A dominant block to HIV-1 replication at reverse transcription in simian cells

Münk, Carsten; Brandt, Stephanie M.; Lucero, Ginger R.; Landau, Nathaniel R.

doi:10.1073/pnas.212400099

Cited by 211 publications

(231 citation statements)

References 36 publications

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“…For example, the diameter of the holes formed at the center of the hexameric rings (ϳ25 Å ) or between hexamers (ϳ107 Å ) could potentially accommodate soluble host factors that may perturb the ability of the CA core to uncoat (34). Such a model is consistent with the observation that the block to HIV-1 infection in monkey cells occurs at a step prior to reverse transcription (15,29,37).…”

supporting

confidence: 65%

“…Similar restrictions for some murine leukemia viruses have been observed with human cells (44). By examining the infection of heterokaryons and by performing infections in the presence of competitor viruses, the cellular factors responsible for retroviral restriction have been demonstrated to be dominant and saturable (2,3,15,28,37). A chimeric HIV-1 reporter virus in which the HIV-1 CA protein was largely replaced with the SIV mac CA sequence escaped the monkey cell restrictions, demonstrating that the CA protein of HIV-1 is an important viral determinant for susceptibility to postentry restriction (39).…”

mentioning

confidence: 54%

“…The factors mediating the postentry restriction to HIV-1 infection in monkey cells can be saturated by noninfectious capsids (15,28,37). To examine whether the HIV-1 capsid mutants bind and compete for the simian restriction factor(s), we infected HeLa and PRL cells with a fixed concentration of wt HIV-1 encoding GFP (HIV-GFP) along with increasing concentrations of either wt or mutant VLPs.…”

Section: Infectivity Of Hiv-1 Capsid Mutants In Primary Target Cells mentioning

confidence: 99%

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Binding and Susceptibility to Postentry Restriction Factors in Monkey Cells Are Specified by Distinct Regions of the Human Immunodeficiency Virus Type 1 Capsid

Owens

Song

Perron

et al. 2004

J Virol

114

118

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In cells of Old World and some New World monkeys, dominant factors restrict human immunodeficiency virus type 1 (HIV-1) infections after virus entry. The simian immunodeficiency virus SIV mac is less susceptible to these restrictions, a property that is determined largely by the viral capsid protein. For this study, we altered exposed amino acid residues on the surface of the HIV-1 capsid, changing them to the corresponding residues found on the SIV mac capsid. We identified two distinct pathways of escape from early, postentry restriction in monkey cells. One set of mutants that were altered near the base of the cyclophilin A-binding loop of the N-terminal capsid domain or in the interdomain linker exhibited a decreased ability to bind the restricting factor(s). Consistent with the location of this putative factor-binding site, cyclophilin A and the restricting factor(s) cooperated to achieve the postentry block. A second set of mutants that were altered in the ridge formed by helices 3 and 6 of the N-terminal capsid domain efficiently bound the restricting factor(s) but were resistant to the consequences of factor binding. These results imply that binding of the simian restricting factor(s) is not sufficient to mediate the postentry block to HIV-1 and that SIV mac capsids escape the block by decreases in both factor binding and susceptibility to the effects of the factor(s).

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supporting

confidence: 65%

mentioning

confidence: 54%

Section: Infectivity Of Hiv-1 Capsid Mutants In Primary Target Cells mentioning

confidence: 99%

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Binding and Susceptibility to Postentry Restriction Factors in Monkey Cells Are Specified by Distinct Regions of the Human Immunodeficiency Virus Type 1 Capsid

Owens

Song

Perron

et al. 2004

J Virol

114

118

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Section: Introductionmentioning

confidence: 99%

“…TRIM5␣-mediated restriction is saturable with high multiplicity of infection (MOI), and the specificity of TRIM5␣-mediated HIV-1 restriction is governed by the recognition of a capsid determinant in the restricted virus similar to the case of Fv1-mediated restriction of MLV infection (Towers et al, 2000;Cowan et al, 2002;Owens et al, 2003Owens et al, , 2004Hatziioannou et al, 2004). However, TRIM5␣-mediated restriction differs from Fv1-mediated restriction in that TRIM5␣-mediated restriction is manifested earlier in the infectious pathway, before the accumulation of reverse transcription products (Shibata et al, 1995;Himathongkham and Luciw, 1996;Cowan et al, 2002;Munk et al, 2002).Specifically, the TRIM5␣ proteins from rhesus monkey (rhTRIM5␣) and African green monkey (agmTRIM5␣) have been shown to restrict HIV-1 infection Yap et al, 2004;Song et al, 2005c). Additionally, rhTRIM5␣ and agmTRIM5␣ as well as the human variant of TRIM5␣ (huTRIM5␣) were subsequently identified as the factors responsible for restricting the infection by N-tropic MLV in cell lines derived from these species (Hatziioannou et al, 2004;Keckesova et al, 2004;Yap et al, 2004;Song et al, 2005c).…”

