7th International AIDS Conference Florence, Italy — June 16-21, 1991

Int Conf AIDS 1991 Jun 16-21; 7:21 (abstract no. M.A.8)
Goudsmit J, Wolfs T, Kuiken C, Zwart G, Tersmette T; Human Retrovirus Laboratory, University of Amsterdam, Amsterdam, the Netherlands

OBJECTIVE: To determine the relationship between the diversity of the viral population, the emergence of HIV-1 variants escaping V3 specific antibody, the switch in virus phenotype from non-syncytium inducing (NSI) to syncytium inducing (SI), and progression to AIDS.

METHODS: Sequential serum samples were used as source of viral RNA. Sequential peripheral blood lymphocytes (PBLs) were used as source of viral DNA and for virus isolation. After establishing the biological phenotype of the virus in primary lymphocyte cultures, these virus positive cells were used as source of viral DNA as well. Deduced amino acid sequences were used for the production of peptides as antigen for probing reactivity with natural antibody.

RESULTS: Before V3-specific antibodies appear and during the initial antigen and virus replication peak, the V3 coding region shows no or little diversity in RNA and DNA. Subsequent to the rise of antibody to the initially amplified V3 domain, a progressive accumulation of (primarily non-silent) mutants is demonstrated. Co-evolution of mutants is observed and the largest sequence change in viral RNA occurs during disease progression, NSI to SI switch and antigenemia. Peptides derived from the V3 RNA in serum bind to antibodies in the serum and amino acid changes H308 - greater than P308 as well as P308 - greater than H308 define mutants escaping V3 antibody binding. Our data indicate that the diversity of the virus population decreases prior to the emergence of SI virus. The V3 master sequence that emerges in the first SI isolates is already found in an earlier lymphocyte DNA sample. 6 months after the NSI-SI switch, this V3 variant has become the predominant one in PBLs as well. The evolution rate of the V3 domain of isolated NSI virus is close to the one of SI virus (10(-2) nucleotides/site/year) and only during the short period of the switch an increase in V3 evolution rate is observed. G - greater than A transition is the most frequent point mutation observed but does not explain in any case the antigenic switch at position 308.

CONCLUSIONS: Upon HIV-1 transmission the diversity of the V3 coding sequences is limited most likely because of the expansion of the virus population most efficiently propagated by a given host. Our results suggest that V3-specific antibodies select antigenic variants during the period that NSI virus is isolated. Prior to the phenotype shift from NSI to SI virus, a decrease in diversity of the virus population is observed. Emergence of SI variants coincides with a sudden genotypical shift.

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