S4-1.1 Jan. 5 Within-host evolution of non-pathogenic SHIV: positive selection of virus protein motifs coincides with CD4 loss. SMITH, M.S.*; NIU, Y.; YANG, R.K.; TEFERA, P.; KELLY, J.K.; Univ. of Kansas Medical Center, Kansas City; Univ. of Kansas Medical Center, Kansas City; Univ. of Kansas Medical Center, Kansas City; Univ. of Kansas, Lawrence; Univ. of Kansas, Lawrence email@example.com
We have used chimeric simian/human immunodeficiency virus infection of macaques for examining virus evolution within the host. Due to the rapid replication cycles and the total number of infected particles produced per day, and with a small genome size and an error-prone polymerase, this virus evolves very rapidly under selective pressures. Macaques were infected with a molecular clone of non-pathogenic SHIV virus to study within-host virus evolution. At 2.5 yr, we released in one animal the virus from immune control with anti-CD8 antibody. During virus rebound, blood from this animal was injected into two new macaques. Periodic plasma, biopsies, and blood cells were examined. We examined the sequence in these samples of the viral gene nef, important for disease progression. Clones of nef from early weeks from blood cells and plasma virus RNA were consistent with the rebound virus from the donor. Sequences from cerebrospinal fluid versus plasma showed evidence of distinct variants in the 2 compartments. Quantitative measures revealed higher viral expression in biopsies in one recipient, consistent with the higher plasma virus levels and greatly reduced CD4 cell counts, as in human HIV-1 infection. Both recipients lost CD4 cells to below 10, indicating onset of AIDS. We analyzed the nef sequences for positive selection using a maximum likelihood method, and compared the results with previous rapid-passage experiments using the same parental virus. We have examined the evolution of a clonal SHIV in the nef gene over time and in different compartments of the body, and found a correlation with an increase in pathogenicity.