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Tail-interacting protein TIP47 is a connector between Gag and Env and is required for Env incorporation into HIV-1 virions.

ABSTRACT: The presence of the envelope glycoprotein Env in HIV-1 virions is essential for infectivity. To date, the molecular mechanism by which Env is packaged into virions has been largely unknown. Here, we show that TIP47 (tail-interacting protein of 47 kDa), which has been shown to interact with Env, also binds the MA (matrix) domain of HIV-1 Gag protein and that these three proteins form a ternary complex. Mutations in Gag that abrogate interaction with TIP47 inhibit Env incorporation and virion infectivity as well as colocalization between Gag and Env. We also show that TIP47 silencing impairs Env incorporation and infectivity and abolishes coimmunoprecipitation of Gag with Env. In contrast, overexpression of TIP47 increases Env packaging. Last, we demonstrate that TIP47 can interact simultaneously with Env and Gag. Taken together, our results show that TIP47 is a cellular cofactor that plays an essential role in Env incorporation, allowing the encounter and the physical association between HIV-1 Gag and Env proteins during the viral assembly process.

SUBMITTER: Lopez-Verges S

PROVIDER: S-EPMC1595456 | biostudies-literature | 2006 Oct

REPOSITORIES: biostudies-literature

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Tail-interacting protein TIP47 is a connector between Gag and Env and is required for Env incorporation into HIV-1 virions.

Lopez-Vergès Sandra S Camus Grégory G Blot Guillaume G Beauvoir Roxane R Benarous Richard R Berlioz-Torrent Clarisse C

Proceedings of the National Academy of Sciences of the United States of America 20060926 40

The presence of the envelope glycoprotein Env in HIV-1 virions is essential for infectivity. To date, the molecular mechanism by which Env is packaged into virions has been largely unknown. Here, we show that TIP47 (tail-interacting protein of 47 kDa), which has been shown to interact with Env, also binds the MA (matrix) domain of HIV-1 Gag protein and that these three proteins form a ternary complex. Mutations in Gag that abrogate interaction with TIP47 inhibit Env incorporation and virion infe ...[more]

PMID: 17003132

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Project description:HIV-1 nucleotide substitution rates are central for understanding the evolution of HIV-1. Their accurate estimation is critical for analysis of viral dynamics, identification of divergence time of HIV variants, inference of HIV transmission clusters, and modeling of viral evolution.Intra-patient nucleotide substitution rates in HIV-1C gag and env gp120 V1C5 were analyzed in a longitudinal cohort of 32 individuals infected with a single viral variant. Viral quasispecies were derived by single genome amplification/sequencing from serially sampled blood specimens collected at median (IQR) of 5 (4-6) times per subject from enrollment (during Fiebig stages II to V) over a median (IQR) of 417 (351-471) days post-seroconversion (p/s). HIV-1C evolutionary rates were estimated by BEAST v.1.7 using a relaxed lognormal molecular clock model. The effect of antiretroviral therapy (ART) on substitution rates in gag and env was assessed in a subset of six individuals who started ARV therapy during the follow-up period.During primary HIV-1C infection, the intra-patient substitution rates were estimated at a median (IQR) of 5.22E-03 (3.28E-03-7.55E-03) substitutions per site per year of infection within gag, and 1.58E-02 (9.99E-03-2.04E-02) substitutions per site per year within env gp120 V1C5. The substitution rates in env gp120 V1C5 were higher than in gag (p<0.001, Wilcoxon signed rank test). The median (IQR) relative rates of evolution at codon positions 1, 2, and 3 were 0.73 (0.48-0.84), 0.67 (0.52-0.86), and 1.54 (1.21-1.71) in gag, and 1.01 (0.86-1.15), 1.05 (0.99-1.21), and 0.86 (0.67-0.94) in env gp120 V1C5, respectively. A first to the third position codon rate ratio >1.0 within env was found in 25 (78.1%) cases, but only in 4 (12.5%) cases in gag, while a second to the third position codon rate ratio >1.0 in env was observed in 26 (81.3%) cases, but in gag only in 2 (6.3%) cases (p<0.001 for both comparisons, Fisher's exact test). No ART effect on substitution rates in gag and env was found, at least within the first 3-4 months after ART initiation. Individuals with early viral set point ?4.0 log10 copies/ml had higher substitution rates in env gp120 V1C5 (median (IQR) 1.88E-02 (1.54E-02-2.46E-02) vs. 1.04E (7.24E-03-1.55E-02) substitutions per site per year; p=0.017, Mann-Whitney sum rank test), while individuals with early viral set point ?3.0 log10 copies/ml had higher substitution rates in gag (median (IQR) 5.66E-03 (3.45E-03-7.94E-03) vs. 1.78E-03 (4.57E-04-5.15E-03); p=0.028; Mann-Whitney sum rank test).The results suggest that in primary HIV-1C infection, (1) intra-host evolutionary rates in env gp120 V1C5 are about 3-fold higher than in gag; (2) selection pressure in env is more frequent than in gag; (3) initiation of ART does not change substitution rates in HIV-1C env or gag, at least within the first 3-4 months after starting ART; and (4) intra-host evolutionary rates in gag and env gp120 V1C5 are higher in individuals with elevated levels of early viral set point.

Dataset Information

Tail-interacting protein TIP47 is a connector between Gag and Env and is required for Env incorporation into HIV-1 virions.

Publications

Tail-interacting protein TIP47 is a connector between Gag and Env and is required for Env incorporation into HIV-1 virions.

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