Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The narrow host range of human immunodeficiency virus type 1 (HIV-1) is caused in part by innate cellular factors such as apolipoprotein B mRNA-editing enzyme-catalytic polypeptide-like 3G (APOBEC3G) and TRIM5alpha, which restrict virus replication in monkey cells. Variant HIV-1 molecular clones containing both a 21-nucleotide simian immunodeficiency virus (SIV) Gag CA element, corresponding to the HIV-1 cyclophilin A-binding site, and the entire SIV vif gene were constructed. Long-term passage in a cynomolgus monkey lymphoid cell line resulted in the acquisition of two nonsynonymous changes in env, which conferred improved replication properties. A proviral molecular clone, derived from infected cells and designated NL-DT5R, was used to generate virus stocks capable of establishing spreading infections in the cynomolgus monkey T cell line and CD8-depleted peripheral blood mononuclear cells from five of five pig-tailed macaques and one of three rhesus monkeys. NL-DT5R, which genetically is >93% HIV-1, provides the opportunity, not possible with currently available SIV/HIV chimeric viruses, to analyze the function of multiple HIV-1 genes in a broad range of nonhuman primate species.
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PMID:Generation of HIV-1 derivatives that productively infect macaque monkey lymphoid cells. 1706 15

In order to characterize the antiviral activity of human TRIM5alpha in more detail human derived indicator cell lines over expressing wild type human TRIM5alpha were generated and challenged with HIV-1 and HIV-2 viruses pseudotyped with HIV envelope proteins in comparison to VSV-G pseudotyped particles. HIV envelope protein pseudotyped particles (HIV-1[NL4.3], HIV-1[BaL]) showed a similar restriction to infection (12 fold inhibition) compared to VSV-G pseudotyped viruses after challenging TZM-huTRIM5alpha cells. For HIV-2 a stronger restriction to infection was observed when the homologous envelope protein Env42S was pseudotyped onto these particles compared to VSV-G pseudotyped HIV-2 particles (8.6 fold inhibition versus 3.4 fold inhibition). It has been shown that HIV-2 is restricted by the restriction factor Lv2, acting on capsid like TRIM5alpha. A mutation of amino acid 73 (I73V) of HIV-2 capsid renders this virus Lv2-insensitive. Lv2-insensitive VSV-G pseudotyped HIV-2/I73V particles showed a similar restriction to infection as did HIV-2[VSV-G] particles (4 fold inhibition). HIV-2 envelope protein (Env42S)-pseudotyped HIV-2/I73V particles revealed a 9.3 fold increase in infection in TZM cells but remained restricted in TZM-huTRIM5alpha cells (80.6 fold inhibition) clearly indicating that at least two restriction factors, TRIM5alpha and Lv2, act on incoming HIV-2 particles. Further challenge experiments using primary isolates from different HIV-1 subtypes and from HIV-1 group O showed that wild type human TRIM5alpha restricted infection independent of coreceptor use of the infecting particle but to variable degrees (between 1.2 and 19.6 fold restriction).
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PMID:Human TRIM5alpha mediated restriction of different HIV-1 subtypes and Lv2 sensitive and insensitive HIV-2 variants. 1708 20

HIV-1 infects immature dendritic cells (iDCs), but infection is inefficient compared with activated CD4+ T cells and only involves a small subset of iDCs. We analyzed whether this could be attributed to specific cellular restrictions during the viral life cycle. To study env-independent restriction to HIV-1 infection, we used a single-round infection assay with HIV-1 pseudotyped with vesicular stomatitis virus G protein (HIV-VSVG). Small interfering RNA-mediated depletion of APOBEC3G/3F (A3G/3F), but not TRIM5alpha, enhanced HIV-1 infection of iDCs, indicating that A3G/3F controls the sensitivity of iDCs to HIV-1 infection. Furthermore, sequences of HIV reverse transcripts revealed G-to-A hypermutation of HIV genomes during iDC infection, demonstrating A3G/3F cytidine deaminase activity in iDCs. When we separated the fraction of iDCs that was susceptible to HIV, we found the cells to be deficient in A3G messenger RNA and protein. We also noted that during DC maturation, which further reduces susceptibility to infection, A3G levels increased. These findings highlight a role for A3G/3F in explaining the resistance of most DCs to HIV-1 infection, as well as the susceptibility of a fraction of iDCs. An increase in the A3G/3F-mediated intrinsic resistance of iDCs could result in a block of HIV infection at its mucosal point of entry.
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PMID:APOBEC3G/3F mediates intrinsic resistance of monocyte-derived dendritic cells to HIV-1 infection. 1714 55

