HIV replication

IhRNAs have also been used to induce an anti-HIV-1 RNAi response (Barichievy et al. 2007 Konstantinova et al. 2006, 2007 Liu et al. 2007). These IhRNAs can be processed into multiple effective siRNAs, thus preventing the chance of viral escape. Although IhRNA have been shown to effectively inhibit HIV-1 replication, there is currently no data on their ability to prevent viral escape. The use of multiple siRNAs or IhRNAs should take into account the increased danger of side effects due to interference with cellular miRNA processing and function. 

Suppression of chemokine receptor expression by RNA interference allows for inhibition of HIV-1 replication, AIDS 16 2385-2390... 

Bai J, Rossi J, Akkina R (2001) Multivalent anti-CCR ribozymes for stem cell-based HIV type 1 gene therapy. AIDS Res Hum Retroviruses 17 385-399 Bai J, Sui J, Zhu RY, TaUarico AS, Gennari F, Zhang D, Marasco WA (2003) Inhibition of Tat-mediated transactivation and HIV-1 replication by human anti-hCychnTl intrabodies. J Biol Chem 278 1433-1442... 

Kleim JP, ROsner M, Winkler I, Paessens A, Kirsch R, Hsiou Y, Arnolds E, Riess G (1996) Selective pressure of a quinoxaline nonnucleoside inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) on HIV-1 replication results in the emergence of nucleoside RT-inhibitor-specific (RT Leu-74 -> Val or He and Val-75 - > Leu or He) HIV-1 mutants, Proc Natl Acad Sci USA 93 34-38... 

Kaushik N., Pandey V. N. PNA targeting the PBS and A-loop sequences of HIV-1 genome destabilizes packaged tRNA3(Lys) in the virions and inhibits HIV-1 replication. Virology 2002 ... 

Kaushik N., Basu A., Pandey V. N. Inhibition of HIV-1 replication by anti-trans-activation responsive polyamide nucleotide analog. Antiviral Res. 2002 56 13-27. 

Kieffer TL, Finucane MM, Nettles RE, Quinn TC, Broman KW, Ray SC, Persaud D, SUiciano RF (2004) Genotypic analysis of HIV-1 drug resistance at the limit of detection virus production without evolution in treated adults with undetectable HIV loads. J Infect Dis 189(8) 1452-1465 Kinoshita S, Su L, Amano M, Timmerman LA, Kaneshima H, Nolan GP (1997) The T cell activation factor NF-ATc positively regulates HIV-1 replication and gene expression in T cells. Immunity 6(3) 235-244... 

Vicenzi E, Alfano M, Ghezzi S, et al. Divergent regulation of HIV-1 replication in PBMC of infected individuals by CC chemokines suppression by RANTES, MIP-lalpha, and MCP-3, and enhancement by MCP-1. J Leukoc Biol 2000 68(3) 405-412. 

Yet other compounds have been found to inhibit HIV-1 replication through a specific interaction with HIV-1 RT (i.e., quinoxaline S-2720 [68], 5-chloro-3-(phenylsulfonyl)indole-2-carboxamide [69], dihydrothiazolo-isoindolones [70] and a number of natural substances (e.g., calanolide A and inophyllums, from the tropical rain forest trees Calophyllum lanigerum and Calophyllum inophyllum, respectively) [71,72]. All these and yet other compounds could be considered to be NNRTIs. The most potent among the NNRTIs, some of the HEPT derivatives (E-EBU-dM) [63] and a-... 

APA derivatives (R89439) [67], inhibit HIV-1 replication at a concentration of approximately 1 ng/mL, that is, 100,000-fold below the cytotoxicity threshold. 

H, Janssen MAC, De Clercq E, Janssen PAJ. Potent and selective inhibition of HIV-1 replication in vitro by a novel series of TIBO derivatives. Nature... 

NO acts as an autocrine factor that mediates HIV-1 replication as at the molecular level, NO seems to stimulate long-terminal repeat-mediated transcription [125]. It was noted that exogenous NO increases replication of HIV-1 T-tropic isolates in primary T cells or T-cell lines, and inhibitors of iNOS partly block HIV-1 replication, especially that induced by tumor necrosis factor a [125]. The contrasting effects of exogenous NO, particularly NO donors, may depend on the type of NO donors, their releasing kinetics, and the dose used in the study design. 

The antiretrovirus properties of NO were shown in mice infected with Friend leukemia virus, a murine retrovirus. NO produced by NO-generating compounds or activated macrophages inhibits viral replication in fibroblast cultures, and is involved in defens against this murine retrovirus in vivo [134]. It was also reported that NO donors can inhibit HIV-1 replication in human monocytes through induction ofiNOS [135],... 

In several studies on the antiviral effects of NO on HIV-1 infection, the proviral or antiviral effects of NO seem to be strictly related to the active production of NO during HIV-1 infection. The universal speculative interpretation of the dichotomous effect of NO is that overproduction of this substance, especially in the primary infection and in late stages of the disease, leads to active viral replication with consequent harmful effects on the course of the disease. Conversely, low production of NO may cause a reduction in or inhibition of HIV-1 replication, especially during the symptomless stage of the disease, or during treatment with highly active combined antiretroviral drugs. 

Recently, it has been found that NO donors inhibit HIV-1 replication in acutely infected human peripheral blood mononuclear cells (PBMCs), and have an additive inhibitory effect on HIV-1 replication in combination with 3 -azido-3 -deoxythymisylate (AZT) [139, 140]. S-nitrosothiols (RSNOs) inhibit HIV-1 replication at a step in the viral replicative cycle after reverse transcription, but before or during viral protein expression through a cGMP-independent mechanism. In the latently infected U1 cell line, NO donors and intracellular NO production stimulate HIV-1 reactivation. These studies suggest that NO both inhibits HIV-1 replication in acutely infected cells and stimulates HIV-1 reactivation in chronically infected cells. Thus, NO donors may be useful in the treatment of HIV-1 disease by inhibiting acute infection, or reactivating a latent virus. 

GSK163929 is a potent CCR5 antagonist that inhibits HIV-1 replication at low nanomolar level. GSK163929 has successfully completed preclinical studies [47]. 

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