Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0021051 (immunodeficiency)
71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Murine primary cells are poorly permissive to human immunodeficiency virus type 1 (HIV-1) vector infection. Retroviral infectivity is influenced by dominant inhibitors such as TRIM5alpha. Sensitivity to TRIM5alpha is altered by interactions between cyclophilin A and the HIV-1 capsid. Here we demonstrate that competitive inhibitors of cyclophilins, cyclosporine or the related Debio-025, stimulate HIV-1 vector transduction of primary murine cells, including bone marrow and macrophages, up to 20-fold. Unexpectedly, the infectivity of an HIV-1 mutant or a simian lentivirus that does not recruit cyclophilin A is also stimulated by these drugs. We propose that cyclosporine and related compounds will be useful tools for experimental infection of murine primary cells. It is possible that HIV-1 infection of murine cells is inhibited by dominant factors related to immunophilins.
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PMID:Cyclosporine increases human immunodeficiency virus type 1 vector transduction of primary mouse cells. 1684 Mar 58

TRIM5alpha acts on several retroviruses, including human immunodeficiency virus (HIV-1), to restrict cross-species transmission. Using natural history cohorts and tissue culture systems, we examined the effect of polymorphism in human TRIM5alpha on HIV-1 infection. In African Americans, the frequencies of two non-coding SNP variant alleles in exon 1 and intron 1 of TRIM5 were elevated in HIV-1-infected persons compared with uninfected subjects. By contrast, the frequency of the variant allele encoding TRIM5alpha 136Q was relatively elevated in uninfected individuals, suggesting a possible protective effect. TRIM5alpha 136Q protein exhibited slightly better anti-HIV-1 activity in tissue culture than the TRIM5alpha R136 protein. The 43Y variant of TRIM5alpha was less efficient than the H43 variant at restricting HIV-1 and murine leukemia virus infections in cultured cells. The ancestral TRIM5 haplotype specifying no observed variant alleles appeared to be protective against infection, and the corresponding wild-type protein partially restricted HIV-1 replication in vitro. A single logistic regression model with a permutation test indicated the global corrected P value of <0.05 for both SNPs and haplotypes. Thus, polymorphism in human TRIM5 may influence susceptibility to HIV-1 infection, a possibility that merits additional evaluation in independent cohorts.
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PMID:Effects of human TRIM5alpha polymorphisms on antiretroviral function and susceptibility to human immunodeficiency virus infection. 1688 63

Old World monkey TRIM5alpha targets incoming human immunodeficiency virus type 1 (HIV-1) viral capsid, whereas the apolipoprotein B mRNA-editing enzyme-catalytic polypeptide-like (APOBEC)3 family hypermutate/degrade viral sequences. Here, we show the potentials of simian TRIM5alpha and APOBEC3G as therapeutic sequences for AIDS gene therapy. Both rhesus and African green monkey (agm) TRIM5alpha efficiently restrict HIV-1 vectors with divergent Gag from different HIV-1 subtypes. Human T cells genetically engineered to express agm-TRIM5alpha block or delay HIV-1 replication. Although agm-APOBEC3G expression alone only transiently suppresses HIV-1 replication, co-expression of agm-APOBEC3G and agm-TRIM5alpha successfully block the virus replication for more than 5 weeks.
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PMID:Inhibition of HIV-1 replication by simian restriction factors, TRIM5alpha and APOBEC3G. 1694 52

The primate TRIM5 proteins constitute a class of restriction factors that prevent host cell infection by retroviruses from different species. The TRIM5 proteins act early after virion entry and prevent viral reverse transcription products from accumulating. We recently found that proteasome inhibitors altered the rhesus monkey TRIM5alpha restriction of human immunodeficiency virus type 1 (HIV-1), allowing reverse transcription products to accumulate even though viral infection remained blocked. To assess whether sensitivity to proteasome inhibitors was a common feature of primate TRIM5 proteins, we conducted a similar analysis of restriction mediated by owl monkey TRIM-cyclophilin A (CypA) or human TRIM5alpha. Similar to rhesus monkey TRIM5alpha restriction, proteasome inhibition prevented owl monkey TRIM-CypA restriction of HIV-1 reverse transcription, even though HIV-1 infection and the output of 2-LTR circles remained impaired. Likewise, proteasome inhibition alleviated human TRIM5alpha restriction of N-tropic murine leukemia virus reverse transcription. Finally, HIV-1 reverse transcription products escaping rhesus TRIM5alpha restriction by proteasome inhibition were fully competent for integration in vitro, demonstrating that TRIM5alpha likely prevents the viral cDNA from accessing chromosomal target DNA. Collectively, these data indicate that the diverse TRIM5 proteins inhibit retroviral infection in multiple ways and that inhibition of reverse transcription products is not necessary for TRIM5-mediated restriction of retroviral infection.
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PMID:Proteasome inhibition reveals that a functional preintegration complex intermediate can be generated during restriction by diverse TRIM5 proteins. 1697 79

