Smith SM, Klase Z, Pentlicky S, Neuveut C, Marx P, Jeang KT; Conference on Retroviruses and Opportunistic Infections.
Abstr 10th Conf Retrovir Oppor Infect Feb 10 14 2003 Hynes Conv Cent Boston Mass USA Conf Retrovir Oppor Infect 10th 2003 Boston Mass. 2003 Feb 10-14; 10: abstract no. 48a.
St Michael's Med Ctr, Newark, NJ
BACKGROUND: The Tat proteins of HIV/SIV are encoded by 2 exons. The role of the 2nd exon of HIV or SIV Tat has not been evaluated in vivo.METHODS: We constructed a clone (SIVtat1ex) of SIVmac239, which encodes for only the 1st exon of Tat, and studied it in vivo. Codons 96 and 97 were changed from GCA TCA to TGA TAA. Macaques were infected with SIVmac239 (SIVtat2ex) (2 animals; M154 and N361) or SIVtat1ex (4 animals; L840, L855, L882, and N200).RESULTS: Viral load peaks were equivalent (~108 copies/ml) in the 2 groups. In the post-acute period, the SIVtat2ex animals had high set point plasma viral loads. The viral loads in 2 SIVtat1ex animals (L882 and N200) remained near 10(6) copies/ml. The viral load values in the 2 other SIVtat1ex animals (L840 and L855) became undetectable. The CD4 counts of the SIVtat2ex animals steadily declined after infection; each died of AIDS by 7 months (mos) PI. In the 2 SIVtat1ex infected animals, with undetectable viremia, the CD4 counts rose after the first 4 wks. Both SIVtat1ex infected animals with high viremia had persistently low CD4 counts. L882 died of AIDS after 9 mos PI. The stop codons at the end of the 1st exon of tat in L882's virus opened at 2-3 months PI. The other (N200) remained well for > 2 yrs, but died of simian AIDS at 2.7 yrs PI; N200's virus had intact stop codons throughout. At 14 mos PI, L855's viral load increased from undetectable to > 10(6) copies/ml and its CD4 count fell substantially; L855's virus contemporaneously opened. L840's virus at 9 mos PI had opened. However, by 14 mos PI, L840's virus reverted back to SIVtat1ex. L840 had persistently low level of viremia and a normal CD4 T-cell count. Only L840 developed a strong response to Tat exon 2 peptides. We also analyzed viral sequences from 3 laboratory workers (LW) infected with HXB2R, which has a premature stop codon in the second exon of Tat. Virus in one of the 3 LWs reverted and this reversion was associated with more rapid disease. In another LW, the majority virus was temporarily open, but was again replaced by virus with the original stop codon.CONCLUSIONS: The 2nd exon of SIVmac Tat contributes to chronic virus replication and pathogenesis. Data from HXB2R infected LWs corroborates our animal study findings. Together, these data suggest that a vaccine, which induces a strong cellular response to Tat exon 2 epitopes, could select for less pathogenic HIV, which only encodes the first Tat exon.
Publication Types:
Keywords:
- AIDS Vaccines
- Animals
- CD4 Lymphocyte Count
- Exons
- Gene Products, tat
- Genes, tat
- HIV
- HIV Antibodies
- HIV Infections
- HIV Long Terminal Repeat
- HIV Seropositivity
- Humans
- Simian Acquired Immunodeficiency Syndrome
- Simian immunodeficiency virus
- Viral Load
- Viremia
- Virus Replication
- genetics
- virology
Other ID:
UI: 102261096
From Meeting Abstracts