AEGiS-11IAC: Increasing virulence and decreasing genetic variation during SIVsm adaptation to rhesus macaques.

11th International AIDS Conference

Vancouver, British Columbia — July 7-12, 1996

Increasing virulence and decreasing genetic variation during SIVsm adaptation to rhesus macaques.

Int Conf AIDS 1996 Jul 7-12; 11:17 (abstract no. Th.A.920)
Valli PJ, Lukashov W, Heeney JL, Goudsmit J; Department of Human Retrovirology, Academic Medical Center, University of Amsterdam, The Netherlands. Fax: (31-20)-691-6531.

OBJECTIVE: To study the interrelations between SIVsm virulence and envelope evolution during adaptation to a new species. Method: An Asian macaque was experimentally infected with 5x10(2) infectious doses of SIVsmB670 and upon cuthanization due to AIDS 2x10(6) PBMCs from this macaque were used to infect a second macaque. This serial population passage of final blood sample was repeated 5 times (passage 1 death (PID) to passage 6 (P6)). A sensitive RT-PCR was used to amplify and clone the envelope V1 to V4 region from infected serum and 5 clones from both seroconversion (P#S) and death (P#D) timepoints were sequenced from each animal. Changes in T cell subsets were monitored by FACSCAN and plasma antigen concentrations were determined by SIV p27 antigen capture assay.

RESULTS: Serial population passage of SIVsmB670 drastically shortened the time of disease progression from 18 months (PI) to 1 month (P6). The rate of CD4 cell loss increased with the heightened virulence of the passaged virus. No marked changes were seen in the clinical or pathological manifestations of the disease except for p27 concentrations rising from less than 10 ng/ml (PI) to 100 ng/ml (P4 to P6). This increased virulence was followed by the decrease of both intrahost and interhost (interpassage) genetic variation in the envelope gene. The mean nucleotide distance between SIV sequences present in PI was 0.0361, significantly higher than sequence variation in P6 at 0.0156. Similarly observed was the mean interpassage nucleotide distances between PI and seroconversion in P2 at 0.0444 and P4D (table: see text) to P6 which was only 0.0204. The interpassage distance between the input virus (PI) and the output virus (P6) was 0.0417. With serial passages the synonymous/nonsynonymous substitution rate (Ks/Ka) increased along with the virulence as the total rate of nucleotide substitution decreased. There was a significant association between increasing virulence, increasing Ks/Ka and decreasing evolution or interpassage variation. Variation within the 50 clones sequenced was confined mainly to the variable regions with the V3 being the least variable. The fixed mutations in the early passages occurred mainly in the V1 and V4 regions with the V2 and V3 mutations occurring after the P3S (passage #3 seroconversion) period. Variation in the V3 region was restrained to the amino acids just downstream of the V3 loop as commonly seen in HIV infections.

CONCLUSION: Adaptation of SIVsm after serial population passages causes greatly increased virulence. The decreasing rate of variable region variation and stable constant regions implies a direct role for envelope evolution in virulence.

Keywords: AEGIS, Macaca mulatta, SIV, Variation (Genetics), Macaca, Virulence, Evolution, Acclimatization, Mutation, HIV Infections, Animal, pathogenicity, genetics, ICA11

960707
ThA920