AEGiS-14IAC: In vivo evidence for a contributory determinant for chronic viral replication and disease in the second exon of Tat.

14th International AIDS Conference

Barcelona, Spain - July 7-12, 2002

In vivo evidence for a contributory determinant for chronic viral replication and disease in the second exon of Tat.

Int Conf AIDS 2002 Jul 7-12; 14:(abstract no. WeOrA1256)

Smith SM, Pentlicky S, Neuveut C, Marx P, Jeang KT
New Jersey Medical School-UMDNJ, Newark, NJ 07102 USA, Newark, NJ, United States

BACKGROUND: HIV and SIV Tat are encoded by two exons. Aside from its obvious role in transcription, the contribution of Tat to HIV-disease has remained murky.

METHODS: From wildtype SIVmac239 (SIVtat2ex), we constructed SIVtat1ex which was mutated (by insertion of stop codons) to encode only a one-exon Tat. 6 rhesus macaques were intravenously infected with 100 TCID50 of SIVSIVtat2ex (2 animals; M154 & N361) or SIVtat1ex (4 animals; L840, L855, L882, & N200).

RESULTS: Viral loads in all animals peaked between Days 14 and 17 (~108 copies/ml). In the post-acute period (> 6 weeks), the two SIVtat2ex animals had high set point. Loads in two SIVtat1ex animals (L882 & N200) remained consistent near 106 copies/ml while loads in L840 & L855 became undetectable. CD4 counts in SIVtat2ex animals steadily declined; both died of simian AIDS by 7 months. Two SIVtat1ex animals controlled viremia post-acutely and their CD4 counts rose after the first four weeks. The other two SIVtat1ex-animals (L882 & N200) did not control viremia and had persistently low CD4 counts. One (L882) died of AIDS after 9 months. The other (N200) remained well for >2 years and then became ill and died at 2.7 years. The stop codons in L882 was found to have been removed reverting this SIVtat1ex virus to SIVtat2ex. Unexpectedly, at 14 months post-infection, the viral load in L855, which had initially controlled virema, increased from undetectable to >106 copies/ml. Sequence analyses revealed that the stop codons in the Tat gene of L855's virus had also opened-- again, converting SIVtat1ex to SIVtat2ex . By comparison, SIVtat1ex in L840, >2.7 years later, remained unchanged. L840 had persistently low viremia and normal CD4 count.

CONCLUSIONS: Reversion of SIVtat1ex virus to SIVtat2ex virus is accompanied by disease. We will discuss these results in the context of data regarding the "reversion" of the pseudo-1exon HIV-1 Tat gene in 3 lab workers infected with HIV-1 HXB2.

Keywords: AEGIS, SIV, Simian Acquired Immunodeficiency Syndrome, Virus Replication, CD4 Lymphocyte Count, Exons, HIV-1, Viral Load, Genes, tat, Viremia, HIV Infections, Macaca mulatta, HIV Antibodies, HIV, HIV Seropositivity, HIV Long Terminal Repeat, Animal, virology, genetics, immunology

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