The tripartite motif (TRIM) protein, TRIM5alpha, restricts some retroviruses, including human immunodeficiency virus (HIV-1), from infecting the cells of particular species. TRIM proteins contain RING, B-box, coiled-coil and, in some cases, B30.2(SPRY) domains. We investigated the properties of human TRIM family members closely related to TRIM5. These TRIM proteins, like TRIM5alpha, assembled into homotrimers and co-localized in the cytoplasm with TRIM5alpha. TRIM5alpha turned over more rapidly than related TRIM proteins. TRIM5alpha, TRIM34 and TRIM6 associated with HIV-1 capsid-nucleocapsid complexes assembled in vitro; the TRIM5alpha and TRIM34 interactions with these complexes were dependent on their B30.2(SPRY) domains. Only TRIM5alpha potently restricted infection by the retroviruses studied; overexpression of TRIM34 resulted in modest inhibition of simian immunodeficiency virus (SIV(mac)) infection. In contrast to the other TRIM genes examined, TRIM5 exhibited evidence of positive selection. The unique features of TRIM5alpha among its TRIM relatives underscore its special status as an antiviral factor.
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PMID:Unique features of TRIM5alpha among closely related human TRIM family members. 1715 11

Immunological analyses performed in healthy adolescents born of HIV-infected (seroreverters) or healthy mothers (healthy controls; HC) showed that immune activation and a skewing of postthymic differentiation are present in adolescent seroreverters. In-utero HIV exposure results in long-lasting imprinting on the immune system. Alternatively, an immune response naturally more prone to activation could prevent vertical infection. Endogenous antivirals (APOBEC, TRIM5alpha) were comparable in seroreverters and HC, and might not play a role in resistance to vertical HIV infection.
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PMID:Immune activation and normal levels of endogenous antivirals are seen in healthy adolescents born of HIV-infected mothers. 1719 20

The replication of human immunodeficiency type-1 (HIV-1) is restricted in macaque cells, in part due to host factors that provide intrinsic immunity after entry. Here we show that a rhesus macaque epithelial cell line engineered to express human CD4, sMAGI cells, has at least two post-entry restrictions to HIV-1 replication: one that is dependent on a previously described post-entry restriction factor of macaque cells, TRIM5alpha, and another that is primarily TRIM5alpha-independent. The TRIM5alpha restriction, which was observed with particles that had an HIV-1 core pseudotyped with VSV-G envelope, is saturable and can be completely abrogated by introducing TRIM5alpha-specific siRNA into the cells. A similar TRIM5alpha-dependent restriction was observed when sMAGI cells expressing human CCR5 were infected with an R5-HIV-1. In contrast, even when viruses enter sMAGI cells using CD4 and an endogenous rhesus coreceptor at levels sufficient to saturate TRIM5alpha, they do not productively infect the sMAGI cells. Nor does treatment of sMAGI cells with TRIM5alpha-specific siRNA relieve this post-entry restriction; this was true whether the HIV-1 core was pseudotyped with SIV envelope or an R5-HIV-1 envelope. Together these data suggest that there is an alternate restriction to replication, here called Lv3, that is encountered by viruses that enter via interaction with CD4 and an endogenous rhesus coreceptor. Thus, these findings suggest that post-entry events are dependent upon the mechanism by which HIV-1 enters the cell.
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PMID:A TRIM5alpha-independent post-entry restriction to HIV-1 infection of macaque cells that is dependent on the path of entry. 1735 67

