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139 First Evidence Showing Absence of in Vivo Evolution in HIV-1 over Time: Implications for HIV Vaccine Development
B. Wang*, M. Mikhail, and N. K. Saksena
CVR, Westmead Millennium Inst., Westmead Hosp., Univ. of Sydney, Sydney, NSW, Australia
Background: So far, several studies have clearly demonstrated that a large majority of HIV-infected long-term nonprogressors slowly progress toward AIDS. A small subpopulation of HIV-infected patients (<0.8%) have shown no signs of progression for >15 years. These individuals are therapy naïve and are characterized by stable CD4+ and CD8+ T-cell counts. Nonprogressive infection with HIV in some individuals has been found to be associated with viral and host gene defects or due to changes in host immune system that also partially control HIV disease progression. Here we show an evidence demonstrating a complete absence of HIV-1 evolution in vivo over time in an extremely rare therapy naïve patient who has been infected for >14 years. He has remained below detection for plasma viremia (<50 copies/ml), low proviral DNA load (<10 copies/million cells), and absence of any culturable virus for the past 8 years since we have followed him. His present CD4+ T-cell counts remains at 790/muL blood and his CD8+T-cell count at 3,200/muL blood.
Methods: Viral gene amplification from PBMC samples collected between 1993 and 2001 was carried out in the Gag, Pol, Env, nef, and vpr genes. Furthermore, full-length viral genomes (>9,000 bp) were also derived from uncultured PBMC samples obtained from 1999, 2000, and 2001, respectively, using a highly sensitive primer couple. To establish evolutionary relationships, phylogenetic analysis was carried out using neighbor joining algorithm.
Results: Three full-length HIV-1 genomes derived from PBMC between 1999 and 2001 showed near identical sequences in vivo, which was also in concordance with small genomic segments derived in gag, pol, nef, env, and vpr genes between 1993 and 2001. A critical analysis of full-length genomes (>9 kb) clearly showed the presence of stop codons in the Gag p17, Gag p24, and Pol RT. These stop codons were a direct consequence of G-A hypermutation causing disruption of reading frames through the displacement of tryptophan residues (W). This is one of the plausible explanations for its nonreplicative nature in vivo.
Conclusions: This is the first evidence showing the complete absence of viral evolution and viral replication in an HIV-infected patient who has remained therapy naïve. This evidence in favor of this nonreplicative/nonevolving HIV-1 in this individual is of immense significance and may possibly form the basis for future DNA-based anti-HIV vaccines.
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