3rd International Workshop on HIV Drug Resistance 2-5 August 1994, Kauai, Hawaii, USA

DISCORDANCE OF RT SEQUENCES CONFERRING ZDV RESISTANCE IN PROVIRAL DNA FROM BRAIN AND SPLEEN

Int Wkshop HIV Drug Res 1994 Aug 2-5;3:46 (abstract no. 45)

J.K. Wong, N.J.S. Fitch, F. Torriani, D. Havlir and D.O. Richman
University of California, San Diego and the VAMC, San Diego, California, USA

HIV infection of the central nervous system occurs early in the course of disease and is associated with characteristic clinical and pathological features in AIDS patients. Therapy with zidovudine(ZDV) has been of value in patients with HIV encephalopathy. Viral isolates from patients administered ZDV demonstrate in vitro resistance of varying degree associated with the sequential acquisition of mutations in nucleic acid sequences encoding the reverse transcriptase (RT). The isolates from these patients can revert to wild type phenotypically and genotypically, months to years after discontinuing ZDV therapy. Previous studies have demonstrated that viral envelope sequences (including but not restricted to the V3 region) derived from CNS sources can differ significantly from viral sequences obtained from other tissues. To date, there have been no published reports of differences in RT sequences derived from brain when compared with peripheral tissues.

We analyzed RT sequences from an individual who died of AIDS related complications including HIV encephalopathy. This individual had received 2 years of prior ZDV therapy which was discontinued 2 years before his death. DNA extraction was carried out on brain and spleen tissue obtained at autopsy. A nested PCR procedure was performed and the resultant fragments were cloned into phage M13. Clones were processed and manually sequenced.

All clones derived from brain samples and none of the spleen derived clones exhibited the M41L,T215Y genotype. The D67N , K70R and K219Q mutations were not seen. Variation of codon usage in the RT, not thought to affect drug suceptibility, indicated the evolution of distinct populations in these two organs.

We conclude that the viral populations in brain and spleen can differ in their RT sequences with regards to mutations conferring ZDV resistance. This observation confirms previous data based on env sequence analysis that distinct genotypic and phenotypic populations of virus are maintained in different organs and further, suggests differences in the evolution of ZDV resistance mutations within different tissue compartments. Specimens from additional patients are now under investigation.

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1994-08-02
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