The TRIM5alpha (tripartite motif 5alpha protein) has been linked to the cross-species restriction in human immunodeficiency virus type 1 (HIV-1) infection of non-human cells, but the mechanism by which this occurs remains to be fully elucidated. Here we demonstrate that the capsid (CA) protein of HIV-1 is more rapidly degraded in cells expressing monkey TRIM5alpha than in cells expressing human TRIM5alpha. Other proteins encoded by Gag and Pol are not subject to TRIM5alpha-mediated accelerated degradation. The accelerated CA degradation by TRIM5alpha apparently occurs via a nonproteosomal pathway. TRIM5alpha selectively accelerates degradation of the CA population, which reached the cytosol of restrictive cells, but not the CA population, which ended into the vesicular compartment. Given that cytosolic CA represents "productively" entered cores, whereas vesicular CA represents "nonproductively" entered cores, our findings suggest that TRIM5alpha interrupts the infectious pathway of HIV-1 by acting on the incoming cytosolic CA. The mode of viral entry does not influence the accelerated degradation of cytosolic CA by TRIM5alpha. Thus, this study reveals a correlation between TRIM5alpha-mediated HIV-1 restriction and a selective degradation of cytosolic CA normally associated with productive viral entry.
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PMID:Trim5alpha accelerates degradation of cytosolic capsid associated with productive HIV-1 entry. 1702 89

An interplay or battle between virus and its host has been observed within a single cell. Upon an infection with retroviruses including human immunodeficiency virus type 1 (HIV-1), the viral genome is subjected to several processes that include uncoating, reverse transcription of the viral genomic RNA into a cDNA copy, transport of this cDNA into the nucleus, and integration of the cDNA into the host chromosome. Antiretroviral restriction factors such as TRIM5 alpha and APOBEC3G have been recently identified. In addition, nuclear membrane protect host chromosomal DNA against incoming viral genome. For successful retroviral infection, viral genome must overcome these cellular barriers to establish proviral state, in which viral cDNA was stably integrated into host chromosomal DNA. In this review, I would summarize the host factors that regulate the intercellular dynamics of HIV-1 genome during the early phase of infection, especially focusing on factors interacting with HIV-1 integrase and the preintegration complex.
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PMID:[Host factors that regulate the intercellular dynamics of HIV-1 genome during the early phase of infection]. 1703 11

The introduction of highly active antiretroviral therapy (HAART) combining potent drugs that can inhibit reverse transcriptase, integrase and protease activities has changed the natural history of the human immunodeficiency virus (HIV) type 1 disease. Unfortunately, poor penetrability into different anatomic compartments, toxicity and drug resistance are some of the problems related to their prolonged use. The ability of HIV to mutate and become resistant, along with the ongoing viral replication during HAART, can lead to the emergence of independently evolving viral strains in different anatomic compartments (i.e., brain, testes, lymph nodes, etc.). In addition, HAART predominantly effects the viral replication in the activated or differentiating CD(+) T lymphocytes, but appears to have a very limited effect on HIV-1 preintegration complexes in the latently infected cells. Existing drug therapies do not eliminate these viral reservoirs, nor do they prevent their formation. New strategies are needed for eliminating protected areas of HIV-1 in vivo. Therefore, the persistence of latent HIV-1 reservoirs is the principal barrier in the complete eradication of HIV-1 infection in patients by antiretroviral therapy at present. African non-human primates (NHPs) naturally infected with various simian immunodeficiency viruses (SIVs) appear not to develop immunodeficiency or AIDS, whereas Asian NHPs, which are unnatural hosts, infected with SIVs, as well humans infected with HIV-1, will nearly always develop progressive loss of CD(+) T lymphocytes and a gradual destruction of immune functions. Understanding the difference in the host responses between natural and unnatural hosts, and deciphering which host factors are responsible for the non-pathogenic course of natural SIV infections, would be valuable in developing more-effective treatment or prevention strategies for HIV/AIDS. A number of factors encoded by host cells have been identified that appear to play critical roles in the SIV infection process. Two of these factors, TRIM5alpha (a member of a large family of proteins known as the TRIM proteins) and cellular apolipoprotein B mRNA-editing enzyme-catalytic polypeptide-like-3G (APOBEC3G) have been recently identified. APOBEC3G genes belong to a family of primate genes that produce enzymes (in this case, APOBEC3G) that 'edit' RNA by replacing cytosine with guanine into viral particles as the virus undergoes reverse transcription in the cytoplasm of the host cell. HIV-1, in turn, counters with a protein called viral infectivity factor (Vif), which binds to the APOBEC3G enzyme that degrades it. Several other blocking factors have been described, including lentiviral blocking factor (Lv)1 and 2. These factors appear to block the infection at a postentry step; after reverse transcription has occurred, but before proviral integration. Thus, it is crucial to understand the molecular mechanisms involved in the establishment, maintenance and reactivation of lentiviral latency. This review presents various models of HIV-1 latency and forward a new unified model of lentiviral latency.
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PMID:A unified concept of HIV latency. 1704 12

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

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

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


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