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confidence: 99%

TRIM5α Cytoplasmic Bodies Are Highly Dynamic Structures

Campbell

Dodding

Yap

et al. 2007

MBoC

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Tripartite motif (TRIM)5␣ has recently been identified as a host restriction factor that has the ability to block infection by certain retroviruses in a species-dependent manner. One interesting feature of this protein is that it is localized in distinct cytoplasmic clusters designated as cytoplasmic bodies. The potential role of these cytoplasmic bodies in TRIM5␣ function remains to be defined. By using fluorescent fusion proteins and live cell microscopy, we studied the localization and dynamics of TRIM5␣ cytoplasmic bodies. This analysis reveals that cytoplasmic bodies are highly mobile, exhibiting both short saltatory movements and unidirectional long-distance movements along the microtubule network. The morphology of the cytoplasmic bodies is also dynamic. Finally, photobleaching and photoactivation analysis reveals that the TRIM5␣ protein present in the cytoplasmic bodies is very dynamic, rapidly exchanging between cytoplasmic bodies and a more diffuse cytoplasmic population. Therefore, TRIM5␣ cytoplasmic bodies are dynamic structures more consistent with a role in function or regulation rather than protein aggregates or inclusion bodies that represent dead-end static structures. INTRODUCTIONThe species-specific tropism of many retroviruses is determined by cellular restriction factors present in the cells of the host. One of the most well characterized restriction factors is the murine Fv1 gene, which prevents infection by particular strains of murine leukemia virus (MLV) (Best et al., 1996; for review, see Bieniasz, 2004;Goff, 2004). It is known that restriction by Fv1 involves the recognition of a capsid determinant in MLV (DesGroseillers et al., 1983;Kozak and Chakraborti, 1996). Analysis of Fv1 restriction indicates that restricted MLV strains can generate reverse transcription products but that they are unable to complete subsequent steps in infection (Pryciak and Varmus, 1992) and also that this restriction of infection is saturable, because it can be overcome with high levels of virus (Pincus et al., 1975;Duran-Troise et al., 1977).A similar restriction to human immunodeficiency virus 1 (HIV-1) infection in primates has also been well characterized; and recently, the cellular factor present in the cells of Old World monkeys responsible for restricting infection by HIV-1 was cloned and identified as the cytoplasmic body component tripartite motif (TRIM)5␣ . Restriction of HIV-1 infection by TRIM5␣ resembles restriction of MLV infection by Fv1 in many ways. TRIM5␣-mediated restriction is saturable with high multiplicity of infection (MOI), and the specificity of TRIM5␣-mediated HIV-1 restriction is governed by the recognition of a capsid determinant in the restricted virus similar to the case of Fv1-mediated restriction of MLV infection (Towers et al., 2000;Cowan et al., 2002;Owens et al., 2003Owens et al., , 2004Hatziioannou et al., 2004). However, TRIM5␣-mediated restriction differs from Fv1-mediated restriction in that TRIM5␣-mediated restriction is manifested earlier in the infectious pathway, b...

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Nonhuman Primate Models for HIV/AIDS Vaccine Development

et al. 2013

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The development of HIV vaccines has been hampered by the lack of an animal model that can accurately predict vaccine efficacy. Chimpanzees can be infected with HIV-1 but are not practical for research. However, several species of macaques are susceptible to the Simian Immunodeficiency Viruses (SIV) that causes a disease in macaques that closely mimics HIV in humans. Thus, macaque-SIV models of HIV infection have become a critical foundation for AIDS vaccine development. Here, we examine the multiple variables and considerations that must be taken into account to use this NHP model effectively. These include the species and subspecies of macaques, virus strain, dose and route of administration and macaque genetics including Major Histocompatibility Complex molecules that affect immune responses and other virus restriction factors. We illustrate how these NHP models can be used to carry out studies of immune responses in mucosal and other tissues than could not easily be performed on human volunteers. Futhermore macaques are an ideal model system to optimize adjuvants, test vaccine platforms, and identify correlates of protection that can advance the HIV vaccine field. We also illustrate techniques used to identify different macaque lymphocyte populations and review some poxvirus vaccine candidates that are in various stages of clinical trials. Understanding how to effectively use this valuable model will greatly increase the likelihood of finding a successful vaccine for HIV.

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A dominant block to HIV-1 replication at reverse transcription in simian cells

Cited by 211 publications

References 36 publications

Binding and Susceptibility to Postentry Restriction Factors in Monkey Cells Are Specified by Distinct Regions of the Human Immunodeficiency Virus Type 1 Capsid

Binding and Susceptibility to Postentry Restriction Factors in Monkey Cells Are Specified by Distinct Regions of the Human Immunodeficiency Virus Type 1 Capsid

TRIM5α Cytoplasmic Bodies Are Highly Dynamic Structures

Nonhuman Primate Models for HIV/AIDS Vaccine Development

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