Inhibition of infectious agents by exogenous oligonucleotides

#The Retroviridae virus family includes viruses which contain an RNA genome and an RNA-dependent DNA polymerase activity (reverse transcriptase). During their growth cycle, retroviridae, or retroviruses as they are more commonly called, copy their RNA into proviral DNA. Proviral DNA becomes inserted (integrated) into the chromosomal DNA of the host where it uses the transcriptional and translational machinery of the host to express viral RNA and proteins. Viruses are released from the cell by budding from the cytoplasmic membrane. Most infections do not necessarily kill cells. Rather, infected cells may continue to grow and differentiate while continuously producing virus.

#Three major classes of human retroviruses have been identified: 1) T-cell lymphotropic viruses; 2) endogenous genetic elements related to primate C-type viruses; and 3) foamy viruses.

#Human T-cell leukemia-lymphotropic virus (HTLV) refers to a family of a T cell tropic retroviruses. Such viruses, which have a role in causing certain T cell neoplasms, are generally divided into three main types or subgroups: 1) HTLV-type I (HTLV-I), which appears to cause adult T-cell leukemia-lymphoma (ATLL); 2) HTLV-type II (HTLV-II), which has been isolated from an individual having a T-cell variant of hairy cell leukemia; and 3) HTLV-type III (HTLV-III), which has been identified as the etiologic agent of acquired immune deficiency syndrome (AIDS). HTLV-III is also known as lymphadenopathy-associated virus (LAV), AIDS related virus (ARV) and human immunodeficiency virus (HIV-1). Popovic, M. et al., Science, 224:497-500 (1984); Gallo, R. C. et al., Science, 224:500-503 (1984); Wong-Staal, F. and Gallo, R. C., Nature, 317:395-403 (1985); and Curran, J. W. et al., Science, 229:1352-1357 (1985). More recently, HIV-2 has been discovered by Montagnier in patients who have AIDS but show no signs of HIV-1 infection. Science, 236:390-392 (1987).

#The FIGURE is a schematic representation of the primary nucleotide sequence of the HTLV-III genome and of the location on the genome of oligonucleotide competitive inhibition targets.

#Inhibition of HTLV-III

#The primary nucleotide sequence of the HTLV-III/LAV genome has been determined by several groups of investigators. Ratner, L. et al., Nature 313:277-284 (1985); Wain-Hobson, S. et al., Cell 40:9-17 (1985); Sanchez-Pescador, R. et al., Science 227:484-492 (1985); Muesing, M. A. et al., Nature 313:450-458 (1985).

#The genome of HTLV-III is shown in the FIGURE. The HTLV-III genome has been shown to be considerably more variable than the genomes of most retroviruses. RNA Tumor Viruses (2d edition) Volume 2, p 446, Cold Spring Harbor Laboratory (1985). Like other retroviruses, HTLV-III has in its genome three genes which encode viral proteins: 1) the gag gene, which encodes nucleocapsid or internal structural proteins of the virus; 2) the pol gene, which encodes reverse transcriptase (an RNA-directed DNA polymerase responsible for transcribing RNA into DNA); and 3) the env gene, which encodes the envelope glycoproteins of the virion. In addition, two other open reading frames are known; one (sor) overlaps with the 3′ end of the pol gene and the other (3′ ORF), located at the extreme 3′ end of the genome, slightly overlaps the env gene and continues through most of the U3 region. The genome has also been shown to contain tat-III and art. Tat-III is the trans-activation gene of HTLV-III; it encodes trans-activator protein, which greatly accelerates viral protein synthesis in infected cells. Art (antirepression of the translation-transactivator gene) has only recently been found in the HTLV-III genome and appears to work cooperatively with tat in producing viral core and envelope proteins.