Pathogenic Conversion of Live Attenuated Simian Immunodeficiency Virus Vaccines Is Associated with Expression of Truncated Nef

Sawai, Earl T.; Hamza, Malak; Ye, Michael; Shaw, Katharina S.; Luciw, Paul A.

doi:10.1128/jvi.74.4.2038-2045.2000

Cited by 72 publications

(67 citation statements)

References 30 publications

(29 reference statements)

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“…Similarly, in vivo studies in rhesus macaques infected with SIV strain carrying a mutation in the PXXP motif led to discordant results regarding the role of NAK-Nef association in disease progression (59,62,63,66). Because the P72A/P75A mutation affects not only the binding of Nef to PAK2 but also is known to abrogate its association with the Src family members, in particular Hck (41), conclusions about the involvement of PAK activity in HIV or SIV pathogenesis with this single mutant may be difficult.…”

Section: Discussionmentioning

confidence: 99%

Activation of p21-activated Kinase 2 and Its Association with Nef Are Conserved in Murine Cells but Are Not Sufficient to Induce an AIDS-like Disease in CD4C/HIV Transgenic Mice

Vincent

Priceputu

Kay

et al. 2006

Journal of Biological Chemistry

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A well conserved feature of human immunodeficiency virus, type 1 (HIV-1) and simian immunodeficiency virus (SIV) Nef is the interaction with and activation of the human p21-activated kinase 2 (PAK2). The conservation of this interaction in other species and its significance for Nef pathogenesis in vivo are poorly documented. In the present study, we measured these parameters in Nef-expressing thymocytes, macrophages, and dendritic cells of a transgenic (Tg) mouse model of AIDS (CD4C/HIV). We found that Nef binds to and activates PAK2, but not PAK1 and -3, in these three cell subsets. Nef associates with only a small fraction of PAK2. The Nef-PAK2 complex also comprises ␤-PIX-COOL. The impact of the Nef-PAK2 association on disease development was also analyzed in Tg mice expressing 10 different Nef mutant alleles. CD4C/HIV Tg mice expressing Nef alleles defective in Nef-PAK2 association (P69A, P72A/P75A, R105A/R106A, ⌬56 -66, or G2A (myristoylation site)) failed to develop disease of the non-lymphoid organs (kidneys and lungs). Among these, only Tg mice expressing Nef P69A and Nef G2Ashowed some depletion of CD4 ؉ T cells, although a down-regulation of the CD4 surface protein was documented in all these Tg lines, except those expressing Nef ⌬56 -66 . Among other Tg mice expressing Nef mutants having conserved the Nef-PAK2 association (RD35AA, D174K, P147A/P150A, ⌬8 -17, and ⌬25-65), only Tg mice expressing Nef ⌬8 -17 develop kidney and lung diseases, but all showed partial CD4 ؉ T cell depletion despite some being defective for CD4 down-regulation (RD35AA and D174K). Therefore, Nef can activate murine PAK2 and associate with a small fraction of it, as in human cells. Such activation and binding of PAK2 is clearly not sufficient but may be required to induce a multiorgan AIDS-like disease in Tg mice.

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Section: Discussionmentioning

confidence: 99%

Activation of p21-activated Kinase 2 and Its Association with Nef Are Conserved in Murine Cells but Are Not Sufficient to Induce an AIDS-like Disease in CD4C/HIV Transgenic Mice

Vincent

Priceputu

Kay

et al. 2006

Journal of Biological Chemistry

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“…The flexible loop in SIV Nef is also a key determinant for SIV infectivity in human lymphocytes (31), and the ability of Nef to internalize CD4 (via the flexible loop) was correlated with its role in the pathogenesis of simian AIDS (reference 31 and references therein). Finally, with a truncated Nef protein that resulted from larger deletions of the nef gene in SIVmac239, the restoration of virion infectivity correlated with the return of the flexible loop (6,43). Of interest is that p6* sequences are highly divergent between HIV-1 and SIV, and our preliminary studies reveal a species-specific restriction to interactions between Nef and p6* from HIV-1 and SIV (data not shown).…”

mentioning

confidence: 99%

Nef Binds p6* in GagPol during Replication of Human Immunodeficiency Virus Type 1

Costa

Zheng

Sabotič

et al. 2004

J Virol

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Human immunodeficiency virus type 1 (HIV-1), the causative agent of AIDS, encodes 16 distinct proteins that are expressed differentially during the viral replicative cycle. Initially, the early regulatory proteins Tat and Rev and the socalled negative effector (Nef) are translated from multiply spliced mRNA species. During late phases, singly spliced or unspliced transcripts direct the expression of viral accessory proteins (viral proteins R and U [Vpr and Vpu] and viral infectivity factor [Vif]), as well as structural group-specific antigen (Gag), Gag and polymerase (GagPol), and envelope (Env) polyproteins (see reference 20 and references therein).

