1st National Conference Human Retroviruses and Related Infections Washington, DC - December 12-16, 1993

Natl Conf Hum Retrovir Relat Infect 1993 Dec 12-16;1: (abstract no. 4)

Kozal M, Winters M, Shafer R, Kroodsma K, Katzenstein D, Merigan T
Stanford University, Stanford, CA

OBJECTIVE: To determine the incidence and inter- relationship of the HIV pol gene mutation at codons 74 & 215 in 62 AZT treated patients changed to ddI, enrolled in ACTG protocols 116/117/118 at Stanford. Methods: Serial serum samples underwent HIV RNA extraction and reverse transcription to c-DNA using primer NE-1(35). Nested PCR was used to determine the sequence at codons 74 and 215 (wild type(WT) vs. mutant(MUT)). An external-controlled RT-PCR assay was used to measure serum virus burden.

RESULTS: 48/62 (77%) patients were MUT at codon 215 before starting ddI. After 6 months of ddI monotherapy: 1) 25% of patients with a 215 MUT reverted to WT; 75% continued to have the 215 MUT. 2) At codon 74, 60% of patients developed a mutation and 40% remained WT. Patients with the codon 74 MUT had a greater serum virus burden than patients WT at codon 74 (182,000 vs. 48,600 HIV RNA copies per ml serum, p<0.01). After 6 months of ddI therapy the most frequent serum virus genotype found was 74 MUT/215 MUT. Data on ddI susceptibilities, SI/NSI, serial serum virus burden and CD4 cell changes related to these genotypes will also be presented.

CONCLUSION: In patients changed from AZT to ddI, the codon 74 MUT occurred frequently and usually with a persisting codon 215 MUT. Patients with a codon 74 MUT had a greater serum virus burden than patients WT at codon 74. The high frequency of both 215 and 74 MUT suggests a replicative advantage for this genotype during ddI monotherapy. In contrast, combination therapy with AZT/ddI (ACTG 143) prevents mutation at codon 74 but not at 215. This may be explained by a replicative advantage during AZT/ddI therapy for virus having only the codon 215 MUT as compared to having both codon 74 & 215 MUT.

Keywords: Acquired Immunodeficiency Syndrome, Anti-HIV Agents, Base Sequence, CD4-Positive T-Lymphocytes, Codon, Didanosine, Genes, pol, Genotype, HIV, HIV Infections, HIV Seropositivity, HIV-1 Reverse Transcriptase, Humans, Mutation, Zidovudine, genetics

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1993-12-12
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