The human tripartite motif (TRIM) family comprises 70 members, including HIV restriction factor TRIM5alpha and disease-associated proteins TRIM20 (pyrin) and TRIM21. TRIM proteins have conserved domain architecture but diverse cellular roles. Here, we describe how the C-terminal PRYSPRY domain mediates diverse TRIM functions. The crystal structure of TRIM21 PRYSPRY in complex with its target IgG Fc reveals a canonical binding interface comprised of two discrete pockets formed by antibody-like variable loops. Alanine scanning of this interface has identified the hot-spot residues that control TRIM21 binding to Fc; the same hot-spots control HIV/murine leukemia virus restriction by TRIM5alpha and mediate severe familial Mediterranean fever in TRIM20/pyrin. Characterization of the IgG binding site for TRIM21 PRYSPRY reveals TRIM21 as a superantigen analogous to bacterial protein A and suggests that an antibody bipolar bridging mechanism may contribute to the pathogenic accumulation of anti-TRIM21 autoantibody immune complex in autoimmune disease.
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PMID:Structural basis for PRYSPRY-mediated tripartite motif (TRIM) protein function. 1740 Jul 54

Human immunodeficiency virus type 2 (HIV-2) strains vary widely in their abilities to grow in Old World monkey (OWM) cells such as those of cynomolgus monkeys (CM). We evaluated eight HIV-2 isolates for their sensitivities to CM TRIM5alpha, an anti-HIV factor in OWM cells. We found that different HIV-2 isolates showed differences in their sensitivities to CM TRIM5alpha. Sequence analysis showed that TRIM5alpha-sensitive viruses had proline at the 120th position of the capsid protein (CA), whereas TRIM5alpha-resistant viruses had either alanine or glutamine. Mutagenesis studies indicated that the single amino acid at the 120th position indeed affected the sensitivity of the virus to CM TRIM5alpha.
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PMID:A single amino acid of the human immunodeficiency virus type 2 capsid affects its replication in the presence of cynomolgus monkey and human TRIM5alphas. 1747 50

Productive infection with HIV-1 is mediated by fusion of the HIV-1 envelope with the cell membrane and subsequent entry of the virion core into the cytoplasm. The core is then rearranged to form the reverse transcription complex which is responsible for conversion of the genomic RNA to its double-stranded DNA copy. Various genetic, biochemical and microscopy studies have shed light on the role of viral proteins in the core in this process; Gag cleavage products, in particular, are crucial. It is also at this point that core is potentially exposed to the action of restriction factors such as TRIM5alpha and APOBEC3G, highlighting the vulnerability of this stage of the retrovirus life-cycle to the cell's defenses. Rearrangement of the core may be an active process involving host-cell activities, although this is not clear, but may also be partly passive due to the instability of the structure. What regulates this process is unknown. Several host-cell kinase activities are important for replication and have been shown to be incorporated in the virion. We speculate that these kinases may regulate core rearrangement or the interaction of the reverse transcription complex/pre-integration complex with the cytoplasm. Recent real-time microscopy experiments with fluorescent-labeled probes suggest a model in which the virion utilizes the cytoskeleton for transport whilst in the cytoplasm. After entering the cell, the virion interacts initially with actin filaments which assist binding to microtubles enabling transport to the nuclear periphery. An actin-transport process may then facilitate the remaining short journey to the nuclear membrane.
Curr HIV Res 2007 May
PMID:HIV-1 replication from after cell entry to the nuclear periphery. 1750 71

The retroviral restriction factors, TRIM5alpha and TRIMCyp, consist of RING and B-box 2 domains separated by a coiled coil from carboxy-terminal domains. These carboxy-terminal domains (the B30.2(SPRY) domain in TRIM5alpha and the cyclophilin A domain in TRIMCyp) recognize the retroviral capsid. Here we show that some B-box 2 changes in TRIM5alpha, but not in TRIMCyp, resulted in decreased human immunodeficiency virus (HIV-1) capsid binding. The phenotypic effects of these B-box 2 changes on the restriction of retroviral infection depended on the potency of restriction and the affinity of the TRIM5alpha interaction with the viral capsid, two properties specified by the B30.2(SPRY) domain. Thus, some alterations in the TRIM5alpha B-box 2 domain apparently affect the orientation or conformation of the B30.2(SPRY) domain, influencing capsid recognition.
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PMID:Functional interplay between the B-box 2 and the B30.2(SPRY) domains of TRIM5alpha. 1754 65


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