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“…Experimental deletion within the simian immunodeficiency virus nef gene reduces viral load, delays the onset of AIDS-like disease, and offers immune protection against challenge with pathogenic simian immunodeficiency virus in rhesus macaques (4,5). Strong selective pressure has been demonstrated for a functional nef gene, because some animals infected with non-pathogenic, nef-mutant simian immunodeficiency virus show in vivo repair of the mutation and progression to AIDS-like disease (5)(6)(7). In addition, some HIV-positive individuals that fail to develop AIDS exhibit nef mutations or deletions (8 -12), supporting the hypothesis that nef is essential for efficient disease progression.…”

mentioning

confidence: 99%

HIV-1 Nef Selectively Activates Src Family Kinases Hck, Lyn, and c-Src through Direct SH3 Domain Interaction

Trible

Emert-Sedlak

Smithgall

2006

Journal of Biological Chemistry

131

188

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Nef is an HIV-1 virulence factor that promotes viral pathogenicity by altering host cell signaling pathways. Nef binds several members of the Src kinase family, and these interactions have been implicated in the pathogenesis of HIV/AIDS. However, the direct effect of Nef interaction on Src family kinase (SFK) regulation and activity has not been systematically addressed. We explored this issue using Saccharomyces cerevisiae, a well defined model system for the study of SFK regulation. Previous studies have shown that ectopic expression of c-Src arrests yeast cell growth in a kinase-dependent manner. We expressed Fgr, Fyn, Hck, Lck, Lyn, and Yes as well as c-Src in yeast and found that each kinase was active and induced growth suppression. Co-expression of the negative regulatory kinase Csk suppressed SFK activity and reversed the growth-inhibitory effect. We then co-expressed each SFK with HIV-1 Nef in the presence of Csk. Nef strongly activated Hck, Lyn, and c-Src but did not detectably affect Fgr, Fyn, Lck, or Yes. Mutagenesis of the Nef PXXP motif essential for SH3 domain binding greatly reduced the effect of Nef on Hck, Lyn, and c-Src, suggesting that Nef activates these Src family members through allosteric displacement of intramolecular SH3-linker interactions. These data show that Nef selectively activates Hck, Lyn, and c-Src among SFKs, identifying these kinases as proximal effectors of Nef signaling and potential targets for anti-HIV drug discovery.Nef is an accessory protein encoded by the human (HIV-1 and HIV-2) 2 and simian immunodeficiency viruses and is an essential mediator of viral pathogenicity (1-3). Experimental deletion within the simian immunodeficiency virus nef gene reduces viral load, delays the onset of AIDS-like disease, and offers immune protection against challenge with pathogenic simian immunodeficiency virus in rhesus macaques (4, 5). Strong selective pressure has been demonstrated for a functional nef gene, because some animals infected with non-pathogenic, nef-mutant simian immunodeficiency virus show in vivo repair of the mutation and progression to AIDS-like disease (5-7). In addition, some HIV-positive individuals that fail to develop AIDS exhibit nef mutations or deletions (8 -12), supporting the hypothesis that nef is essential for efficient disease progression.Nef has no known catalytic function and is believed to promote viral pathogenicity by altering signaling pathways in infected cells through its interactions with cellular proteins. Nef affects several distinct classes of host cell proteins, including immune receptors, protein kinases, trafficking proteins, and guanine nucleotide exchange factors (13-15). Through interactions with these and other signaling proteins, Nef can affect multiple cellular processes leading to enhancement of viral replication, immune evasion, and enhanced survival in T-cells and macrophages (1, 16 -18).Protein kinases are a major class of Nef effector proteins, and members of the Src family of non-receptor protein-tyrosine kinases have been str...

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Pathogenic Conversion of Live Attenuated Simian Immunodeficiency Virus Vaccines Is Associated with Expression of Truncated Nef

Cited by 72 publications

References 30 publications

Activation of p21-activated Kinase 2 and Its Association with Nef Are Conserved in Murine Cells but Are Not Sufficient to Induce an AIDS-like Disease in CD4C/HIV Transgenic Mice

Activation of p21-activated Kinase 2 and Its Association with Nef Are Conserved in Murine Cells but Are Not Sufficient to Induce an AIDS-like Disease in CD4C/HIV Transgenic Mice

Nef Binds p6* in GagPol during Replication of Human Immunodeficiency Virus Type 1

HIV-1 Nef Selectively Activates Src Family Kinases Hck, Lyn, and c-Src through Direct SH3 Domain Interaction

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