CD4 down-modulation and the susceptibility of HIV-1-infected T cells to superinfection using proviral HIV-1 constructs containing individual and combined defects in vpu, env, and nef and expressing red or green fluorescent proteins. T cells infected with HIV-1 mutants containing functional nef genes expressed low surface levels of CD4 from the first moment that viral gene expression became detectable. In comparison, Vpu and Env had only minor to moderate effects on CD4 during later stages of infection. Consistent with these quantitative differences, Nef inhibited superinfection more efficiently than Vpu and Env. Notably, nef alleles from AIDS patients were more effective in preventing superinfection than those derived from a nonprogressor of HIV-1 infection. Our data suggest that protection against X4-tropic HIV-1 superinfection involves both CD4-independent and CD4-dependent mechanisms of HIV-1 Nef. X4 was effectively down-regulated by simian immunodeficiency virus and HIV-2 but not by HIV-1 Nef proteins. Thus, maximal protection seems to involve an as-yet-unknown mechanism that is independent of CD4 or coreceptor downmodulation. Finally, we demonstrate that superinfected primary T cells show enhanced levels of apoptosis. Accordingly, one reason that HIV-1 inhibits CD4 surface expression and superinfection is to prevent premature cell death in order to expand the period of effective virus production.

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“…The Nef activity can be substituted for by a portion of the MLV glycosylated-Gag protein gPr80 gag , which retains only the N-terminal cytoplasmic domain, the transmembrane region, and most of the matrix (MA) domain, termed glycoMA (13,18). Moreover, Nef has been found to interact with the cholesterol biosynthesis pathway to increase HIV-1 infectivity (19,20). Together, these pioneering works provided valuable insights into how Nef enhances HIV-1 infectivity in viral producer cells, but the precise mechanism was still quite unclear.…”

mentioning

confidence: 99%

Identification of SERINC5-001 as the Predominant Spliced Isoform for HIV-1 Restriction

Zhang

Zhou

Yang

et al. 2017

J Virol

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Among the five serine incorporator (SERINC) family members, SERINC5 (Ser5) was reported to strongly inhibit HIV-1 replication, which is counteracted by Nef. Ser5 produces 5 alternatively spliced isoforms: Ser5-001 has 10 putative transmembrane domains, whereas Ser5-004, -005, -008a, and -008b do not have the last one. Here, we confirmed the strong Ser5 anti-HIV-1 activity and investigated its isoforms' expression and antiviral activities. It was found that Ser5-001 transcripts were detected at least 10-fold more than the other isoforms by real-time quantitative PCR. When Ser5-001 and its two isoforms Ser5-005 and Ser5-008a were expressed from the same mammalian expression vector, only Ser5-001 was stably expressed, whereas the others were poorly expressed due to rapid degradation. In addition, unlike the other isoforms, which are located mainly in the cytoplasm, Ser5-001 is localized primarily to the plasma membrane. To map the critical determinant, Ser5 mutants bearing C-terminal deletions were created. It was found that the 10th transmembrane domain is required for Ser5 stable expression and plasma membrane localization. As expected, only Ser5-001 strongly inhibits HIV-1 infectivity, whereas the other Ser5 isoforms and mutants that do not have the 10th transmembrane domain show very poor activity. It was also observed that the Nef counteractive activity could be easily saturated by Ser5 overexpression. Thus, we conclude that Ser5-001 is the predominant antiviral isoform that restricts HIV-1, and the 10th transmembrane domain plays a critical role in this process by regulating its protein stability and plasma membrane targeting. IMPORTANCE Human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) express a small protein, Nef, to enhance viral pathogenesis in vivo.Nef has an important in vitro function, which is to make virus particles more infectious, but the mechanism has been unclear. Recently, Nef was reported to counteract a novel anti-HIV host protein, SERINC5 (Ser5). Ser5 has five alternatively spliced isoforms, Ser5-001, -004, -005, -008a, and -008b, and only Ser5-001 has an extra C-terminal transmembrane domain. We now show that the Ser5-001 transcripts are produced at least 10-fold more than the others, and only Ser5-001 produces stable proteins that are targeted to the plasma membrane. Importantly, only Ser5-001 shows strong anti-HIV-1 activity. We further demonstrate that the extra transmembrane domain is required for Ser5 stable expression and plasma membrane localization. These results suggest that plasma membrane localization is required for Ser5 antiviral activity, and Ser5-001 is the predominant isoform that contributes to the activity.KEYWORDS HIV-1, Nef, SERINC3, SERINC5, infectivity, restriction factor

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Nef Induces Multiple Genes Involved in Cholesterol Synthesis and Uptake in Human Immunodeficiency Virus Type 1-Infected T Cells

Cited by 91 publications

References 24 publications

HIV-1 Nef mobilizes lipid rafts in macrophages through a pathway that competes with ABCA1-dependent cholesterol efflux

HIV-1 Nef mobilizes lipid rafts in macrophages through a pathway that competes with ABCA1-dependent cholesterol efflux

Contribution of Vpu, Env, and Nef to CD4 Down-Modulation and Resistance of Human Immunodeficiency Virus Type 1-Infected T Cells to Superinfection

Identification of SERINC5-001 as the Predominant Spliced Isoform for HIV-1 Restriction

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